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Sample records for acquired multidrug resistance

  1. Acquired Drug Resistance in Mycobacterium tuberculosis and Poor Outcomes among Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Kipiani, Maia; Mirtskhulava, Veriko; Tukvadze, Nestani; Magee, Matthew J.; Blumberg, Henry M.

    2015-01-01

    Rates and risk factors for acquired drug resistance and association with outcomes among patients with multidrug-resistant tuberculosis (MDR TB) are not well defined. In an MDR TB cohort from the country of Georgia, drug susceptibility testing for second-line drugs (SLDs) was performed at baseline and every third month. Acquired resistance was defined as any SLD whose status changed from susceptible at baseline to resistant at follow-up. Among 141 patients, acquired resistance in Mycobacterium tuberculosis was observed in 19 (14%); prevalence was 9.1% for ofloxacin and 9.8% for capreomycin or kanamycin. Baseline cavitary disease and resistance to >6 drugs were associated with acquired resistance. Patients with M. tuberculosis that had acquired resistance were at significantly increased risk for poor treatment outcome compared with patients without these isolates (89% vs. 36%; p<0.01). Acquired resistance occurs commonly among patients with MDR TB and impedes successful treatment outcomes. PMID:25993036

  2. Extensive Drug Resistance Acquired During Treatment of Multidrug-Resistant Tuberculosis

    PubMed Central

    Cegielski, J. Peter; Dalton, Tracy; Yagui, Martin; Wattanaamornkiet, Wanpen; Volchenkov, Grigory V.; Via, Laura E.; Van Der Walt, Martie; Tupasi, Thelma; Smith, Sarah E.; Odendaal, Ronel; Leimane, Vaira; Kvasnovsky, Charlotte; Kuznetsova, Tatiana; Kurbatova, Ekaterina; Kummik, Tiina; Kuksa, Liga; Kliiman, Kai; Kiryanova, Elena V.; Kim, HeeJin; Kim, Chang-ki; Kazennyy, Boris Y.; Jou, Ruwen; Huang, Wei-Lun; Ershova, Julia; Erokhin, Vladislav V.; Diem, Lois; Contreras, Carmen; Cho, Sang Nae; Chernousova, Larisa N.; Chen, Michael P.; Caoili, Janice Campos; Bayona, Jaime; Akksilp, Somsak; Calahuanca, Gloria Yale; Wolfgang, Melanie; Viiklepp, Piret; Vasilieva, Irina A.; Taylor, Allison; Tan, Kathrine; Suarez, Carmen; Sture, Ingrida; Somova, Tatiana; Smirnova, Tatyana G.; Sigman, Erika; Skenders, Girts; Sitti, Wanlaya; Shamputa, Isdore C.; Riekstina, Vija; Pua, Kristine Rose; Therese, M.; Perez, C.; Park, Seungkyu; Norvaisha, Inga; Nemtsova, Evgenia S.; Min, Seonyeong; Metchock, Beverly; Levina, Klavdia; Lei, Yung-Chao; Lee, Jongseok; Larionova, Elena E.; Lancaster, Joey; Jeon, Doosoo; Jave, Oswaldo; Khorosheva, Tatiana; Hwang, Soo Hee; Huang, Angela Song-En; Gler, M. Tarcela; Dravniece, Gunta; Eum, Seokyong; Demikhova, Olga V.; Degtyareva, Irina; Danilovits, Manfred; Cirula, Anda; Cho, Eunjin; Cai, Ying; Brand, Jeanette; Bonilla, Cesar; Barry, Clifton E.; Asencios, Luis; Andreevskaya, Sofia N.; Akksilp, Rattanawadee

    2014-01-01

    Background. Increasing access to drugs for the treatment of multidrug-resistant (MDR) tuberculosis is crucial but could lead to increasing resistance to these same drugs. In 2000, the international Green Light Committee (GLC) initiative began to increase access while attempting to prevent acquired resistance. Methods. To assess the GLC's impact, we followed adults with pulmonary MDR tuberculosis from the start to the end of treatment with monthly sputum cultures, drug susceptibility testing, and genotyping. We compared the frequency and predictors of acquired resistance to second-line drugs (SLDs) in 9 countries that volunteered to participate, 5 countries that met GLC criteria, and 4 countries that did not apply to the GLC. Results. In total, 832 subjects were enrolled. Of those without baseline resistance to specific SLDs, 68 (8.9%) acquired extensively drug-resistant (XDR) tuberculosis, 79 (11.2%) acquired fluoroquinolone (FQ) resistance, and 56 (7.8%) acquired resistance to second-line injectable drugs (SLIs). The relative risk (95% confidence interval [CI]) of acquired resistance was lower at GLC-approved sites: 0.27 (.16–.47) for XDR tuberculosis, 0.28 (.17–.45) for FQ, and 0.15 (.06–.39) to 0.60 (.34–1.05) for 3 different SLIs. The risk increased as the number of potentially effective drugs decreased. Controlling for baseline drug resistance and differences between sites, the odds ratios (95% CIs) were 0.21 (.07–.62) for acquired XDR tuberculosis and 0.23 (.09–.59) for acquired FQ resistance. Conclusions. Treatment of MDR tuberculosis involves substantial risk of acquired resistance to SLDs, increasing as baseline drug resistance increases. The risk was significantly lower in programs documented by the GLC to meet specific standards. PMID:25057101

  3. Acquired Multidrug Antifungal Resistance in Candida lusitaniae during Therapy

    PubMed Central

    Asner, Sandra A.; Giulieri, Stefano; Diezi, Manuel; Marchetti, Oscar

    2015-01-01

    -flurocytosine. This clinical report describes resistance of C. lusitaniae to all common antifungals. While candins or azole resistance followed monotherapy, multidrug antifungal resistance emerged during combined therapy. PMID:26438490

  4. A family cluster of tuberculosis cases, including a case of acquired multidrug resistant tuberculosis.

    PubMed

    Holden, Julie; Trachtman, Louis

    2012-01-01

    Although the number of tuberculosis cases in the US is at an all-time low, with progressive declines seen for the past 17 years, many goals in the tuberculosis elimination process remain unrealized. This report describes a cluster of four tuberculosis cases in a family, including one case of acquired multidrug resistant tuberculosis. It also underscores some important issues in tuberculosis control today, including significant disparities in the foreign-born population with multidrug resistant tuberculosis as a looming problem, as well as utilization of therapeutic drug level monitoring in complicated cases. PMID:22533114

  5. Multidrug efflux pumps as main players in intrinsic and acquired resistance to antimicrobials.

    PubMed

    Hernando-Amado, Sara; Blanco, Paula; Alcalde-Rico, Manuel; Corona, Fernando; Reales-Calderón, Jose A; Sánchez, María B; Martínez, José L

    2016-09-01

    Multidrug efflux pumps constitute a group of transporters that are ubiquitously found in any organism. In addition to other functions with relevance for the cell physiology, efflux pumps contribute to the resistance to compounds used for treating different diseases, including resistance to anticancer drugs, antibiotics or antifungal compounds. In the case of antimicrobials, efflux pumps are major players in both intrinsic and acquired resistance to drugs currently in use for the treatment of infectious diseases. One important aspect not fully explored of efflux pumps consists on the identification of effectors able to induce their expression. Indeed, whereas the analysis of clinical isolates have shown that mutants overexpressing these resistance elements are frequently found, less is known on the conditions that may trigger expression of efflux pumps, hence leading to transient induction of resistance in vivo, a situation that is barely detectable using classical susceptibility tests. In the current article we review the structure and mechanisms of regulation of the expression of bacterial and fungal efflux pumps, with a particular focus in those for which a role in clinically relevant resistance has been reported. PMID:27620952

  6. Mutational and acquired carbapenem resistance mechanisms in multidrug resistant Pseudomonas aeruginosa clinical isolates from Recife, Brazil

    PubMed Central

    Cavalcanti, Felipe Lira de Sá; Mirones, Cristina Rodríguez; Paucar, Elena Román; Montes, Laura Álvarez; Leal-Balbino, Tereza Cristina; de Morais, Marcia Maria Camargo; Martínez-Martínez, Luis; Ocampo-Sosa, Alain Antonio

    2015-01-01

    An investigation was carried out into the genetic mechanisms responsible for multidrug resistance in nine carbapenem-resistant Pseudomonas aeruginosaisolates from different hospitals in Recife, Brazil. Susceptibility to antimicrobial agents was determined by broth microdilution. Polymerase chain reaction (PCR) was employed to detect the presence of genes encoding β-lactamases, aminoglycoside-modifying enzymes (AMEs), 16S rRNA methylases, integron-related genes and OprD. Expression of genes coding for efflux pumps and AmpC cephalosporinase were assessed by quantitative PCR. The outer membrane proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The blaSPM-1, blaKPC-2 and blaGES-1 genes were detected in P. aeruginosaisolates in addition to different AME genes. The loss of OprD in nine isolates was mainly due to frameshift mutations, premature stop codons and point mutations. An association of loss of OprD with the overexpression of MexAB-OprM and MexXY-OprM was observed in most isolates. Hyper-production of AmpC was also observed in three isolates. Clonal relationship of the isolates was determined by repetitive element palindromic-PCR and multilocus sequence typing. Our results show that the loss of OprD along with overexpression of efflux pumps and β-lactamase production were responsible for the multidrug resistance in the isolates analysed. PMID:26676375

  7. Protein arginine methyltransferase 1 may be involved in pregnane x receptor-activated overexpression of multidrug resistance 1 gene during acquired multidrug resistant

    PubMed Central

    Li, Tingting; Kong, Ah-Ng Tony; Ma, Zhiqiang; Liu, Haiyan; Liu, Pinghua; Xiao, Yu; Jiang, Xuehua; Wang, Ling

    2016-01-01

    Purpose Pregnane x receptor (PXR) - activated overexpression of the multidrug resistance 1 (MDR1) gene is an important way for tumor cells to acquire drug resistance. However, the detailed mechanism still remains unclear. In the present study, we aimed to investigate whether protein arginine methyl transferase 1(PRMT1) is involved in PXR - activated overexpression of MDR1 during acquired multidrug resistant. Experimental Design Arginine methyltransferase inhibitor 1 (AMI-1) was used to pharmacologically block PRMT1 in resistant breast cancer cells (MCF7/adr). The mRNA and protein levels of MDR1 were detected by real-time PCR and western blotting analysis. Immunofluorescence microscopy and co-immunoprecipitation were used to investigate the physical interaction between PXR and PRMT1. Then, 136 candidate compounds were screened for PRMT1 inhibitors. Lastly, luciferase reporter gene and nude mice bearing resistant breast cancer xenografts were adopted to investigate the anti-tumor effect of PRMT1 inhibitors when combined with adriamycin. Results AMI-1 significantly suppressed the expression of MDR1 in MCF7/adr cells and increased cells sensitivity of MCF7/adr to adriamycin. Physical interaction between PRMT1 and PXR exists in MCF7/adr cells, which could be disrupted by AMI-1. Those results suggest that PRMT1 may be involved in PXR-activated overexpression of MDR1 in resistant breast cancer cells, and AMI-1 may suppress MDR1 by disrupting the interaction between PRMT1 and PXR. Then, five compounds including rutin, isoquercitrin, salvianolic acid A, naproxen, and felodipline were identified to be PRMT1 inhibitors. Finally, those PRMT1 inhibitors were observed to significantly decrease MDR1 promoter activity in vitro and enhance the antitumor effect of adriamycin in nude mice that bearing resistant breast cancer xenografts. Conclusions PRMT1 may be an important co-activator of PXR in activating MDR1 gene during acquired resistance, and PRMT1 inhibitor combined with

  8. BIIB021, a synthetic Hsp90 inhibitor, has broad application against tumors with acquired multidrug resistance.

    PubMed

    Zhang, Hong; Neely, Laura; Lundgren, Karen; Yang, Yong-Ching; Lough, Rachel; Timple, Noel; Burrows, Francis

    2010-03-01

    17-AAG, the first-generation clinical Hsp90 inhibitor, exhibits promising antitumor activity in clinical studies, but is limited by poor solubility and hepatotoxicity. To pursue compounds with better biopharmaceutical properties, we have developed a series of fully synthetic orally bioavailable inhibitors of Hsp90. Here, we report that 17-AAG and other ansamycin derivatives are inactive in P-gp and/or MRP-1 expressing cell lines and sensitivity could be restored by coadministration of P-gp or MRP inhibitors. In contrast, the synthetic Hsp90 inhibitor, BIIB021 was active in these models. Accordingly, BIIB021 was considerably more active than 17-AAG against adrenocortical carcinoma, a tumor that naturally expresses P-gp, both in vitro and in vivo. This efflux pump-mediated resistance is manifested in both cytotoxicity assays and measurements of target inhibition, such as client protein degradation. Other than this, the cytotoxic activity of BIIB021 was also not influenced by loss of NQO1 or Bcl-2 overexpression, molecular lesions that do not prevent client loss but are nonetheless associated with reduced cell killing by 17-AAG. Our results indicate that the activity of 17-AAG and other ansamycins may be curtailed in tumors that have upregulated efflux pumps or antiapoptotic proteins or other genetic alterations. These data indicate that the new generation of synthetic anti-Hsp90 drugs, exemplified by BIIB021 that is currently undergoing Phase II testing, may have broader application against tumors with acquired multidrug resistance or tumors located in organs protected by MDR proteins, such as the adrenal glands, brain and testis. PMID:19676042

  9. Community-acquired multidrug-resistant Gram-negative bacterial infective endocarditis

    PubMed Central

    Naha, Sowjanya; Naha, Kushal; Acharya, Vasudev; Hande, H Manjunath; Vivek, G

    2014-01-01

    We describe two cases of bacterial endocarditis secondary to multidrug-resistant Gram-negative organisms. In both cases, the diagnosis was made in accordance with the modified Duke's criteria and confirmed by histopathological analysis. Furthermore, in both instances there were no identifiable sources of bacteraemia and no history of contact with hospital or other medical services prior to the onset of symptoms. The patients were managed in similar fashion with prolonged broad-spectrum antibiotic therapy and surgical intervention and made complete recoveries. These cases highlight Gram-negative organisms as potential agents for endocarditis, as well as expose the dissemination of such multidrug-resistant bacteria into the community. The application of an integrated medical and surgical approach and therapeutic dilemmas encountered in managing these cases are described. PMID:25096655

  10. Surveillance for Travel and Domestically Acquired Multidrug-Resistant Human Shigella Infections-Pennsylvania, 2006-2014.

    PubMed

    Li, Yu Lung; Tewari, Deepanker; Yealy, Courtney C; Fardig, David; M'ikanatha, Nkuchia M

    2016-01-01

    Shigellosis is a leading cause of enteric infections in the United States. We compared antimicrobial resistance in Shigella infections related to overseas travel (travel-associated) and in those acquired domestically by analyzing antimicrobial resistance patterns, geographic distributions, and pulsed-field gel electrophoresis (PFGE) patterns. We tested samples (n = 204) from a collection of isolates recovered from patients in Pennsylvania between 2006 and 2014. Isolates were grouped into travel- and non-travel-associated categories. Eighty-one (79.4%) of the Shigella isolates acquired during international travel were resistant to multiple antibiotics compared to 53 (52.1%) of the infections transmitted in domestic settings. A majority (79.4%) of isolates associated with international travel demonstrated resistance to aminoglycosides and tetracyclines, whereas 47 (46.1%) of the infections acquired domestically were resistant to tetracycline. Almost all isolates (92.2%) transmitted in domestic settings were resistant to aminoglycosides, and 5 isolates from adult male patients were resistant to azithromycin, a drug often used for empiric treatment of severe shigellosis. Twenty (19.6%) isolates associated with illnesses acquired during overseas travel in 4 countries were resistant to quinolones. One S. sonnei PFGE pattern was traced to a multidrug-resistant isolate acquired overseas that had caused a multistate outbreak of shigellosis, suggesting global dissemination of a drug-resistant species. Resistance to certain drugs-for example, tetracycline-increased in both overseas- and domestic-acquired infections during the study period. The prevalence of resistance to macrolides (azithromycin) and third-generation cephalosporins (ceftriaxone) was less than 1%; however, efforts to better monitor changes in drug resistance over time combined with increased antimicrobial stewardship are essential at the local, national, and global levels. PMID:27314654

  11. Emergence of Multidrug-Resistant Campylobacter Species Isolates with a Horizontally Acquired rRNA Methylase

    PubMed Central

    Wang, Yang; Zhang, Maojun; Deng, Fengru; Shen, Zhangqi; Wu, Congming; Zhang, Jianzhong

    2014-01-01

    Antibiotic-resistant Campylobacter constitutes a serious threat to public health, and resistance to macrolides is of particular concern, as this class of antibiotics is the drug of choice for clinical therapy of campylobacteriosis. Very recently, a horizontally transferrable macrolide resistance mediated by the rRNA methylase gene erm(B) was reported in a Campylobacter coli isolate, but little is known about the dissemination of erm(B) among Campylobacter isolates and the association of erm(B)-carrying isolates with clinical disease. To address this question and facilitate the control of antibiotic-resistant Campylobacter, we determined the distribution of erm(B) in 1,554 C. coli and Campylobacter jejuni isolates derived from food-producing animals and clinically confirmed human diarrheal cases. The results revealed that 58 of the examined isolates harbored erm(B) and exhibited high-level resistance to macrolides, and most were recent isolates, derived in 2011-2012. In addition, the erm(B)-positive isolates were all resistant to fluoroquinolones, another clinically important antibiotic used for treating campylobacteriosis. The erm(B) gene is found to be associated with chromosomal multidrug resistance genomic islands (MDRGIs) of Gram-positive origin or with plasmids of various sizes. All MDRGIs were transferrable to macrolide-susceptible C. jejuni by natural transformation under laboratory conditions. Molecular typing of the erm(B)-carrying isolates by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST) identified diverse genotypes and outbreak-associated diarrheal isolates. Molecular typing also suggested zoonotic transmission of erm(B)-positive Campylobacter. These findings reveal an emerging and alarming trend of dissemination of erm(B) and MDRGIs in Campylobacter and underscore the need for heightened efforts to control their further spread. PMID:24982085

  12. Multidrug Resistance in Bacteria

    PubMed Central

    Nikaido, Hiroshi

    2010-01-01

    Large amounts of antibiotics used for human therapy, as well as for farm animals and even for fish in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. Multidrug resistance in bacteria may be generated by one of two mechanisms. First, these bacteria may accumulate multiple genes, each coding for resistance to a single drug, within a single cell. This accumulation occurs typically on resistance (R) plasmids. Second, multidrug resistance may also occur by the increased expression of genes that code for multidrug efflux pumps, extruding a wide range of drugs. This review discusses our current knowledge on the molecular mechanisms involved in both types of resistance. PMID:19231985

  13. Differential involvement of glutathione S-transferase mu 1 and multidrug resistance protein 1 in melanoma acquired resistance to vinca alkaloids.

    PubMed

    Attaoua, Chaker; Vincent, Laure-Anaïs; Abdel Jaoued, Aida; Hadj-Kaddour, Kamel; Baï, Qiang; De Vos, John; Vian, Laurence; Cuq, Pierre

    2015-02-01

    On account of its extreme intrinsic resistance to apoptosis and of its strong ability to become chemoresistant after a primary response to drugs, malignant melanoma (MM) is still a therapeutic challenge. We previously showed that glutathione S-transferase mu 1 (GSTM1) acts in synergy with multidrug resistance protein 1 (MRP1) to protect GSTM1-transfected human CAL1 melanoma cells from toxic effects of vincristine (VCR). Herein, we investigated the role of these proteins in the acquired resistance of CAL1 cells to vinca alkaloids (VAs). Resistant lines were established by continuous exposure (>1 year) of parental CAL1-wt cells to VCR, vindesine (VDS), or vinorelbine (VRB): CAL1R-VCR, CAL1R-VDS, CAL1R-VRB, respectively. All resistant lines displayed more than 10-fold increase in resistance to their selection VA, and specifically expressed GSTM1. Suggesting a direct interaction between this protein and VAs, each VA specifically decreased the GSTM1-mediated glutathione conjugation activity in cell lysates. Curcumin (GSTM1 inhibitor), BSO (glutathione synthesis inhibitor), and MK571 (MRP1 inhibitor) considerably reversed the acquired resistance to VCR and VDS, but not to VRB. Microarray data analysis revealed similar gene expression patterns of CAL1R-VCR and CAL1R-VDS, and a distinct one for CAL1R-VRB. These data suggest a differential involvement of GSTM1 and MRP1 in acquired resistance to VAs. A coordinated expression and activity of GSTM1 and MRP1 is required to protect CAL1 cells from VCR and VDS, while the simple expression of GSTM1 is sufficient, possibly by a direct drug/protein interaction, to confer resistance against VRB. PMID:25283245

  14. Role of multidrug resistance in photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Diddens, Heyke C.

    1992-06-01

    Multidrug resistance in cancer chemotherapy is a well established phenomenon. One of the most common phenotypical changes in acquired or intrinsic multidrug resistance in human tumor cells is the overexpression of the mdrl gene product P-glycoprotein, which acts as an active efflux pump. Increased levels of P-glycoprotein are associated with resistance to a variety of anticancer drugs commonly used in tumor chemotherapy like anthracyclins, vinca- alcaloids, epipodophyllotoxins or actinomycin D. We investigated the efficacy or photodynamic therapy in the treatment of tumor cells expressing the multidrug resistance phenotype. Our data show that multidrug resistant cells are highly cross resistant to the phototoxic stain rhodamine 123 but exhibit only low degrees of cross resistance (2 - 3 -folds) to the photosensitizers Photosan-3, Clorin-2, methylene blue and meso-tetra (4- sulfonatophenyl) porphine (TPPS4). Resistance is associated with a decrease in intracellular accumulation of the photosensitizer. Verapamil, a membrane active compound known to enhance drug sensitivity in multidrug resistant cells by inhibition of P-glycoprotein, also increases phototoxicity in multidrug resistant cells. Our results imply that tumors expressing the multidrug resistance phenotype might fail to respond to photochemotherapy with rhodamine 123. On the other hand, multidrug resistance may not play an important role in photodynamic therapy with Photosan-3, Chlorin-2, methylene blue or TPPS4.

  15. Consequences of cell-to-cell P-glycoprotein transfer on acquired multidrug resistance in breast cancer: a cell population dynamics model

    PubMed Central

    2011-01-01

    Background Cancer is a proliferation disease affecting a genetically unstable cell population, in which molecular alterations can be somatically inherited by genetic, epigenetic or extragenetic transmission processes, leading to a cooperation of neoplastic cells within tumoural tissue. The efflux protein P-glycoprotein (P-gp) is overexpressed in many cancer cells and has known capacity to confer multidrug resistance to cytotoxic therapies. Recently, cell-to-cell P-gp transfers have been shown. Herein, we combine experimental evidence and a mathematical model to examine the consequences of an intercellular P-gp trafficking in the extragenetic transfer of multidrug resistance from resistant to sensitive cell subpopulations. Methodology and Principal Findings We report cell-to-cell transfers of functional P-gp in co-cultures of a P-gp overexpressing human breast cancer MCF-7 cell variant, selected for its resistance towards doxorubicin, with the parental sensitive cell line. We found that P-gp as well as efflux activity distribution are progressively reorganized over time in co-cultures analyzed by flow cytometry. A mathematical model based on a Boltzmann type integro-partial differential equation structured by a continuum variable corresponding to P-gp activity describes the cell populations in co-culture. The mathematical model elucidates the population elements in the experimental data, specifically, the initial proportions, the proliferative growth rates, and the transfer rates of P-gp in the sensitive and resistant subpopulations. Conclusions We confirmed cell-to-cell transfer of functional P-gp. The transfer process depends on the gradient of P-gp expression in the donor-recipient cell interactions, as they evolve over time. Extragenetically acquired drug resistance is an additional aptitude of neoplastic cells which has implications in the diagnostic value of P-gp expression and in the design of chemotherapy regimens. Reviewers This article was reviewed by

  16. Multidrug Resistant Acinetobacter

    PubMed Central

    Manchanda, Vikas; Sanchaita, Sinha; Singh, NP

    2010-01-01

    Emergence and spread of Acinetobacter species, resistant to most of the available antimicrobial agents, is an area of great concern. It is now being frequently associated with healthcare associated infections. Literature was searched at PUBMED, Google Scholar, and Cochrane Library, using the terms ‘Acinetobacter Resistance, multidrug resistant (MDR), Antimicrobial Therapy, Outbreak, Colistin, Tigecycline, AmpC enzymes, and carbapenemases in various combinations. The terms such as MDR, Extensively Drug Resistant (XDR), and Pan Drug Resistant (PDR) have been used in published literature with varied definitions, leading to confusion in the correlation of data from various studies. In this review various mechanisms of resistance in the Acinetobacter species have been discussed. The review also probes upon the current therapeutic options, including combination therapies available to treat infections due to resistant Acinetobacter species in adults as well as children. There is an urgent need to enforce infection control measures and antimicrobial stewardship programs to prevent the further spread of these resistant Acinetobacter species and to delay the emergence of increased resistance in the bacteria. PMID:20927292

  17. Multidrug resistance dissemination by extended-spectrum β-lactamase-producing Escherichia coli causing community-acquired urinary tract infection in the Central-Western Region, Brazil.

    PubMed

    Gonçalves, Laura Fernandes; de Oliveira Martins-Júnior, Paulo; de Melo, Ana Beatriz Fabrício; da Silva, Rafaella Christina Rocha Moreira; de Paulo Martins, Vicente; Pitondo-Silva, André; de Campos, Tatiana Amabile

    2016-09-01

    The aim of this work was to analyse extended-spectrum β-lactamase (ESBL)-producing Escherichia coli strains isolated from outpatients with signs of cystitis in Hospital Universitário de Brasília (Brasília, Brazil) during the period July 2013 to April 2014. E. coli isolated from urine culture were identified and their antibiotic susceptibility profile was determined by VITEK 2. ESBL-producing strains identified were submitted to PCR for Clermont phylotyping, CTX-M group typing and virulence determinant detection, and clonal relationships were determined by enterobacterial repetitive intergenic consensus (ERIC)-PCR. One strain belonging to each cluster of the dendrogram obtained by ERIC-PCR was selected for multilocus sequence typing (MLST). Among 324 uropathogenic E. coli (UPEC) analysed, 23 (7.1%) were identified as producing ESBL. All ESBL-producing strains were multidrug-resistant (MDR), i.e. presented non-susceptibility to at least one agent in three or more antimicrobial categories. Of the 23 ESBL-producing UPEC strains, 9 were assigned to phylogenetic group B2 and 7 each belonged to phylogenetic groups D and A. Virulence genotyping showed that aer was the most prevalent gene observed among the strains (21/23), followed by traT (18/23), pap (5/23), afa (5/23), PAI (5/23), cnf (3/23) and sfa (1/23). Analysis of the dendrogram showed that multidrug resistance and CTX-M ESBL groups were distributed among all strains, independent of clonality and phylogroup. Sequence types (STs) associated with pandemic resistance clones, such as B2-ST131 and D-ST648, were observed among the isolates. In conclusion, the results showed worrisome evidence of the potential for antibiotic multiresistant dissemination among community-acquired urinary tract infection caused by UPEC. PMID:27530830

  18. The Effect of Infection Control Nurses on the Occurrence of Pseudomonas aeruginosa Healthcare-Acquired Infection and Multidrug-Resistant Strains in Critically-Ill Children

    PubMed Central

    Xu, Wei; He, Linxi; Liu, Chunfeng; Rong, Jian; Shi, Yongyan; Song, Wenliang; Zhang, Tao; Wang, Lijie

    2015-01-01

    Background Healthcare-acquired Pseudomonas aeruginosa (P. aeruginosa) infections in the Pediatric Intensive Care Unit (PICU), which have a high incidence, increase treatment costs and mortality, and seriously threaten the safety of critically ill children. It is essential to seek convenient and effective methods to control and prevent healthcare-acquired infections (HAIs). This research was conducted to study the effect of infection control nurses on the occurrence of P. aeruginosa HAIs and multi-drug resistance (MDR) strains in PICU. Methods The clinical data was divided into two groups, with the age ranging from 1 month to 14 years. One group of the critically ill patients(N = 3,722) was admitted to PICU from 2007 to 2010, without the management of infection control nurses. The other group of the critically ill patients (N = 3,943) was admitted to PICU from 2011 to 2013, with the management of infection control nurses. Compare the mortality, morbidity and the incidence of acquired P. aeruginosa infections to evaluate the effect of infection control nurses. Results After implementation of the post of infection control nurses, the patient's overall mortality fell from 4.81% to 3.73%. Among the patients with endotracheal intubation more than 48 hours, the incidence of endotracheal intubation-related pneumonia decreased from 44.6% to 34.32%. The mortality of patients with endotracheal intubation decreased from 16.96% to 10.17%, and the morbidity of HAIs with P. aeruginosa decreased from 1.89% to 1.07%. The mutual different rate (MDR) dropped from 67.95% to 44.23%. There were remarkable differences in these rates between the two groups (p<0.05). Conclusion Implementing the post of infection control nurses is associated with effectively reducing the HAI rate, especially the incidence and morbidity of P. aeruginosa HAIs, reducing PICU mortality, improving P. aeruginosa drug resistance. PMID:26630032

  19. Effectiveness of Chlorhexidine Wipes for the Prevention of Multidrug-Resistant Bacterial Colonization and Hospital-Acquired Infections in Intensive Care Unit Patients: A Randomized Trial in Thailand.

    PubMed

    Boonyasiri, Adhiratha; Thaisiam, Peerapat; Permpikul, Chairat; Judaeng, Tepnimitr; Suiwongsa, Bordeesuda; Apiradeewajeset, Napaporn; Fakthongphan, Teerawan; Suddee, Sunun; Laoagtipparos, Wandee; Thamlikitkul, Visanu

    2016-03-01

    OBJECTIVE To determine the effectiveness of daily bathing with 2% chlorhexidine-impregnated washcloths in preventing multidrug-resistant (MDR) gram-positive bacterial colonization and bloodstream infection. METHODS A randomized, open-label controlled trial was conducted in 4 medical intensive care units (ICUs) in Thailand from December 2013 to January 2015. Patients were randomized to receive cleansing with non-antimicrobial soap (control group) or 2% chlorhexidine-impregnated washcloths used to wipe the patient's body once daily (chlorhexidine group). Swabs were taken from nares, axilla, antecubital, groin, and perianal areas on admission and on day 3, 5, 7, and 14. The 5 outcomes were (1) favorable events ( all samples negative throughout ICU admission, or initially positive samples with subsequent negative samples); (2) MDR bacteria colonization-free time; (3) hospital-acquired infection; (4) length of ICU and hospital stay; (5) adverse skin reactions. RESULTS A total of 481 patients were randomly assigned to the control group (241) or the chlorhexidine group (240). Favorable events at day 14 were observed in 34.8% of patients in the control group and 28.6% in the chlorhexidine group (P=.79). Median MDR bacteria colonization-free times were 5 days in both groups. The incidence rate of hospital-acquired infection and the length of the ICU and hospital stay did not differ significantly between groups. The incidence of adverse skin reactions in the chlorhexidine group was 2.5%. CONCLUSION The effectiveness of 2% chlorhexidine-impregnated washcloths for the prevention of MDR gram-negative bacteria colonization and hospital-acquired infection in adult patients in ICU was not proven. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01989416. Infect. Control Hosp. Epidemiol. 2016;37(3):245-253. PMID:26894621

  20. Antimicrobial susceptibility and serotype distribution of Streptococcus pneumoniae isolated from patients with community-acquired pneumonia and molecular analysis of multidrug-resistant serotype 19F and 23F strains in Japan.

    PubMed

    Qin, L; Watanabe, H; Yoshimine, H; Guio, H; Watanabe, K; Kawakami, K; Iwagaki, A; Nagai, H; Goto, H; Kuriyama, T; Fukuchi, Y; Matsushima, T; Kudoh, S; Shimada, K; Matsumoto, K; Nagatake, T; Mizota, T; Oishi, K

    2006-12-01

    A nationwide study was undertaken to determine the susceptibility to penicillin and serotypes of Streptococcus pneumoniae in Japan. S. pneumoniae was isolated from 114 adult patients with community-acquired pneumonia over 22 months at 20 hospitals and medical centres in different regions in Japan. All but five isolates were from sputum. Forty-eight isolates (42.1%) were susceptible, 40 (35.1%) showed intermediate resistance (MIC, 0.12-1.0 microg/ml) and 26 (22.8%) were resistant (MIC, >or=2.0 microg/ml) to penicillin G. All isolates were susceptible to ceftriaxone (breakpoint 1 microg/ml), imipenem (4 microg/ml) and vancomycin (4 microg/ml). Most were resistant to erythromycin, clarithromycin and azithromycin; only two were resistant to levofloxacin. Differences were found in the distribution of serotypes among isolates showing susceptibility to penicillin (predominant types 3, 6B, and 19F), intermediate resistance (6B, 14, 19F, and 23F) and full resistance (19F and 23F). PFGE typing showed that 14 of the 25 strains of serotype 19F had a single DNA profile, pattern A, a pattern closely similar to that of the Taiwan multidrug-resistant 19F clone. Twelve pattern A strains were not susceptible to penicillin but carried the macrolide resistance gene mef(A). The DNA profiles of the 15 strains of 23F were also heterogeneous but six were highly similar (pattern b) yet distinct from the Spanish multidrug-resistant 23F clone although possibly related to the Taiwan multidrug-resistant 23F clone. The pattern b strains were not susceptible to penicillin and also harboured either mef(A) or erm(B). Our results indicate that multidrug-resistant pneumococci are spreading rapidly in Japan. Efforts to prevent the spread of the pandemic multidrug-resistant serotypes should be intensified. PMID:16650327

  1. Management of multidrug-resistant enterococcal infections

    PubMed Central

    Arias, C. A.; Contreras, G. A.; Murray, B. E.

    2013-01-01

    Enterococci are organisms with a remarkable ability to adapt to the environment and acquire antibiotic resistance determinants. The evolution of antimicrobial resistance in these organisms poses enormous challenges for clinicians when faced with patients affected with severe infections. The increased prevalence and dissemination of multidrug-resistant Enterococcus faecium worldwide has resulted in a major decrease in therapeutic options because the majority of E. faecium isolates are now resistant to ampicillin and vancomycin, and exhibit high-level resistance to aminoglycosides, which are three of the traditionally most useful anti-enterococcal antibiotics. Newer antibiotics such as linezolid, daptomycin and tigecycline have good in vitro activity against enterococcal isolates, although their clinical use may be limited in certain clinical scenarios as a result of reduced rates of success, possible underdosing for enterococci and low serum levels, respectively, and also by the emergence of resistance. The experimental agent oritavancin may offer some hope for the treatment of vancomycin-resistant enterococci but clinical data are still lacking. Thus, optimal therapies for the treatment of multidrug-resistant enterococcal infections continue to be based on empirical observations and extrapolations from in vitro and animal data. Clinical studies evaluating new strategies, including combination therapies, to treat severe vancomycin-resistant E. faecium infections are urgently needed. PMID:20569266

  2. [Multidrug resistance (MDR) in oncology].

    PubMed

    Souvirón Rodríguez, A; Ruiz Gómez, M J; Morales Moreno, J A; Martínez Morillo, M

    1997-03-01

    Multidrug resistance or mdr is a frequent phenomenon for which tumor cells can develop, in only one step, cross-resistance to a different anticancer drugs such as antibiotics, vinca alkaloids and podophylotoxins. This is due to an extrusion of drugs out of the cells, since it is interrelated with the decrease of the intracellular concentration of the drug, compared to sensitive cells. This phenomeno of multidrug resistance (mdr) is considered one of the principal causes of failure in quimiotherapic treatment of cancer, and is associated in many cases to an hyperexpression of mdr-I gene, that codifies for a high molecular weight glycoprotein (p-170) (170-180 Kdaltons), also called p-glycoprotein (pgp). Locadet it in the cellular membrane extracts, like a pump, the quimiotherapic drugs with consumption of ATP. In humans, there are two principal genes that codify for pgp: mdr-I and mdr2/3; being the most important the mdr-I gene. The structure of p-glycoprotein consists in two symmetrical halves anchored in the cellular membrane that includes three extracellular dominances each one, and on intracellular portion with the ATP binding site. Also, has got an for extracellular carbohydrates chain. It is specially important to find drugs that reverse the multidrug resistance. Chemicals such as verapamil, nifedine, quinidine and calmodulin inhibitors are joined to pgp inhibiting it. A Cyclosporine and its non-immunosuppressors derivateds such as SDZ 280-125 and SDZ PSC 833 reverse mdr. At present it is being advancing in clinical trials, but the results are not satisfactory. Most useful chemicals are verapamil, better R-verapamil and A-cyclosporine or its non-immunosuppressors derivates. Futures possibilities are grateful. From diagnostic point of view the mains are: 1. Detection of mdr-I gene. 2. Recognition of the presence of mRNA for pgp. 3. Detection of pgp by flow cytometry or western blot. 4. Immunohistochemistry with monoclonal antibodies to pgp. 5. Rhodamine 123 to

  3. [Proteins in cancer multidrug resistance].

    PubMed

    Popęda, Marta; Płuciennik, Elżbieta; Bednarek, Andrzej K

    2014-01-01

    Multidrug Resistance (MDR) is defined as insensitivity to administered medicines that are structurally unrelated and have different molecular targets. Cancers possess numerous mechanisms of drug resistance, involving various aspects of cell biology. A pivotal role in this phenomenon is played by proteins--enzymatic or structural parts of the cell. Membrane transporters, including the main members of ABC protein family--P-gp, MRP1 and BCRP, as well as LRP, which builds structure of vaults, determine the multidrug-resistant phenotype by decreasing drug concentration within the cell or modifying its distribution to intracellular compartments. The π isoform of protein enzyme--glutathione S-transferase (GSTP-1), is responsible for excessive intensity of detoxification of cytostatics. A common example of altered drug target site that does not respond to chemotherapy is topoisomerase II α (TopoIIa). Alterations of programmed cell death result from expression of metallothionein (MT)--inhibitor of the process, and cytokeratin 18 (CK18), which, if in high concentration, also prevents apoptosis of cells. Several methods of decreasing activity of these proteins have been developed, aiming to overcome MDR in cancer cells. However, for a variety of reasons, their clinical suitability is still very low, leading to continuous increase in death rate among patients. This paper presents current state of knowledge on the most important examples of proteins responsible for MDR of cancer cells and molecular mechanisms of their action. PMID:24864112

  4. Pharmacotherapy for multidrug resistant tuberculosis

    PubMed Central

    Chhabra, Naveen; Aseri, M. L.; Dixit, Ramakant; Gaur, S.

    2012-01-01

    The current global concern in the treatment of tuberculosis (TB) is the emergence of resistance to the two most potent drugs namely, isoniazid and rifampicin. Emergence of multidrug resistance tuberculosis (MDR-TB) is now a health problem faced by most of the developing countries as well as developed countries across the globe. MDR-TB is a man-made disease that is caused by improper treatment, inadequate drug supplies, and poor patient supervision. HIV infection and AIDS have been implicated as important cause for this. The review of a published literature suggests that the most powerful predictor of treatment of MDR-TB is a history of treatment of TB. Although the treatment is efficacious, there are also a number of adverse effects caused by drugs used in the treatment of MDR-TB. PMID:22629081

  5. The involvement of sphingolipids in multidrug resistance.

    PubMed

    Sietsma, H; Veldman, R J; Kok, J W

    2001-06-01

    Administration of most chemotherapeutic agents eventually results in the onset of apoptosis, despite the agents' variety in structure and molecular targets. Ceramide, the central molecule in cellular glycosphingolipid metabolism, has recently been identified as an important mediator of this process. Indeed, one of the events elicited by application of many cytotoxic drugs is an accumulation of this lipid. Treatment failure in cancer chemotherapy is largely attributable to multidrug resistance, in which tumor cells are typically cross-resistant to multiple chemotherapeutic agents. Different cellular mechanisms underlying this phenomenon have been described. Of these the drug efflux pump activity of P-glycoprotein and the multidrug resistance-associated proteins are the most extensively studied examples. Recently, an increased cellular capacity for ceramide glycosylation has been recognized as a novel multidrug resistance mechanism. Indeed, virtually all multidrug-resistant cells exhibit a deviating sphingolipid composition, most typically, increased levels of glucosylceramide. On the other hand, several direct molecular interactions between sphingolipids and drug efflux proteins have been described. Therefore, in addition to a role in the multidrug resistance phenotype by which ceramide accumulation and, thus, the onset of apoptosis are prevented, an indirect role for sphingolipids might be envisaged, by which the activity of these efflux proteins is modulated. In this review, we present an overview of the current understanding of the interesting relations that exist between sphingolipid metabolism and multidrug resistance. PMID:11420602

  6. Draft Genome Sequence of a Dominant, Multidrug-Resistant Neisseria gonorrhoeae Strain, TCDC-NG08107, from a Sexual Group at High Risk of Acquiring Human Immunodeficiency Virus Infection and Syphilis▿

    PubMed Central

    Chen, Chun-Chen; Hsia, Ko-Chiang; Huang, Chung-Ter; Wong, Wing-Wai; Yen, Muh-Yong; Li, Lan-Hui; Lin, Kun-Yen; Chen, Kuo-Wei; Li, Shu-Ying

    2011-01-01

    Neisseria gonorrhoeae infection is the second major cause of sexually transmitted diseases worldwide. Development of resistance to multiple classes of antimicrobials in N. gonorrhoeae has compromised treatment and disease control. Herein, we report the availability of the draft genome sequence of a multidrug-resistant N. gonorrhoeae isolate, TCDC-NG08107, which spread in groups of men who have sex with men (MSM) in Taiwan. PMID:21257765

  7. Impaired 2',3'-dideoxy-3'-thiacytidine accumulation in T-lymphoblastoid cells as a mechanism of acquired resistance independent of multidrug resistant protein 4 with a possible role for ATP-binding cassette C11.

    PubMed Central

    Turriziani, O; Schuetz, J D; Focher, F; Scagnolari, C; Sampath, J; Adachi, M; Bambacioni, F; Riva, E; Antonelli, G

    2002-01-01

    Cellular factors may contribute to the decreased efficacy of chemotherapy in HIV infection. Indeed, prolonged treatment with nucleoside analogues, such as azidothymidine (AZT), 2',3'-deoxycytidine or 9-(2-phosphonylmethoxyethyl)adenine, induces cellular resistance. We have developed a human T lymphoblastoid cell line (CEM 3TC) that is selectively resistant to the antiproliferative effect of 2',3'-dideoxy-3'-thiacytidine (3TC) because the CEM 3TC cells were equally sensitive to AZT, as well as the antimitotic agent, vinblastine. The anti-retroviral activity of 3TC against HIV-1 was also severely impaired in the CEM 3TC cells. Despite similar deoxycytidine kinase activity and unchanged uptake of nucleosides such as AZT and 2'-deoxycytidine, CEM 3TC had profoundly impaired 3TC accumulation. Further studies indicated that CEM 3TC retained much less 3TC. However, despite a small overexpression of multidrug resistance protein (MRP) 4, additional studies with cells specifically engineered to overexpress MRP4 demonstrated there was no impact on either 3TC accumulation or efflux. Finally, an increased expression of the MRP5 homologue, ATP-binding cassette C11 (ABCC11) was observed in the CEM 3TC cells. We speculate that the decreased 3TC accumulation in the CEM 3TC might be due to the upregulation of ABCC11. PMID:12133003

  8. Draft genome sequence of Acinetobacter baumannii strain NCTC 13423, a multidrug-resistant clinical isolate.

    PubMed

    Michiels, Joran E; Van den Bergh, Bram; Fauvart, Maarten; Michiels, Jan

    2016-01-01

    Acinetobacter baumannii is a pathogen that is becoming increasingly important and causes serious hospital-acquired infections. We sequenced the genome of A. baumannii NCTC 13423, a multidrug-resistant strain belonging to the international clone II group, isolated from a human infection in the United Kingdom in 2003. The 3,937,944 bp draft genome has a GC-content of 39.0 % and a total of 3672 predicted protein-coding sequences. The availability of genome sequences of multidrug-resistant A. baumannii isolates will fuel comparative genomic studies to help understand the worrying spread of multidrug resistance in this pathogen. PMID:27594976

  9. MDRO - Multidrug-Resistant Organisms

    MedlinePlus

    ... MRSA in the workplace, see: Methicillin-resistan t Staphylococcus aure us (MRSA) . Provides links with general information, ... of these organisms include: MRSA - Methicillin/oxacillin-resistant Staphylococcus aureus VRE - Vancomycin-resistant enterococci ESBLs - Extended-spectrum ...

  10. Facing multi-drug resistant tuberculosis.

    PubMed

    Sotgiu, Giovanni; Migliori, Giovanni Battista

    2015-06-01

    Multi-drug resistant tuberculosis (MDR-TB) is caused by Mycobacterium tuberculosis strains resistant to at least two of the most effective anti-tuberculosis drugs (i.e., isoniazid and rifampicin). Therapeutic regimens based on second- and third-line anti-tuberculosis medicines showed poor efficacy, safety, and tolerability profiles. It was estimated that in 2012 the multi-drug resistant tuberculosis incidence ranged from 300,000 to 600,000 cases, mainly diagnosed in the Eastern European and Central Asian countries. The highest proportion of cases is among individuals previously exposed to anti-tuberculosis drugs. Three main conditions can favour the emergence and spread of multi-drug resistant tuberculosis: the poor implementation of the DOTS strategy, the shortage or the poor quality of the anti-tuberculosis drugs, and the poor therapeutic adherence of the patients to the prescribed regimens. Consultation with tuberculosis experts (e.g., consilium) is crucial to tailor the best anti-tuberculosis therapy. New therapeutic options are necessary: bedaquiline and delamanid seem promising drugs; in particular, during the development phase they demonstrated a protective effect against the emergence of further resistances towards the backbone drugs. In the recent past, other antibiotics have been administered off-label: the most relevant efficacy, safety, and tolerability profile was proved in linezolid-, meropenem/clavulanate-, cotrimoxazole-containing regimens. New research and development activities are needed in the diagnostic, therapeutic, preventive fields. PMID:24792579

  11. Multidrug resistance in pediatric urinary tract infections.

    PubMed

    Gaspari, Romolo J; Dickson, Eric; Karlowsky, James; Doern, Gary

    2006-01-01

    Urinary tract infections (UTIs) represent a common infection in the pediatric population. Escherichia coli is the most common uropathogen in children, and antimicrobial resistance in this species complicates the treatment of pediatric UTIs. Despite the impact of resistance on empiric antibiotic choice, there is little data on multidrug resistance in pediatric patients. In this paper, we describe characteristics of multidrug-resistant E. coli in pediatric patients using a large national database of uropathogens antimicrobial sensitivities. Antimicrobial susceptibility patterns to commonly prescribed antibiotics were performed on uropathogens isolated from children presenting to participating hospitals between 1999 and 2001. Data were analyzed separately for four pediatric age groups. Single and multidrug resistance to ampicillin, amoxicillin-clavulanate, cefazolin, ciprofloxacin, nitrofurantoin, and trimethoprim-sulfamethoxazole (TMP-SMX) were performed on all specimens. There were a total of 11,341 E. coli urine cultures from 343 infants (0-4 weeks), 1,801 toddlers (5 weeks-24 months), 6,742 preteens (2-12 years), and 2,455 teens (13-17 years). E. coli resistance to ampicillin peaked in toddlers (52.8%) but was high in preteens (52.1%), infants (50.4%), and teens (40.6%). Resistance to two or more antibiotics varied across age groups, with toddlers (27%) leading preteens (23.1%), infants (21%), and teens (15.9%). Resistance to three or more antibiotics was low in all age groups (range 3.1-5.2%). The most common co-resistance in all age groups was ampicillin/TMP-SMZ. In conclusion, less than half of all pediatric UTIs are susceptible to all commonly used antibiotics. In some age groups, there is a significant percentage of co-resistance between the two most commonly used antibiotics (ampicillin and TMP-SMZ). PMID:16922629

  12. Multidrug Resistance Proteins (MRPs) and Cancer Therapy.

    PubMed

    Zhang, Yun-Kai; Wang, Yi-Jun; Gupta, Pranav; Chen, Zhe-Sheng

    2015-07-01

    The ATP-binding cassette (ABC) transporters are members of a protein superfamily that are known to translocate various substrates across membranes, including metabolic products, lipids and sterols, and xenobiotic drugs. Multidrug resistance proteins (MRPs) belong to the subfamily C in the ABC transporter superfamily. MRPs have been implicated in mediating multidrug resistance by actively extruding chemotherapeutic substrates. Moreover, some MRPs are known to be essential in physiological excretory or regulatory pathways. The importance of MRPs in cancer therapy is also implied by their clinical insights. Modulating the function of MRPs to re-sensitize chemotherapeutic agents in cancer therapy shows great promise in cancer therapy; thus, multiple MRP inhibitors have been developed recently. This review article summarizes the structure, distribution, and physiological as well as pharmacological function of MRP1-MRP9 in cancer chemotherapy. Several novel modulators targeting MRPs in cancer therapy are also discussed. PMID:25840885

  13. Phosphorylation of the multidrug resistance associated glycoprotein

    SciTech Connect

    Mellado, W.; Horwitz, S.B.

    1987-11-03

    Drug-resistant cell lines derived from the mouse macrophage-like cell line J774.2 express the multidrug resistant phenotype which includes the overexpression of a membrane glycoprotein (130-140 kilodaltons). Phosphorylation of this resistant-specific glycoprotein (P-glycoprotein) in intact cells and in cell-free membrane fractions has been studied. The phosphorylated glycoprotein can be immunoprecipitated by a rabbit polyclonal antibody specific for the glycoprotein. Phosphorylation studies done with partially purified membrane fractions derived from colchicine-resistant cells indicated that (a) phosphorylation of the glycoprotein in 1 mM MgCl/sub 2/ was enhanced a minimum of 2-fold by 10 ..mu..M cAMP and (b) the purified catalytic subunit of the cAMP-dependent protein kinase (protein kinase A) phosphorylated partially purified glycoprotein that was not phosphorylated by (..gamma..-/sup 32/P)ATP alone, suggesting that autophosphorylation was not involved. These results indicate that the glycoprotein is a phosphoprotein and that at least one of the kinases responsible for its phosphorylation is a membrane-associated protein kinase A. The state of phosphorylation of the glycoprotein, which is a major component of the multidrug resistance phenotype, may be related to the role of the glycoprotein in maintaining drug resistance.

  14. Phosphorylation of the multidrug resistance associated glycoprotein.

    PubMed

    Mellado, W; Horwitz, S B

    1987-11-01

    Drug-resistant cell lines derived from the mouse macrophage-like cell line J774.2 express the multidrug resistance phenotype which includes the overexpression of a membrane glycoprotein (130-140 kilodaltons). Phosphorylation of this resistant-specific glycoprotein (P-glycoprotein) in intact cells and in cell-free membrane fractions has been studied. The phosphorylated glycoprotein can be immunoprecipitated by a rabbit polyclonal antibody specific for the glycoprotein. Phosphorylation studies done with partially purified membrane fractions derived from colchicine-resistant cells indicated that (a) phosphorylation of the glycoprotein in 1 mM MgCl2 was enhanced a minimum of 2-fold by 10 microM cAMP and (b) the purified catalytic subunit of the cAMP-dependent protein kinase (protein kinase A) phosphorylated partially purified glycoprotein that was not phosphorylated by [gamma-32P]ATP alone, suggesting that autophosphorylation was not involved. These results indicate that the glycoprotein is a phosphoprotein and that at least one of the kinases responsible for its phosphorylation is a membrane-associated protein kinase A. The state of phosphorylation of the glycoprotein, which is a major component of the multidrug resistance phenotype, may be related to the role of the glycoprotein in maintaining drug resistance. PMID:3427052

  15. Four decades of transmission of a multidrug-resistant Mycobacterium tuberculosis outbreak strain

    PubMed Central

    Eldholm, Vegard; Monteserin, Johana; Rieux, Adrien; Lopez, Beatriz; Sobkowiak, Benjamin; Ritacco, Viviana; Balloux, Francois

    2015-01-01

    The rise of drug-resistant strains is a major challenge to containing the tuberculosis (TB) pandemic. Yet, little is known about the extent of resistance in early years of chemotherapy and when transmission of resistant strains on a larger scale became a major public health issue. Here we reconstruct the timeline of the acquisition of antimicrobial resistance during a major ongoing outbreak of multidrug-resistant TB in Argentina. We estimate that the progenitor of the outbreak strain acquired resistance to isoniazid, streptomycin and rifampicin by around 1973, indicating continuous circulation of a multidrug-resistant TB strain for four decades. By around 1979 the strain had acquired additional resistance to three more drugs. Our results indicate that Mycobacterium tuberculosis (Mtb) with extensive resistance profiles circulated 15 years before the outbreak was detected, and about one decade before the earliest documented transmission of Mtb strains with such extensive resistance profiles globally. PMID:25960343

  16. Yeast ABC proteins involved in multidrug resistance.

    PubMed

    Piecuch, Agata; Obłąk, Ewa

    2014-03-01

    Pleiotropic drug resistance is a complex phenomenon that involves many proteins that together create a network. One of the common mechanisms of multidrug resistance in eukaryotic cells is the active efflux of a broad range of xenobiotics through ATP-binding cassette (ABC) transporters. Saccharomyces cerevisiae is often used as a model to study such activity because of the functional and structural similarities of its ABC transporters to mammalian ones. Numerous ABC transporters are found in humans and some are associated with the resistance of tumors to chemotherapeutics. Efflux pump modulators that change the activity of ABC proteins are the most promising candidate drugs to overcome such resistance. These modulators can be chemically synthesized or isolated from natural sources (e.g., plant alkaloids) and might also be used in the treatment of fungal infections. There are several generations of synthetic modulators that differ in specificity, toxicity and effectiveness, and are often used for other clinical effects. PMID:24297686

  17. Emerging therapies for multidrug resistant Acinetobacter baumannii.

    PubMed

    García-Quintanilla, Meritxell; Pulido, Marina R; López-Rojas, Rafael; Pachón, Jerónimo; McConnell, Michael J

    2013-03-01

    The global emergence of multidrug resistant Acinetobacter baumannii has reduced the number of clinically available antibiotics that retain activity against this pathogen. For this reason, the development of novel prevention and treatment strategies for infections caused by A. baumannii is necessary. Several studies have begun to characterize nonantibiotic approaches that utilize novel mechanisms of action to achieve antibacterial activity. Recent advances in phage therapy, iron chelation therapy, antimicrobial peptides, prophylactic vaccination, photodynamic therapy, and nitric oxide (NO)-based therapies have all been shown to have activity against A. baumannii. However, before these approaches can be used clinically there are still limitations and remaining questions that must be addressed. PMID:23317680

  18. Congenital Transmission of Multidrug-Resistant Tuberculosis

    PubMed Central

    Espiritu, Nora; Aguirre, Lino; Jave, Oswaldo; Sanchez, Luis; Kirwan, Daniela E.; Gilman, Robert H.

    2014-01-01

    This article presents a case of multidrug-resistant tuberculosis (TB) in a Peruvian infant. His mother was diagnosed with disseminated TB, and treatment commenced 11 days postpartum. The infant was diagnosed with TB after 40 days and died at 2 months and 2 days of age. Congenital transmission of TB to the infant was suspected, because direct postpartum transmission was considered unlikely; also, thorough screening of contacts for TB was negative. Spoligotyping confirmed that both mother and baby were infected with identical strains of the Beijing family (SIT1). PMID:24821847

  19. [Innovative treatments for multidrug-resistant bacteria].

    PubMed

    Pierre, Tattevin; Aurélien, Lorleac'h; Matthieu, Revest

    2014-03-01

    The spread of multidrug-resistant bacteria has accelerated sharply in the last decade. According to the World Health Organization they are responsible for an estimated 25 000 deaths in Europe each year. In addition, few new antibiotics are under development, raising the spectrum of a return to the "pre-antibiotic era". Non antibiotic antibacterial agents have recently attracted renewed interest. The most promising candidates are: i) phages (bacteria-infecting viruses) have been widely used in Eastern European countries since the 1930s but come up against logistic and regulatory obstacles due to the evolutionary nature of these biologic agents, while convincing clinical data are lacking; ii) bacteriocines are smallantibacterialpeptidesproducedby numerous bacteria; some have a rapid bactericidal effect, good tolerability, and a limited impact on the commensal flora; however, clinical use of bacteriocines is complicated by their fragility, poor penetration, and substantial risk of resistance selection ; iii) antisense oligonucleo tides act by inactivating genes through specific interaction with a complementary DNA or RNA fragment, potentially allowing specific inhibition of selected bacterial virulence factors. However, this therapeutic class may be more suitable for viral or genetic diseases than for multidrug-resistant bacterial infections, owing to the difficulty of delivering them inside bacteria. PMID:26427289

  20. Breaking the Spell: Combating Multidrug Resistant 'Superbugs'.

    PubMed

    Khan, Shahper N; Khan, Asad U

    2016-01-01

    Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to "escape" from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing. PMID:26925046

  1. Comparative Genomics of Multidrug Resistance in Acinetobacter baumannii

    PubMed Central

    2006-01-01

    Acinetobacter baumannii is a species of nonfermentative gram-negative bacteria commonly found in water and soil. This organism was susceptible to most antibiotics in the 1970s. It has now become a major cause of hospital-acquired infections worldwide due to its remarkable propensity to rapidly acquire resistance determinants to a wide range of antibacterial agents. Here we use a comparative genomic approach to identify the complete repertoire of resistance genes exhibited by the multidrug-resistant A. baumannii strain AYE, which is epidemic in France, as well as to investigate the mechanisms of their acquisition by comparison with the fully susceptible A. baumannii strain SDF, which is associated with human body lice. The assembly of the whole shotgun genome sequences of the strains AYE and SDF gave an estimated size of 3.9 and 3.2 Mb, respectively. A. baumannii strain AYE exhibits an 86-kb genomic region termed a resistance island—the largest identified to date—in which 45 resistance genes are clustered. At the homologous location, the SDF strain exhibits a 20 kb-genomic island flanked by transposases but devoid of resistance markers. Such a switching genomic structure might be a hotspot that could explain the rapid acquisition of resistance markers under antimicrobial pressure. Sequence similarity and phylogenetic analyses confirm that most of the resistance genes found in the A. baumannii strain AYE have been recently acquired from bacteria of the genera Pseudomonas, Salmonella, or Escherichia. This study also resulted in the discovery of 19 new putative resistance genes. Whole-genome sequencing appears to be a fast and efficient approach to the exhaustive identification of resistance genes in epidemic infectious agents of clinical significance. PMID:16415984

  2. NANOPREPARATIONS TO OVERCOME MULTIDRUG RESISTANCE IN CANCER

    PubMed Central

    Patel, Niravkumar R.; Pattni, Bhushan S.; Abouzeid, Abraham H.; Torchilin, Vladimir P.

    2013-01-01

    Multidrug resistance is the most widely exploited phenomenon by which cancer eludes chemotherapy. Broad variety of factors, ranging from the cellular ones, such as over-expression of efflux transporters, defective apoptotic machineries, and altered molecular targets, to the physiological factors such as higher interstitial fluid pressure, low extracellular pH, and formation of irregular tumor vasculature are responsible for multidrug resistance. A combination of various undesirable factors associated with biological surroundings together with poor solubility and instability of many potential therapeutic small & large molecules within the biological systems and systemic toxicity of chemotherapeutic agents has necessitated the need for nano-preparations to optimize drug delivery. The physiology of solid tumors presents numerous challenges for successful therapy. However, it also offers unique opportunities for the use of nanotechnology. Nanoparticles, up to 400 nm in size, have shown great promise for carrying, protecting and delivering potential therapeutic molecules with diverse physiological properties. In this review, various factors responsible for the MDR and the use of nanotechnology to overcome the MDR, the use of spheroid culture as well as the current technique of producing micro tumor tissues in vitro are discussed in detail. PMID:23973912

  3. Multidrug-Resistant Acinetobacter spp.: Increasingly Problematic Nosocomial Pathogens

    PubMed Central

    Lee, Kyungwon; Yong, Dongeun; Jeong, Seok Hoon

    2011-01-01

    Pathogenic bacteria have increasingly been resisting to antimicrobial therapy. Recently, resistance problem has been relatively much worsened in Gram-negative bacilli. Acinetobacter spp. are typical nosocomial pathogens causing infections and high mortality, almost exclusively in compromised hospital patients. Acinetobacter spp. are intrinsically less susceptible to antibiotics than Enterobacteriaceae, and have propensity to acquire resistance. A surveillance study in Korea in 2009 showed that resistance rates of Acinetobacter spp. were very high: to fluoroquinolone 67%, to amikacin 48%, to ceftazidime 66% and to imipenem 51%. Carbapenem resistance was mostly due to OXA type carbapenemase production in A. baumannii isolates, whereas it was due to metallo-β-lactamase production in non-baumannii Acinetobacter isolates. Colistin-resistant isolates were rare but started to be isolated in Korea. Currently, the infection caused by multidrug-resistant A. baumannii is among the most difficult ones to treat. Analysis at tertiary care hospital in 2010 showed that among the 1,085 isolates of Acinetobacter spp., 14.9% and 41.8% were resistant to seven, and to all eight antimicrobial agents tested, respectively. It is known to be difficult to prevent Acinetobacter spp. infection in hospitalized patients, because the organisms are ubiquitous in hospital environment. Efforts to control resistant bacteria in Korea by hospitals, relevant scientific societies and government agencies have only partially been successful. We need concerted multidisciplinary efforts to preserve the efficacy of currently available antimicrobial agents, by following the principles of antimicrobial stewardship. PMID:22028150

  4. Epidemiology and Treatment of Multidrug Resistant Tuberculosis

    PubMed Central

    Mitnick, Carole D.; Appleton, Sasha C.; Shin, Sonya S.

    2010-01-01

    Multidrug resistant tuberculosis is now thought to afflict between 1 and 2 million patients annually. Although significant regional variability in the distribution of disease has been recorded, surveillance data are limited by several factors. The true burden of disease is likely underestimated. Nevertheless, the estimated burden is substantial enough to warrant concerted action. A range of approaches is possible, but all appropriate interventions require scale-up of laboratories and early treatment with regimens containing a sufficient number of second-line drugs. Ambulatory treatment for most patients, and improved infection control, can facilitate scale-up with decreased risk of nosocomial transmission. Several obstacles have been considered to preclude worldwide scale-up of treatment, mostly attributable to inadequate human, drug, and financial resources. Further delays in scale-up, however, risk continued generation and transmission of resistant tuberculosis, as well as associated morbidity and mortality. PMID:18810684

  5. BRCA2-deficient sarcomatoid mammary tumors exhibit multidrug resistance.

    PubMed

    Jaspers, Janneke E; Sol, Wendy; Kersbergen, Ariena; Schlicker, Andreas; Guyader, Charlotte; Xu, Guotai; Wessels, Lodewyk; Borst, Piet; Jonkers, Jos; Rottenberg, Sven

    2015-02-15

    Pan- or multidrug resistance is a central problem in clinical oncology. Here, we use a genetically engineered mouse model of BRCA2-associated hereditary breast cancer to study drug resistance to several types of chemotherapy and PARP inhibition. We found that multidrug resistance was strongly associated with an EMT-like sarcomatoid phenotype and high expression of the Abcb1b gene, which encodes the drug efflux transporter P-glycoprotein. Inhibition of P-glycoprotein could partly resensitize sarcomatoid tumors to the PARP inhibitor olaparib, docetaxel, and doxorubicin. We propose that multidrug resistance is a multifactorial process and that mouse models are useful to unravel this. PMID:25511378

  6. [Multidrug resistance in Klebsiella pneumoniae: multicenter study].

    PubMed

    Boutiba-Ben Boubaker, Ilhem; Ben Salah, Dorra; Besbes, Makram; Mahjoubi, Faouzia; Ghozzi, Rafiaa; Ben Redjeb, Saida; Ben Hassen, Assia; Hammami, Adnène

    2002-01-01

    The extensive use of broad spectrum antibiotics, especially the third generation cephalosporins (C3G), was followed by the emergence of newer plasmid mediated betalactamases called extended spectrum betalactamases (ESBLs). To assess the impact of K. pneumoniae resistant to 3GC in Tunisia, this study was conducted in 3 teaching hospitals. A total of 1110 strains of K pneumoniae was collected. The antibiotics susceptibilities were tested by diffusion method using Mueller-Hinton agar. The quality control was regularly performed. I ESBLs producing solates were detected using the double-disc synergy test. Data analysis was done using the Whonet 4 software. 23.6% K. pneumoniae isolates showed phenotype pattern of ESBLs producers. The double-disc synergy test was positive in 75% of the cases. These isolates were recovered from hospitalized patients in different wards but mainly from pediatrics (23.6%), medicine (23.2%), surgery (22.9%), intensive care units (11%) and neonatology (11%). 54% were isolated from urines, 22% from blood cultures. These isolates remained susceptible to imipenem (100%) and most of them to cefoxitin (96.4%) but all had associated resistance to aminoglycosides, quinolones and trimethoprim-sulfamethoxazole. The prevalence of multidrug resistant K. pneumoniae is high. This resistance can be minimized by the implementation of infection control measures including handwashing and isolation procedures. PMID:12071040

  7. Nanomedicine to overcome cancer multidrug resistance.

    PubMed

    Yang, Xi; Yi, Cheng; Luo, Na; Gong, Changyang

    2014-01-01

    Cancer is still considered to be one of the most severe diseases so far. Multidrug resistance (MDR) is a major obstacle against curative cancer chemotherapy. The over-expression of drug efflux pumps in cellular membrane plays a critical role in preventing cancer cells from conventional chemotherapy. Nanotechnology is emerging as a class of therapeutics for MDR. This review mainly focuses on some pivotal strategies to combat MDR, including the enhanced permeability and retention (EPR) effect, stealth nanoparticles to prolong circulation time, endosomal escape, active drug delivery, stimuli sensitive drug release, and targeted co-delivery of different compounds. While convinced challenges need combatting, large numbers of preclinical studies strongly suggest that nanomedicine formations have potential application for improving the treatment of MDR. PMID:25255871

  8. Redox Regulation of Multidrug Resistance in Cancer Chemotherapy: Molecular Mechanisms and Therapeutic Opportunities

    PubMed Central

    2009-01-01

    Abstract The development of multidrug resistance to cancer chemotherapy is a major obstacle to the effective treatment of human malignancies. It has been established that membrane proteins, notably multidrug resistance (MDR), multidrug resistance protein (MRP), and breast cancer resistance protein (BCRP) of the ATP binding cassette (ABC) transporter family encoding efflux pumps, play important roles in the development of multidrug resistance. Overexpression of these transporters has been observed frequently in many types of human malignancies and correlated with poor responses to chemotherapeutic agents. Evidence has accumulated showing that redox signals are activated in response to drug treatments that affect the expression and activity of these transporters by multiple mechanisms, including (a) conformational changes in the transporters, (b) regulation of the biosynthesis cofactors required for the transporter's function, (c) regulation of the expression of transporters at transcriptional, posttranscriptional, and epigenetic levels, and (d) amplification of the copy number of genes encoding these transporters. This review describes various specific factors and their relevant signaling pathways that are involved in the regulation. Finally, the roles of redox signaling in the maintenance and evolution of cancer stem cells and their implications in the development of intrinsic and acquired multidrug resistance in cancer chemotherapy are discussed. Antioxid. Redox Signal. 11, 99–133. PMID:18699730

  9. Is Resistance Useless? Multidrug Resistance and Collateral Sensitivity

    PubMed Central

    Hall, Matthew D.; Handley, Misty D.; Gottesman, Michael M.

    2009-01-01

    When cancer cells develop resistance to chemotherapeutics, it is frequently conferred by the ATP-dependent efflux pump P-glycoprotein (MDR1, P-gp, ABCB1). P-gp can efflux a wide range of cancer drugs; thus its expression confers cross-resistance, termed multidrug resistance (MDR), to a wide range of drugs. Strategies to overcome this resistance have been actively sought for over 30 years, yet no clinical solutions exist. A less understood aspect of MDR is the hypersensitivity of resistant cancer cells to other drugs, a phenomenon generally known as collateral sensitivity (CS). This review highlights the extent of this effect for the first time, discusses hypotheses such as ROS generation to account for the underlying generality of this phenomenon, and proposes the exploitation of CS as a strategy to improve response to chemotherapy. PMID:19762091

  10. Phorbol esters induce multidrug resistance in human breast cancer cells

    SciTech Connect

    Fine, R.L.; Patel, J.; Chabner, B.A.

    1988-01-01

    Mechanisms responsible for broad-based resistance to antitumor drugs derived from natural products (multidrug resistance) are incompletely understood. Agents known to reverse the multidrug-resistant phenotype (verapamil and trifluoperazine) can also inhibit the activity of protein kinase C. When the authors assayed human breast cancer cell lines for protein kinase C activity, they found that enzyme activity was 7-fold higher in the multidrug-resistance cancer cells compared with the control, sensitive parent cells. Exposure of drug-sensitive cells to the phorbol ester phorbol 12,13-dibutyate (P(BtO)/sub 2/) led to an increase in protein kinase C activity and induced a drug-resistance phenotype, whereas exposure of drug-resistant cells to P(BtO)/sub 2/ further increased drug resistance. In sensitive cells, this increased resistance was accomplished by a 3.5-fold increased phosphorylation of a 20-kDa particulate protein and a 35-40% decreased intracellular accumulation of doxorubicin and vincristine. P(BtO)/sub 2/ induced resistance to agents involved in the multidrug-resistant phenotype (doxorubicin and vincristine) but did not affect sensitivity to an unrelated alkylating agent (melphalan). The increased resistance was partially or fully reversible by the calcium channel blocker verapamil and by the calmodulin-antagonist trifluoperazine. These data suggest that stimulation of protein kinase C playus a role in the drug-transport changes in multidrug-resistant cells. This may occur through modulation of an efflux pump by protein phosphorylation.

  11. Starvation, detoxification, and multidrug resistance in cancer therapy

    PubMed Central

    Lee, Changhan; Raffaghello, Lizzia; Longo, Valter D.

    2013-01-01

    The selection of chemotherapy drugs is based on the cytotoxicity to specific tumor cell types and the relatively low toxicity to normal cells and tissues. However, the toxicity to normal cells poses a major clinical challenge, particularly when malignant cells have acquired resistance to chemotherapy. This drug resistance of cancer cells results from multiple factors including individual variation, genetic heterogeneity within a tumor, and cellular evolution. Much progress in the understanding of tumor cell resistance has been made in the past 35 years, owing to milestone discoveries such as the identification and characterization of ABC transporters. Nonetheless, the complexity of the genetic and epigenetic rewiring of cancer cells makes drug resistance an equally complex phenomenon that is difficult to overcome. In this review, we discuss how the remarkable changes in the levels of glucose, IGF-I, IGFBP-1 and in other proteins caused by fasting have the potential to improve the efficacy of chemotherapy against tumors by protecting normal cells and tissues and possibly by diminishing multidrug resistance in malignant cells. PMID:22391012

  12. Epidemiology of Primary Multidrug-Resistant Tuberculosis, Vladimir Region, Russia.

    PubMed

    Ershova, Julia V; Volchenkov, Grigory V; Kaminski, Dorothy A; Somova, Tatiana R; Kuznetsova, Tatiana A; Kaunetis, Natalia V; Cegielski, J Peter; Kurbatova, Ekaterina V

    2015-11-01

    We studied the epidemiology of drug-resistant tuberculosis (TB) in Vladimir Region, Russia, in 2012. Most cases of multidrug-resistant TB (MDR TB) were caused by transmission of drug-resistant strains, and >33% were in patients referred for testing after mass radiographic screening. Early diagnosis of drug resistance is essential for preventing transmission of MDR TB. PMID:26488585

  13. Identification of compounds selectively killing multidrug resistant cancer cells

    PubMed Central

    Türk, Dóra; Hall, Matthew D.; Chu, Benjamin F.; Ludwig, Joseph A.; Fales, Henry M.; Gottesman, Michael M.; Szakács, Gergely

    2009-01-01

    There is a great need for the development of novel chemotherapeutic agents that overcome the emergence of multidrug resistance in cancer. We catalogued the National Cancer Institute’s Developmental Therapeutics Program (DTP) drug repository in search of compounds showing increased toxicity in multidrug resistant (MDR) cells. By comparing the sensitivity of parental cell lines with multidrug resistant derivatives, we identified 22 compounds possessing MDR-selective activity. Analysis of structural congeners led to the identification of 15 additional drugs showing increased toxicity in Pgp-expressing cells. Analysis of MDR-selective compounds led to the formulation of structure activity relationships (SAR) and pharmacophore models. This data mining coupled with experimental data points to a possible mechanism of action linked to metal chelation. Taken together, the discovery of the MDR-selective compound set demonstrates the robustness of the developing field of MDR-targeting therapy as a new strategy for resolving Pgp-mediated multidrug resistance. PMID:19843850

  14. Targeting protein kinases to reverse multidrug resistance in sarcoma.

    PubMed

    Chen, Hua; Shen, Jacson; Choy, Edwin; Hornicek, Francis J; Duan, Zhenfeng

    2016-02-01

    Sarcomas are a group of cancers that arise from transformed cells of mesenchymal origin. They can be classified into over 50 subtypes, accounting for approximately 1% of adult and 15% of pediatric cancers. Wide surgical resection, radiotherapy, and chemotherapy are the most common treatments for the majority of sarcomas. Among these therapies, chemotherapy can palliate symptoms and prolong life for some sarcoma patients. However, sarcoma cells can have intrinsic or acquired resistance after treatment with chemotherapeutics drugs, leading to the development of multidrug resistance (MDR). MDR attenuates the efficacy of anticancer drugs and results in treatment failure for sarcomas. Therefore, overcoming MDR is an unmet need for sarcoma therapy. Certain protein kinases demonstrate aberrant expression and/or activity in sarcoma cells, which have been found to be involved in the regulation of sarcoma cell progression, such as cell cycle, apoptosis, and survival. Inhibiting these protein kinases may not only decrease the proliferation and growth of sarcoma cells, but also reverse their resistance to chemotherapeutic drugs to subsequently reduce the doses of anticancer drugs and decrease drug side-effects. The discovery of novel strategies targeting protein kinases opens a door to a new area of sarcoma research and provides insight into the mechanisms of MDR in chemotherapy. This review will focus on the recent studies in targeting protein kinase to reverse chemotherapeutic drug resistance in sarcoma. PMID:26827688

  15. Salvage therapy for multidrug-resistant tuberculosis.

    PubMed

    Seung, K J; Becerra, M C; Atwood, S S; Alcántara, F; Bonilla, C A; Mitnick, C D

    2014-05-01

    Treatment of multidrug-resistant tuberculosis (MDR-TB), defined as Mycobacterium tuberculosis resistant to both isoniazid and rifampicin, is challenging under the best of circumstances, and particularly in resource-limited settings. For patients who remain persistently sputum-culture-positive despite therapy with second-line TB drugs, treatment options are limited, especially if disease is too advanced for resective surgery. Salvage therapy refers to the design of a regimen combining new and previously used drugs in a final effort to attain sputum conversion before declaring treatment to have failed. We retrospectively evaluated the outcomes of salvage therapy in 213 Peruvian patients. Salvage regimens included a median of two new drugs (range 1-6) and nine (range 5-13) total (new plus previously used) drugs. The most frequently used new drug was moxifloxacin, followed by capreomycin, amoxicillin-clavulanate, kanamycin and clarithromycin. Culture conversion occurred in 65 (30.5%) patients. Salvage regimens that included moxifloxacin were significantly more likely to be followed by culture conversion (OR 2.2; p 0.02). Later-generation fluoroquinolones such as moxifloxacin should be used in salvage therapy but also in the initial treatment of MDR-TB, if the best clinical strategy is to use the most effective drugs when the patient has the best chance for cure. New TB drugs are most likely to be initially used in salvage patients, in conditions similar to those described here. Close bacteriological monitoring of these patients will be essential, as useful information about the best way to use these new drugs can be gained from analysis of salvage therapy cohorts. PMID:23991934

  16. Characterization of a Multidrug-Resistant, Novel Bacteroides Genomospecies

    PubMed Central

    Salipante, Stephen J.; Kalapila, Aley; Pottinger, Paul S.; Hoogestraat, Daniel R.; Cummings, Lisa; Duchin, Jeffrey S.; Sengupta, Dhruba J.; Pergam, Steven A.; Cookson, Brad T.

    2015-01-01

    Metronidazole- and carbapenem-resistant Bacteroides fragilis are rare in the United States. We isolated a multidrug-resistant anaerobe from the bloodstream and intraabdominal abscesses of a patient who had traveled to India. Whole-genome sequencing identified the organism as a novel Bacteroides genomospecies. Physicians should be aware of the possibility for concomitant carbapenem- and metronidazole-resistant Bacteroides infections. PMID:25529016

  17. Intrinsic and acquired resistance mechanisms in enterococcus

    PubMed Central

    Hollenbeck, Brian L.; Rice, Louis B.

    2012-01-01

    Enterococci have the potential for resistance to virtually all clinically useful antibiotics. Their emergence as important nosocomial pathogens has coincided with increased expression of antimicrobial resistance by members of the genus. The mechanisms underlying antibiotic resistance in enterococci may be intrinsic to the species or acquired through mutation of intrinsic genes or horizontal exchange of genetic material encoding resistance determinants. This paper reviews the antibiotic resistance mechanisms in Enterococcus faecium and Enterococcus faecalis and discusses treatment options. PMID:23076243

  18. Reversal of multidrug resistance by 7-O-benzoylpyripyropene A in multidrug-resistant tumor cells.

    PubMed

    Rho, M C; Hayashi, M; Fukami, A; Obata, R; Sunazuka, T; Tomoda, H; Komiyama, K; Omura, S

    2000-10-01

    7-O-Benzoylpyripyropene A (7-O-BzP), a semi-synthetic analog of pyripyropene, was investigated for its reversing effect on multidrug-resistant (MDR) tumor cells. 7-O-BzP (6.25 microg/ml) completely reversed resistance against vincristine and adriamycin in vincristine-resistant KB cells (VJ-300) and adriamycin-resistant P388 cells (P388/ADR), respectively. 7-O-BzP alone had no effect on the growth of drug sensitive and drug-resistant cells. 7-O-BzP (6.25 microg/ml) significantly enhanced accumulation of [3H]vincristine in VJ-300 cells and completely inhibited the binding of [3H]azidopine to the P-glycoprotein in VJ-300 cells and P388/ADR cells. The result suggests that 7-O-BzP effectively reverses P-glycoprotein-related MDR by interacting directly with P-glycoprotein in drug resistant VJ-300 and P388/ADR cells. PMID:11132967

  19. Biosynthesis of heterogeneous forms of multidrug resistance-associated glycoproteins.

    PubMed

    Greenberger, L M; Williams, S S; Horwitz, S B

    1987-10-01

    Multidrug-resistant J774.2 mouse macrophage-like cells, selected for resistance to colchicine, vinblastine, or taxol, overexpress antigenically related glycoproteins with distinct electrophoretic mobilities. These plasma membrane glycoproteins are likely to play a pivotal role in the expression of the multidrug resistance phenotype. To determine how these multidrug resistance-associated glycoproteins differ, the biosynthesis and N-linked carbohydrate composition of these proteins were examined and compared. Vinblastineor colchicine-selected cells made a 125-kDa precursor that was rapidly processed (t1/2 approximately equal to 20 min) to mature forms of 135 and 140 kDa, respectively. Heterogeneity between the 135- and 140-kDa forms of the molecule can be attributed to N-linked carbohydrate. In contrast, taxol-selected cells made two precursors, 125 and 120 kDa, which appeared within 5 and 15 min after the onset of pulse labeling, respectively. They were processed to mature forms of 140 and 130 kDa. Since a single deglycosylated precursor or mature form was not observed after enzymatic removal of N-linked oligosaccharides, other differences, besides N-linked glycosylation, which occur in early processing compartments, are likely to account for the two multidrug resistance-associated glycoproteins in taxol-selected cells. These results demonstrate that a family of multidrug resistance-associated glycoproteins can be differentially expressed. PMID:2888763

  20. Mammalian multidrug-resistance proteins (MRPs).

    PubMed

    Slot, Andrew J; Molinski, Steven V; Cole, Susan P C

    2011-09-01

    Subfamily C of the human ABC (ATP-binding cassette) superfamily contains nine proteins that are often referred to as the MRPs (multidrug-resistance proteins). The 'short' MRP/ABCC transporters (MRP4, MRP5, MRP8 and ABCC12) have a typical ABC structure with four domains comprising two membrane-spanning domains (MSD1 and MSD2) each followed by a nucleotide-binding domain (NBD1 and NBD2). The 'long' MRP/ABCCs (MRP1, MRP2, MRP3, ABCC6 and MRP7) have five domains with the extra domain, MSD0, at the N-terminus. The proteins encoded by the ABCC6 and ABCC12 genes are not known to transport drugs and are therefore referred to as ABCC6 and ABCC12 (rather than MRP6 and MRP9) respectively. A large number of molecules are transported across the plasma membrane by the MRPs. Many are organic anions derived from exogenous sources such as conjugated drug metabolites. Others are endogenous metabolites such as the cysteinyl leukotrienes and prostaglandins which have important signalling functions in the cell. Some MRPs share a degree of overlap in substrate specificity (at least in vitro), but differences in transport kinetics are often substantial. In some cases, the in vivo substrates for some MRPs have been discovered aided by studies in gene-knockout mice. However, the molecules that are transported in vivo by others, including MRP5, MRP7, ABCC6 and ABCC12, still remain unknown. Important differences in the tissue distribution of the MRPs and their membrane localization (apical in contrast with basolateral) in polarized cells also exist. Together, these differences are responsible for the unique pharmacological and physiological functions of each of the nine ABCC transporters known as the MRPs. PMID:21967058

  1. Stress responses as determinants of antimicrobial resistance in Pseudomonas aeruginosa: multidrug efflux and more.

    PubMed

    Poole, Keith

    2014-12-01

    Pseudomonas aeruginosa is a notoriously antimicrobial-resistant organism that is increasingly refractory to antimicrobial chemotherapy. While the usual array of acquired resistance mechanisms contribute to resistance development in this organism a multitude of endogenous genes also play a role. These include a variety of multidrug efflux loci that contribute to both intrinsic and acquired antimicrobial resistance. Despite their roles in resistance, however, it is clear that these efflux systems function in more than just antimicrobial efflux. Indeed, recent data indicate that they are recruited in response to environmental stress and, therefore, function as components of the organism's stress responses. In fact, a number of endogenous resistance-promoting genes are linked to environmental stress, functioning as part of known stress responses or recruited in response to a variety of environmental stress stimuli. Stress responses are, thus, important determinants of antimicrobial resistance in P. aeruginosa. As such, they represent possible therapeutic targets in countering antimicrobial resistance in this organism. PMID:25388098

  2. Multidrug Resistant and Extensively Drug Resistant Bacteria: A Study

    PubMed Central

    Basak, Silpi; Singh, Priyanka; Rajurkar, Monali

    2016-01-01

    Background and Objective. Antimicrobial resistance is now a major challenge to clinicians for treating patients. Hence, this short term study was undertaken to detect the incidence of multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) bacterial isolates in a tertiary care hospital. Material and Methods. The clinical samples were cultured and bacterial strains were identified in the department of microbiology. The antibiotic susceptibility profile of different bacterial isolates was studied to detect MDR, XDR, and PDR bacteria. Results. The antibiotic susceptibility profile of 1060 bacterial strains was studied. 393 (37.1%) bacterial strains were MDR, 146 (13.8%) strains were XDR, and no PDR was isolated. All (100%) Gram negative bacterial strains were sensitive to colistin whereas all (100%) Gram positive bacterial strains were sensitive to vancomycin. Conclusion. Close monitoring of MDR, XDR, or even PDR must be done by all clinical microbiology laboratories to implement effective measures to reduce the menace of antimicrobial resistance. PMID:26942013

  3. Chromosome-Mediated Multidrug Resistance in Salmonella enterica Serovar Typhi

    PubMed Central

    Alam, Munirul; Kuo, Jung-Che; Liu, Yen-Yi; Wang, Pei-Jen

    2014-01-01

    A salmonella genomic island, designated SGI11, was found in 18 of 26 multidrug-resistant Salmonella enterica serovar Typhi isolates from Bangladesh. SGI11 was an IS1 composite transposon and carried 7 resistance genes that conferred resistance to 5 first-line antimicrobials. Eleven of the 18 SGI11-carrying S. Typhi isolates had developed resistance to high levels of ciprofloxacin. PMID:25367917

  4. [Should we screen for colonization to control the spread of multidrug resistant bacteria?].

    PubMed

    Lepelletier, D; Perron, S; Huguenin, H; Picard, M; Bemer, P; Caillon, J; Juvin, M-E; Drugeon, H

    2003-10-01

    Should we screen for colonization to control the spread of multidrug-resistant bacteria? A multidrug-resistant bacteria surveillance program was performed in 1999 at Laënnec Hospital (Nantes, France). After a 3-year period, the results permit us to determine the strategy to strengthen their spread. In 2001, Staphylococcus aureus resistant to methicillin represented 45% of the 202 multidrug-resistant bacteria isolated. The global incidence rate per 100 admissions remained stable between 1999 and 2001 (0.42%), but those of infections acquired in our institution decreased significantly from 0.27% in 1999 to 0.18% in 2001 (P < 0.05), particularly in medical care units (P < 0.04). In spite of this surveillance program and hygiene trainings, the global incidence remained stable during the study period, even if our action contributed to decrease the incidence of S. aureus resistant to methicillin acquired in our institution. Isolation precautions and screening for colonization policy in intensive care units are not sufficient to control the spread of MRB at hospital level. They should be strengthened by procedures for the transfer of infected or colonized patients and by antibiotic use control. PMID:14568591

  5. Vitamin E derivative-based multifunctional nanoemulsions for overcoming multidrug resistance in cancer.

    PubMed

    Zheng, Nannan; Gao, Yanan; Ji, Hongyu; Wu, Linhua; Qi, Xuejing; Liu, Xiaona; Tang, Jingling

    2016-08-01

    The multidrug resistance (MDR), including intrinsic and acquired multidrug resistance, is a major problem in tumor chemotherapy. Here, we proposed a strategy for modulating intrinsic and/or acquired multidrug resistance by altering the levels of Bax and Bcl-2 expression and inhibiting the transport function of P-gp, increasing the intracellular concentration of its substrate anticancer drugs. Vitamin E derivative-based nanoemulsions containing paclitaxel (MNEs-PTX) were fabricated in this study, and in vitro anticancer efficacy of the nanoemulsion system was evaluated in the paclitaxel-resistant human ovarian carcinoma cell line A2780/Taxol. The MNEs-PTX exhibited a remarkably enhanced antiproliferation effect on A2780/Taxol cells than free paclitaxel (PTX) (p < 0.01). Compared with that in the Taxol group, MNEs-PTX further decreased mitochondrial potential. Vitamin E derivative-based multifunctional nanoemulsion (MNEs) obviously increased intracellular accumulation of rhodamine 123 (P-gp substrate). Overexpression of Bcl-2 is generally associated with tumor drug resistance, we found that MNEs could reduce Bcl-2 protein level and increase Bax protein level. Taken together, our findings suggest that anticancer drugs associated with MNEs could play a role in the development of MDR in cancers. PMID:26710274

  6. Isolation of multidrug-resistant Salmonella in Singapore

    PubMed Central

    Phoon, Yee Wei; Chan, Yuen Yue Candice; Koh, Tze Hsien

    2015-01-01

    Multidrug-resistant Salmonella is a well-recognised problem worldwide, especially in developing countries such as India, where non-typhoidal Salmonella infections and enteric fever are endemic. Antimicrobial resistance, particularly to fluoroquinolones, is common and leads to the frequent use of alternative agents, such as azithromycin. We herein describe the first reported case of azithromycin-resistant Salmonella gastroenteritis in a Singaporean patient. PMID:26311915

  7. Multidrug Resistant Shigella flexneri Infection Simulating Intestinal Intussusception.

    PubMed

    Sreenivasan, Srirangaraj; Kali, Arunava; Pradeep, Jothimani

    2016-01-01

    Shigella enteritis remains an important cause of mortality and morbidity in all age groups, in developing as well as developed countries. Owing to the emerging resistance to multiple antibiotics among Shigella spp., it has been recognized as a major global public health concern and warrants constant monitoring of its resistance pattern. We report a case of segmental ileitis caused by non.-ESBL producing multidrug resistant Shigella flexneri in an infant clinically mimicking intussusception, which was effectively treated by ceftriaxone. PMID:27013815

  8. Multidrug Resistant Shigella flexneri Infection Simulating Intestinal Intussusception

    PubMed Central

    Sreenivasan, Srirangaraj; Kali, Arunava; Pradeep, Jothimani

    2016-01-01

    Shigella enteritis remains an important cause of mortality and morbidity in all age groups, in developing as well as developed countries. Owing to the emerging resistance to multiple antibiotics among Shigella spp., it has been recognized as a major global public health concern and warrants constant monitoring of its resistance pattern. We report a case of segmental ileitis caused by non.-ESBL producing multidrug resistant Shigella flexneri in an infant clinically mimicking intussusception, which was effectively treated by ceftriaxone. PMID:27013815

  9. Aquariums as Reservoirs for Multidrug-resistant Salmonella Paratyphi B

    PubMed Central

    Levings, Renee S.; Lightfoot, Diane; Hall, Ruth M.

    2006-01-01

    Multidrug-resistant Salmonella enterica serovar Paratyphi B dT+ isolates from patients with gastroenteritis were identical with isolates from their home aquariums. Matched isolates had identical phage types, XbaI and IS200 profiles, and Salmonella genomic island 1 (SGI1). Ornamental fish tanks are reservoirs for SGI1-containing S. Paratyphi B dT+. PMID:16704796

  10. Multidrug-Resistant Acinetobacter baumannii in Veterinary Clinics, Germany

    PubMed Central

    Prenger-Berninghoff, Ellen; Weiss, Reinhard; van der Reijden, Tanny; van den Broek, Peterhans; Baljer, Georg; Dijkshoorn, Lenie

    2011-01-01

    An increase in prevalence of multidrug-resistant Acinetobacter spp. in hospitalized animals was observed at the Justus-Liebig-University (Germany). Genotypic analysis of 56 isolates during 2000–2008 showed 3 clusters that corresponded to European clones I–III. Results indicate spread of genotypically related strains within and among veterinary clinics in Germany. PMID:21888812

  11. Risk Factors for Acquisition of Drug Resistance during Multidrug-Resistant Tuberculosis Treatment, Arkhangelsk Oblast, Russia, 2005–2010

    PubMed Central

    Ershova, Julia; Vlasova, Natalia; Nikishova, Elena; Tarasova, Irina; Eliseev, Platon; Maryandyshev, Andrey O.; Shemyakin, Igor G.; Kurbatova, Ekaterina; Cegielski, J. Peter

    2015-01-01

    Acquired resistance to antituberculosis drugs decreases effective treatment options and the likelihood of treatment success. We identified risk factors for acquisition of drug resistance during treatment for multidrug-resistant tuberculosis (MDR TB) and evaluated the effect on treatment outcomes. Data were collected prospectively from adults from Arkhangelsk Oblast, Russia, who had pulmonary MDR TB during 2005–2008. Acquisition of resistance to capreomycin and of extensively drug-resistant TB were more likely among patients who received <3 effective drugs than among patients who received >3 effective drugs (9.4% vs. 0% and 8.6% vs. 0.8%, respectively). Poor outcomes were more likely among patients with acquired capreomycin resistance (100% vs. 25.9%), acquired ofloxacin resistance (83.6% vs. 22.7%), or acquired extensive drug resistance (100% vs. 24.4%). To prevent acquired drug resistance and poor outcomes, baseline susceptibility to first- and second-line drugs should be determined quickly, and treatment should be adjusted to contain >3 effective drugs. PMID:25988954

  12. Combination Approaches to Combat Multi-Drug Resistant Bacteria

    PubMed Central

    Worthington, Roberta J.; Melander, Christian

    2013-01-01

    The increasing prevalence of infections caused by multi-drug resistant bacteria is a global health problem that is exacerbated by the dearth of novel classes of antibiotics entering the clinic over the past 40 years. Herein we describe recent developments toward combination therapies for the treatment of multi-drug resistant bacterial infections. These efforts include antibiotic-antibiotic combinations, and the development of adjuvants that either directly target resistance mechanisms such as the inhibition of β-lactamase enzymes, or indirectly target resistance by interfering with bacterial signaling pathways such as two-component systems. We also discuss screening of libraries of previously approved drugs to identify non-obvious antimicrobial adjuvants. PMID:23333434

  13. Acquired Antibiotic Resistance Genes: An Overview

    PubMed Central

    van Hoek, Angela H. A. M.; Mevius, Dik; Guerra, Beatriz; Mullany, Peter; Roberts, Adam Paul; Aarts, Henk J. M.

    2011-01-01

    In this review an overview is given on antibiotic resistance (AR) mechanisms with special attentions to the AR genes described so far preceded by a short introduction on the discovery and mode of action of the different classes of antibiotics. As this review is only dealing with acquired resistance, attention is also paid to mobile genetic elements such as plasmids, transposons, and integrons, which are associated with AR genes, and involved in the dispersal of antimicrobial determinants between different bacteria. PMID:22046172

  14. Acquired resistance to immunotherapy and future challenges.

    PubMed

    Restifo, Nicholas P; Smyth, Mark J; Snyder, Alexandra

    2016-02-01

    Advances in immunotherapy have resulted in remarkable clinical responses in some patients. However, one of the biggest challenges in cancer therapeutics is the development of resistant disease and disease progression on or after therapy. Given that many patients have now received various types of immunotherapy, we asked three scientists to give their views on the current evidence for whether acquired resistance to immunotherapy exists in patients and the future challenges posed by immunotherapy. PMID:26822578

  15. Modulation of Bacterial Multidrug Resistance Efflux Pumps of the Major Facilitator Superfamily

    PubMed Central

    Kumar, Sanath; Mukherjee, Mun Mun; Varela, Manuel F.

    2013-01-01

    Bacterial infections pose a serious public health concern, especially when an infectious disease has a multidrug resistant causative agent. Such multidrug resistant bacteria can compromise the clinical utility of major chemotherapeutic antimicrobial agents. Drug and multidrug resistant bacteria harbor several distinct molecular mechanisms for resistance. Bacterial antimicrobial agent efflux pumps represent a major mechanism of clinical resistance. The major facilitator superfamily (MFS) is one of the largest groups of solute transporters to date and includes a significant number of bacterial drug and multidrug efflux pumps. We review recent work on the modulation of multidrug efflux pumps, paying special attention to those transporters belonging primarily to the MFS. PMID:25750934

  16. Aminoglycoside Resistance: The Emergence of Acquired 16S Ribosomal RNA Methyltransferases.

    PubMed

    Doi, Yohei; Wachino, Jun-Ichi; Arakawa, Yoshichika

    2016-06-01

    Aminoglycoside-producing Actinobacteria are known to protect themselves from their own aminoglycoside metabolites by producing 16S ribosomal RNA methyltransferase (16S-RMTase), which prevents them from binding to the 16S rRNA targets. Ten acquired 16S-RMTases have been reported from gram-negative pathogens. Most of them posttranscriptionally methylate residue G1405 of 16S rRNA resulting in high-level resistance to gentamicin, tobramycin, amikacin, and plazomicin. Strains that produce 16S-RMTase are frequently multidrug-resistant or even extensively drug-resistant. Although the direct clinical impact of high-level aminoglycoside resistance resulting from production of 16S-RMTase is yet to be determined, ongoing spread of this mechanism will further limit treatment options for multidrug-resistant and extensively drug-resistant gram-negative infections. PMID:27208771

  17. Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant Enterobacter aerogenes

    PubMed Central

    Li, Erna; Wei, Xiao; Ma, Yanyan; Yin, Zhe; Li, Huan; Lin, Weishi; Wang, Xuesong; Li, Chao; Shen, Zhiqiang; Zhao, Ruixiang; Yang, Huiying; Jiang, Aimin; Yang, Wenhui; Yuan, Jing; Zhao, Xiangna

    2016-01-01

    Enterobacter aerogenes (Enterobacteriaceae) is an important opportunistic pathogen that causes hospital-acquired pneumonia, bacteremia, and urinary tract infections. Recently, multidrug-resistant E. aerogenes have been a public health problem. To develop an effective antimicrobial agent, bacteriophage phiEap-2 was isolated from sewage and its genome was sequenced because of its ability to lyse the multidrug-resistant clinical E. aerogenes strain 3-SP. Morphological observations suggested that the phage belongs to the Siphoviridae family. Comparative genome analysis revealed that phage phiEap-2 is related to the Salmonella phage FSL SP-031 (KC139518). All of the structural gene products (except capsid protein) encoded by phiEap-2 had orthologous gene products in FSL SP-031 and Serratia phage Eta (KC460990). Here, we report the complete genome sequence of phiEap-2 and major findings from the genomic analysis. Knowledge of this phage might be helpful for developing therapeutic strategies against E. aerogenes. PMID:27320081

  18. Isolation and characterization of a bacteriophage phiEap-2 infecting multidrug resistant Enterobacter aerogenes.

    PubMed

    Li, Erna; Wei, Xiao; Ma, Yanyan; Yin, Zhe; Li, Huan; Lin, Weishi; Wang, Xuesong; Li, Chao; Shen, Zhiqiang; Zhao, Ruixiang; Yang, Huiying; Jiang, Aimin; Yang, Wenhui; Yuan, Jing; Zhao, Xiangna

    2016-01-01

    Enterobacter aerogenes (Enterobacteriaceae) is an important opportunistic pathogen that causes hospital-acquired pneumonia, bacteremia, and urinary tract infections. Recently, multidrug-resistant E. aerogenes have been a public health problem. To develop an effective antimicrobial agent, bacteriophage phiEap-2 was isolated from sewage and its genome was sequenced because of its ability to lyse the multidrug-resistant clinical E. aerogenes strain 3-SP. Morphological observations suggested that the phage belongs to the Siphoviridae family. Comparative genome analysis revealed that phage phiEap-2 is related to the Salmonella phage FSL SP-031 (KC139518). All of the structural gene products (except capsid protein) encoded by phiEap-2 had orthologous gene products in FSL SP-031 and Serratia phage Eta (KC460990). Here, we report the complete genome sequence of phiEap-2 and major findings from the genomic analysis. Knowledge of this phage might be helpful for developing therapeutic strategies against E. aerogenes. PMID:27320081

  19. Multidrug-resistant tuberculosis that required 2 years for diagnosis.

    PubMed

    Yano, Shuichi; Kobayashi, Kanako; Ikeda, Toshikazu

    2012-01-01

    Isoniazid (H) or rifampicin (R) mono-resistant disease can be treated easily and effectively with first-line drugs, while combined H and R resistance (ie, multidrug-resistant tuberculosis (MDRTB)) requires treatment with at least four agents, including a quinolone and an injectable agent. Drug-resistant Mycobacterium tuberculosis strains are reported to be extremely difficult to cultivate invitro. The authors report a case of MDRTB that required 2 years for diagnosis, and was detected only in sputum culture on solid medium. Physicians should consider MDRTB if TB is suspected but pathogens are not detected. PMID:22605803

  20. Natural and acquired macrolide resistance in mycobacteria.

    PubMed

    Doucet-Populaire, F; Buriánková, K; Weiser, J; Pernodet, J-L

    2002-12-01

    The genus Mycobacterium contains two of the most important human pathogens, Mycobacterium tuberculosis and Mycobacterium leprae, the etiologic agents of tuberculosis and leprosy, respectively. Other mycobacteria are mostly saprophytic organisms, living in soil and water, but some of them can cause opportunistic infections. The increasing incidence of tuberculosis as well as infections with non-tuberculous mycobacteria (NTM) in AIDS patients has renewed interest in molecular mechanisms of drug resistance in these pathogens. Mycobacteria show a high degree of intrinsic resistance to most common antibiotics. For instance, species from the M. tuberculosis complex (MTC) are intrinsically resistant to macrolides. Nevertheless, some semi-synthetic macrolides as the erythromycin derivatives clarithromycin, azithromycin and most recently the ketolides, are active against NTM, particularly Mycobacterium avium, and some of them are widely used for infection treatment. However, shortly after the introduction of these new drugs, resistant strains appeared due to mutations in the macrolide target, the ribosome. The mycobacterial cell wall with its specific composition and structure is considered to be a major factor in promoting the natural resistance of mycobacteria to various antibiotics. However, to explain the difference in macrolide sensitivity between the MTC and NTM, the synergistic contribution of a specific resistance mechanism might be required, in addition to possible differences in cell wall permeability. This mini-review summarizes the current knowledge on the natural and acquired macrolide resistance in mycobacteria, gives an overview of potential mechanisms implicated in the intrinsic resistance and brings recent data concerning a macrolide resistance determinant in the MTC. PMID:12570741

  1. Identification of acquired antimicrobial resistance genes

    PubMed Central

    Zankari, Ea; Hasman, Henrik; Cosentino, Salvatore; Vestergaard, Martin; Rasmussen, Simon; Lund, Ole; Aarestrup, Frank M.; Larsen, Mette Voldby

    2012-01-01

    Objectives Identification of antimicrobial resistance genes is important for understanding the underlying mechanisms and the epidemiology of antimicrobial resistance. As the costs of whole-genome sequencing (WGS) continue to decline, it becomes increasingly available in routine diagnostic laboratories and is anticipated to substitute traditional methods for resistance gene identification. Thus, the current challenge is to extract the relevant information from the large amount of generated data. Methods We developed a web-based method, ResFinder that uses BLAST for identification of acquired antimicrobial resistance genes in whole-genome data. As input, the method can use both pre-assembled, complete or partial genomes, and short sequence reads from four different sequencing platforms. The method was evaluated on 1862 GenBank files containing 1411 different resistance genes, as well as on 23 de-novo-sequenced isolates. Results When testing the 1862 GenBank files, the method identified the resistance genes with an ID = 100% (100% identity) to the genes in ResFinder. Agreement between in silico predictions and phenotypic testing was found when the method was further tested on 23 isolates of five different bacterial species, with available phenotypes. Furthermore, ResFinder was evaluated on WGS chromosomes and plasmids of 30 isolates. Seven of these isolates were annotated to have antimicrobial resistance, and in all cases, annotations were compatible with the ResFinder results. Conclusions A web server providing a convenient way of identifying acquired antimicrobial resistance genes in completely sequenced isolates was created. ResFinder can be accessed at www.genomicepidemiology.org. ResFinder will continuously be updated as new resistance genes are identified. PMID:22782487

  2. Tetracycline resistance genes acquired at birth.

    PubMed

    Alicea-Serrano, Angela M; Contreras, Mónica; Magris, Magda; Hidalgo, Glida; Dominguez-Bello, Maria G

    2013-06-01

    Newborns acquire their first microbiota at birth. Maternal vaginal or skin bacteria colonize newborns delivered vaginally or by C-section, respectively (Dominguez-Bello et al. 2010 #884). We aimed to determine differences in the presence of four tetracycline (tet) resistance genes, in the microbes of ten newborns and in the mouth and vagina of their mothers, at the time of birth. DNA was amplified by PCR with primers specific for [tet(M), tet(O), tet(Q), and tet(W)]. Maternal vaginas harbored all four tet resistance genes, but most commonly tet(M) and tet(O) (63 and 38 %, respectively). Genes coding for tet resistance differed by birth mode, with 50 % of vaginally delivered babies had tet(M) and tet(O) and 16 and 13 % of infants born by C-section had tet(O) and tet(W), respectively. Newborns acquire antibiotic resistance genes at birth, and the resistance gene profile varies by mode of delivery. PMID:23483141

  3. Multidrug-resistant Salmonella Typhimurium in Four Animal Facilities

    PubMed Central

    Wright, Jennifer G.; Tengelsen, Leslie A.; Smith, Kirk E.; Bender, Jeff B.; Frank, Rodney K.; Grendon, John H.; Rice, Daniel H.; Thiessen, Ann Marie B.; Gilbertson, Catherine Jo; Sivapalasingam, Sumathi; Barrett, Timothy J.; Besser, Thomas E.; Hancock, Dale D.

    2005-01-01

    In 1999 and 2000, 3 state health departments reported 4 outbreaks of gastrointestinal illness due to Salmonella enterica serotype Typhimurium in employees, clients, and client animals from 3 companion animal veterinary clinics and 1 animal shelter. More than 45 persons and companion animals became ill. Four independent investigations resulted in the testing of 19 human samples and >200 animal samples; 18 persons and 36 animals were culture-positive for S. Typhimurium. One outbreak was due to multidrug-resistant S. Typhimurium R-type ACKSSuT, while the other 3 were due to multidrug-resistant S. Typhimurium R-type ACSSuT DT104. This report documents nosocomial transmission of S. Typhimurium and demonstrates that companion animal facilities may serve as foci of transmission for salmonellae between animals and humans if adequate precautions are not followed. PMID:16102313

  4. Pregnane glycoside multidrug-resistance modulators from Cynanchum wilfordii.

    PubMed

    Hwang, B Y; Kim, S E; Kim, Y H; Kim, H S; Hong, Y S; Ro, J S; Lee, K S; Lee, J J

    1999-04-01

    The methanol-soluble extracts of the roots of Cynanchum wilfordii showed a significant multidrug-resistance-reversing activity, and four known pregnane glycosides were isolated by bioassay-directed fractionation and separation. Their structures were identified as gagaminin 3-O-beta-D-cymaropyranosyl-(1-->4)-beta-D-oleandropyranosyl- (1-->4)-b eta-D-cymaropyranosyl-(1-->4)-beta-D-cymaropyranoside (1), wilfoside K1N (2), wilfoside C1N (3), and cynauricuoside A (4). In particular, compound 1, at a concentration level of 1 microM, was found to completely reverse the multidrug-resistance of KB-V1 and MCF7/ADR cells to adriamycin, vinblastine, and colchicine. PMID:10217732

  5. Multidrug-resistant Fusarium keratitis: diagnosis and treatment considerations.

    PubMed

    Sara, Sergio; Sharpe, Kendall; Morris, Sharon

    2016-01-01

    Mycotic keratitis is an ocular infective process derived from any fungal species capable of corneal invasion. Despite its rarity in developed countries, its challenging and elusive diagnosis may result in keratoplasty or enucleation following failed medical management. Filamentous fungi such as Fusarium are often implicated in mycotic keratitis. Bearing greater morbidity than its bacterial counterpart, mycotic keratitis requires early clinical suspicion and initiation of antifungal therapy to prevent devastating consequences. We describe a case of multidrug-resistant mycotic keratitis in a 46-year-old man who continued to decline despite maximal therapy and therapeutic keratoplasty. Finally, enucleation was performed as a means of source control preventing dissemination of a likely untreatable fungal infection into the orbit. Multidrug-resistant Fusarium is rare, and may progress to endophthalmitis. We discuss potential management options which may enhance diagnosis and outcome in this condition. PMID:27489066

  6. Multidrug-resistant tuberculosis treatment with linezolid-containing regimen

    PubMed Central

    Farshidpour, Maham; Ebrahimi, Golnaz; Mirsaeidi, Mehdi

    2014-01-01

    The following is a case of multidrug-resistant pulmonary tuberculosis (MDR-TB) that was treated successfully with a linezolid-containing regimen. It was found that linezolid is an efficient medicine for MDR-TB treatment with an acceptable side effect profile. Treatment was maintained for 18 months, and closely monitoring toxicities did not reveal evidence of any neurologic adverse effects. However, despite our expectation, thrombocytopenia was seen after 2 years follow-up. PMID:25110635

  7. Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients

    PubMed Central

    Göhring, Katharina; Hamprecht, Klaus; Jahn, Gerhard

    2015-01-01

    In pediatric and adult patients after stem cell transplantation (SCT) disseminated infections caused by human cytomegalovirus (HCMV) can cause life threatening diseases. For treatment, the three antivirals ganciclovir (GCV), foscarnet (PFA) and cidofovir (CDV) are approved and most frequently used. Resistance to all of these antiviral drugs may induce a severe problem in this patient cohort. Responsible for resistance phenomena are mutations in the HCMV phosphotransferase-gene (UL97) and the polymerase-gene (UL54). Most frequently mutations in the UL97-gene are associated with resistance to GCV. Resistance against all three drugs is associated to mutations in the UL54-gene. Monitoring of drug resistance by genotyping is mostly done by PCR-based Sanger sequencing. For phenotyping with cell culture the isolation of HCMV is a prerequisite. The development of multidrug resistance with mutation in both genes is rare, but it is often associated with a fatal outcome. The manifestation of multidrug resistance is mostly associated with combined UL97/UL54-mutations. Normally, mutations in the UL97 gene occur initially followed by UL54 mutation after therapy switch. The appearance of UL54-mutation alone without any detection of UL97-mutation is rare. Interestingly, in a number of patients the UL97 mutation could be detected in specific compartments exclusively and not in blood. PMID:25750703

  8. Draft Genome Sequence of Neisseria gonorrhoeae Sequence Type 1407, a Multidrug-Resistant Clinical Isolate.

    PubMed

    Anselmo, A; Ciammaruconi, A; Carannante, A; Neri, A; Fazio, C; Fortunato, A; Palozzi, A M; Vacca, P; Fillo, S; Lista, F; Stefanelli, P

    2015-01-01

    Gonorrhea may become untreatable due to the spread of resistant or multidrug-resistant strains. Cefixime-resistant gonococci belonging to sequence type 1407 have been described worldwide. We report the genome sequence of Neisseria gonorrhoeae strain G2891, a multidrug-resistant isolate of sequence type 1407, collected in Italy in 2013. PMID:26272575

  9. Importance of multidrug efflux pumps in the antimicrobial resistance property of clinical multidrug-resistant isolates of Neisseria gonorrhoeae.

    PubMed

    Golparian, Daniel; Shafer, William M; Ohnishi, Makoto; Unemo, Magnus

    2014-06-01

    The contribution of drug efflux pumps in clinical isolates of Neisseria gonorrhoeae that express extensively drug-resistant or multidrug-resistant phenotypes has heretofore not been examined. Accordingly, we assessed the effect on antimicrobial resistance of loss of the three gonococcal efflux pumps associated with a known capacity to export antimicrobials (MtrC-MtrD-MtrE, MacA-MacB, and NorM) in such clinical isolates. We report that the MIC of several antimicrobials, including seven previously and currently recommended for treatment was significantly impacted. PMID:24733458

  10. Structural basis and dynamics of multidrug recognition in a minimal bacterial multidrug resistance system

    PubMed Central

    Habazettl, Judith; Allan, Martin; Jensen, Pernille Rose; Sass, Hans-Jürgen; Thompson, Charles J.; Grzesiek, Stephan

    2014-01-01

    TipA is a transcriptional regulator found in diverse bacteria. It constitutes a minimal autoregulated multidrug resistance system against numerous thiopeptide antibiotics. Here we report the structures of its drug-binding domain TipAS in complexes with promothiocin A and nosiheptide, and a model of the thiostrepton complex. Drug binding induces a large transition from a partially unfolded to a globin-like structure. The structures rationalize the mechanism of promiscuous, yet specific, drug recognition: (i) a four-ring motif present in all known TipA-inducing antibiotics is recognized specifically by conserved TipAS amino acids; and (ii) the variable part of the antibiotic is accommodated within a flexible cleft that rigidifies upon drug binding. Remarkably, the identified four-ring motif is also the major interacting part of the antibiotic with the ribosome. Hence the TipA multidrug resistance mechanism is directed against the same chemical motif that inhibits protein synthesis. The observed identity of chemical motifs responsible for antibiotic function and resistance may be a general principle and could help to better define new leads for antibiotics. PMID:25489067

  11. Draft Genome Sequences of Two Multidrug Resistant Klebsiella pneumoniae ST258 Isolates Resistant to Colistin

    PubMed Central

    Comandatore, Francesco; Sassera, Davide; Ambretti, Simone; Landini, Maria Paola; Daffonchio, Daniele; Marone, Piero; Sambri, Vittorio; Bandi, Claudio

    2013-01-01

    Sequence type 258 (ST258) is the most widespread multidrug resistant (MDR) Klebsiella pneumoniae strain worldwide. Here, we report the draft genome sequences of two colistin-resistant MDR K. pneumoniae ST258 clinical strains isolated from hospital patients in Italy. These strains are resistant to β-lactams, cephalosporins, fluoroquinolones, aminoglycosides, macrolides, tetracyclines, carbapenems, and colistin. PMID:23405348

  12. Environmental contamination by multidrug-resistant microorganisms after daily cleaning.

    PubMed

    Gavaldà, Laura; Pequeño, Sandra; Soriano, Ana; Dominguez, M Angeles

    2015-07-01

    We analyzed 91 samples of high-touch surfaces obtained within the first hour after daily cleaning in intensive care unit rooms occupied with patients with multidrug-resistant organisms (MDROs). We determined that 22% of high-touch surfaces in rooms with methicillin-resistant Staphylococcus aureus patients and 5% of high-touch surfaces in rooms with multiresistant Pseudomonas aeruginosa patients were colonized with the same strain as the patient. We postulated that textile cleaning wipes could be contaminated with MDROs and may contribute to its spreading within the room. PMID:25907783

  13. Multidrug-Resistant Bacteria in the Community: Trends and Lessons Learned.

    PubMed

    van Duin, David; Paterson, David L

    2016-06-01

    Multidrug resistant (MDR) bacteria are one of the most important threats to public health. Typically, MDR bacteria are associated with nosocomial infections. However, some MDR bacteria have become prevalent causes of community-acquired infections. The spread of MDR bacteria into the community is a crucial development, and is associated with increased morbidity, mortality, health care costs, and antibiotic use. Factors associated with community dissemination of MDR bacteria overlap but are distinct from those associated with nosocomial spread. Prevention of further community spread of MDR bacteria is of the utmost importance, and requires a multidisciplinary approach involving all stakeholders. PMID:27208764

  14. Multidrug-resistant bacteria in hematology patients: emerging threats.

    PubMed

    Tatarelli, Paola; Mikulska, Malgorzata

    2016-06-01

    Multidrug-resistant (MDR) bacteria, particularly Gram negatives, such as Enterobacteriaceae resistant to third-generation cephalosporins or carbapenems and MDR Pseudomonas aeruginosa, are increasingly frequent in hematology patients. The prevalence of different resistant species varies significantly between centers. Thus, the knowledge of local epidemiology is mandatory for deciding the most appr-opriate management protocols. In the era of increasing antibiotic resistance, empirical therapy of febrile neutropenia should be individualized. A de-escalation approach is recommended in case of severe clinical presentation in patients who are at high risk for infection with a resistant strain. Targeted therapy of an MDR Gram negative usually calls for a combination treatment, although no large randomized trials exist in this setting. Infection control measures are the cornerstone of limiting the spread of MDR pathogens in hematology units. PMID:27196948

  15. Antisense RNA regulation and application in the development of novel antibiotics to combat multidrug resistant bacteria.

    PubMed

    Ji, Yinduo; Lei, Ting

    2013-01-01

    Despite the availability of antibiotics and vaccines, infectious diseases remain one of most dangerous threats to humans and animals. The overuse and misuse of antibacterial agents have led to the emergence of multidrug resistant bacterial pathogens. Bacterial cells are often resilient enough to survive in even the most extreme environments. To do so, the organisms have evolved different mechanisms, including a variety of two-component signal transduction systems, which allow the bacteria to sense the surrounding environment and regulate gene expression in order to adapt and respond to environmental stimuli. In addition, some bacteria evolve resistance to antibacterial agents while many bacterial cells are able to acquire resistance genes from other bacterial species to enable them to survive in the presence of toxic antimicrobial agents. The crisis of antimicrobial resistance is an unremitting menace to human health and a burden on public health. The rapid increase in antimicrobial resistant organisms and limited options for development of new classes of antibiotics heighten the urgent need to develop novel potent antibacterial therapeutics in order to combat multidrug resistant infections. In this review, we introduce the regulatory mechanisms of antisense RNA and significant applications of regulated antisense RNA interference technology in early drug discovery. This includes the identification and evaluation of drug targets in vitro and in vivo, the determination of mode of action for antibiotics and new antibacterial agents, as well as the development of peptide-nucleic acid conjugates as novel antibacterials. PMID:23738437

  16. Probable Levofloxacin-associated Secondary Intracranial Hypertension in a Child With Multidrug-resistant Tuberculosis.

    PubMed

    van der Laan, Louvina E; Schaaf, H Simon; Solomons, Regan; Willemse, Marianne; Mohamed, Nabil; Baboolal, Sandika O; Hesseling, Anneke C; van Toorn, Ronald; Garcia-Prats, Anthony J

    2016-06-01

    Fluoroquinolones are a key component of multidrug-resistant tuberculosis treatment. We describe the first reported case of probable levofloxacin-associated intracranial hypertension in a 6-year-old girl with pulmonary multidrug-resistant tuberculosis. The case highlights the potential risk of secondary intracranial hypertension in multidrug-resistant tuberculosis patients who require prolonged fluoroquinolone therapy and the need for ophthalmologic screening in children with suggestive signs and symptoms. PMID:26974890

  17. Signal regulators of systemic acquired resistance

    PubMed Central

    Gao, Qing-Ming; Zhu, Shifeng; Kachroo, Pradeep; Kachroo, Aardra

    2015-01-01

    Salicylic acid (SA) is an important phytohormone that plays a vital role in a number of physiological responses, including plant defense. The last two decades have witnessed a number of breakthroughs related to biosynthesis, transport, perception and signaling mediated by SA. These findings demonstrate that SA plays a crictical role in both local and systemic defense responses. Systemic acquired resistance (SAR) is one such SA-dependent response. SAR is a long distance signaling mechanism that provides broad spectrum and long-lasting resistance to secondary infections throughout the plant. This unique feature makes SAR a highly desirable trait in crop production. This review summarizes the recent advances in the role of SA in SAR and discusses its relationship to other SAR inducers. PMID:25918514

  18. Multidrug-Resistant Shigella Infections in Patients with Diarrhea, Cambodia, 2014–2015

    PubMed Central

    Poramathikul, Kamonporn; Chiek, Sivhour; Oransathid, Wilawan; Ruekit, Sirigade; Nobthai, Panida; Lurchachaiwong, Woradee; Serichantalergs, Oralak; Lon, Chanthap; Swierczewski, Brett

    2016-01-01

    We observed multidrug resistance in 10 (91%) of 11 Shigella isolates from a diarrheal surveillance study in Cambodia. One isolate was resistant to fluoroquinolones and cephalosporins and showed decreased susceptibility to azithromycin. We found mutations in gyrA, parC, β-lactamase, and mphA genes. Multidrug resistance increases concern about shigellosis treatment options. PMID:27532684

  19. Multidrug-Resistant Shigella Infections in Patients with Diarrhea, Cambodia, 2014-2015.

    PubMed

    Poramathikul, Kamonporn; Bodhidatta, Ladaporn; Chiek, Sivhour; Oransathid, Wilawan; Ruekit, Sirigade; Nobthai, Panida; Lurchachaiwong, Woradee; Serichantalergs, Oralak; Lon, Chanthap; Swierczewski, Brett

    2016-09-01

    We observed multidrug resistance in 10 (91%) of 11 Shigella isolates from a diarrheal surveillance study in Cambodia. One isolate was resistant to fluoroquinolones and cephalosporins and showed decreased susceptibility to azithromycin. We found mutations in gyrA, parC, β-lactamase, and mphA genes. Multidrug resistance increases concern about shigellosis treatment options. PMID:27532684

  20. Overcoming Multidrug Resistance in Cancer Stem Cells

    PubMed Central

    Moitra, Karobi

    2015-01-01

    The principle mechanism of protection of stem cells is through the expression of ATP-binding cassette (ABC) transporters. These transporters serve as the guardians of the stem cell population in the body. Unfortunately these very same ABC efflux pumps afford protection to cancer stem cells in tumors, shielding them from the adverse effects of chemotherapy. A number of strategies to circumvent the function of these transporters in cancer stem cells are currently under investigation. These strategies include the development of competitive and allosteric modulators, nanoparticle mediated delivery of inhibitors, targeted transcriptional regulation of ABC transporters, miRNA mediated inhibition, and targeting of signaling pathways that modulate ABC transporters. The role of ABC transporters in cancer stem cells will be explored in this paper and strategies aimed at overcoming drug resistance caused by these particular transporters will also be discussed. PMID:26649310

  1. Chinese hamster pleiotropic multidrug-resistant cells are not radioresistant

    SciTech Connect

    Mitchell, J.B.; Gamson, J.; Russo, A.; Friedman, N.; DeGraff, W.; Carmichael, J.; Glatstein, E.

    1988-01-01

    The inherent cellular radiosensitivity of a Chinese hamster ovary pleiotropic cell line that is multidrug resistant (CHRC5) was compared to that of its parental cell line (AuxB1). Radiation survival curve parameters n and D0 were 4.5 and 1.1 Gy, respectively, for the CHRC5 line and 5.0 and 1.2 Gy, respectively, for the parental line. Thus, the inherent radiosensitivity of the two lines was similar even though key intracellular free radical scavenging and detoxifying systems employing glutathione, glutathione transferase, and catalase produced enzyme levels that were 2.0-, 1.9-, and 1.9-fold higher, respectively, in the drug-resistant cell line. Glutathione depletion by buthionine sulfoximine resulted in the same extent of aerobic radiosensitization in both lines (approximately 10%). Incorporation of iododeoxyuridine into cellular DNA sensitized both cell lines to radiation. These studies indicate that pleiotropic drug resistance does not necessarily confer radiation resistance.

  2. Photoexcited quantum dots for killing multidrug-resistant bacteria

    NASA Astrophysics Data System (ADS)

    Courtney, Colleen M.; Goodman, Samuel M.; McDaniel, Jessica A.; Madinger, Nancy E.; Chatterjee, Anushree; Nagpal, Prashant

    2016-05-01

    Multidrug-resistant bacterial infections are an ever-growing threat because of the shrinking arsenal of efficacious antibiotics. Metal nanoparticles can induce cell death, yet the toxicity effect is typically nonspecific. Here, we show that photoexcited quantum dots (QDs) can kill a wide range of multidrug-resistant bacterial clinical isolates, including methicillin-resistant Staphylococcus aureus, carbapenem-resistant Escherichia coli, and extended-spectrum β-lactamase-producing Klebsiella pneumoniae and Salmonella typhimurium. The killing effect is independent of material and controlled by the redox potentials of the photogenerated charge carriers, which selectively alter the cellular redox state. We also show that the QDs can be tailored to kill 92% of bacterial cells in a monoculture, and in a co-culture of E. coli and HEK 293T cells, while leaving the mammalian cells intact, or to increase bacterial proliferation. Photoexcited QDs could be used in the study of the effect of redox states on living systems, and lead to clinical phototherapy for the treatment of infections.

  3. Endemic carbapenem-resistant Pseudomonas aeruginosa with acquired metallo-beta-lactamase determinants in European hospital.

    PubMed

    Lagatolla, Cristina; Tonin, Enrico A; Monti-Bragadin, Carlo; Dolzani, Lucilla; Gombac, Francesca; Bearzi, Claudia; Edalucci, Elisabetta; Gionechetti, Fabrizia; Rossolini, Gian Maria

    2004-03-01

    Acquired metallo-beta-lactamases (MBLs) can confer broad-spectrum beta-lactam resistance (including carbapenems) not reversible by conventional beta-lactamase inhibitors and are emerging resistance determinants of remarkable clinical importance. In 2001, multidrug-resistant Pseudomonas aeruginosa carrying bla(VIM) MBL genes were found to be widespread (approximately 20% of all P. aeruginosa isolates and 70% of the carbapenem-resistant isolates) at Trieste University Hospital. Clonal diversity and heterogeneity of resistance determinants (either bla(VIM-1)-like or bla(VIM-2)-like) were detected among MBL producers. This evidence is the first that acquired MBLs can rapidly emerge and establish a condition of endemicity in certain epidemiologic settings. PMID:15109432

  4. Prevalence of Multidrug Resistant Pulmonary Tuberculosis in North Bihar

    PubMed Central

    Kumar, Rajesh; Singh, Surya Deo

    2015-01-01

    Introduction Multidrug resistant tuberculosis (MDR-TB) is caused by Infection with Mycobacterium tuberculosis which is resistant to both isoniazid (INH) and rifampicin (RIF), with or without any other anti tubercular drug. It is caused by resistant mutant strains due to inadequate treatment and poor compliance. Due to time taking conventional diagnostic methods, drug resistant strains continue to spread. Therefore rapid diagnosis and treatment of MDR-TB strains are prerequisites for the worldwide fight against TB. Objective To determine the prevalence of MDR TB in North Bihar by molecular diagnostic method and to facilitate early diagnosis and treatment. Also, to find out the number of those diagnosed cases who were successfully initiated the treatment in MDR TB Centre of DMCH. Materials and Methods This six month observational study was carried out in IRL Darbhanga, Damien TB research Centre of the Darbhanga Medical College and Hospital, Bihar, India. During the period of February-July 2014, 256 sputum samples were collected from suspected cases of multidrug resistant tuberculosis, from 6 districts of North Bihar around Darbhanga. These samples were subjected to routine microscopy and culture to detect Mycobacterium tuberculosis. Positive cases were subjected to drug sensitivity test by a molecular diagnostic method, Using Genotype MTBDR plus kit. Result Out of 256 sputum samples from suspected cases of MDR TB, 122 cases were microscopy positive for tuberculosis. Among these 122 cases, tuberculosis was confirmed by PCR in 114 cases. Finally with the help of Line Probe Assay (LPA), 39(15%) samples were found to have resistance to both INH and Rifampicin. Male female ratio was 4:1. Conclusion The Prevalence of Multi drug resistant pulmonary tuberculosis in North Bihar is 15%. It needs early diagnosis by molecular diagnostic method and prompt treatment to reduce the spread of MDR TB cases. PMID:26674711

  5. Multidrug-Resistant Tuberculosis in Europe, 2010–2011

    PubMed Central

    Günther, Gunar; van Leth, Frank; Alexandru, Sofia; Altet, Neus; Avsar, Korkut; Bang, Didi; Barbuta, Raisa; Bothamley, Graham; Ciobanu, Ana; Crudu, Valeriu; Davilovits, Manfred; Dedicoat, Martin; Duarte, Raquel; Gualano, Gina; Kunst, Heinke; de Lange, Wiel; Leimane, Vaira; Magis-Escurra, Cecile; McLaughlin, Anne-Marie; Muylle, Inge; Polcová, Veronika; Pontali, Emanuele; Popa, Christina; Rumetshofer, Rudolf; Skrahina, Alena; Solodovnikova, Varvara; Spinu, Victor; Tiberi, Simon; Viiklepp, Piret

    2015-01-01

    Drug-resistant Mycobacterium tuberculosis is challenging elimination of tuberculosis (TB). We evaluated risk factors for TB and levels of second-line drug resistance in M. tuberculosis in patients in Europe with multidrug-resistant (MDR) TB. A total of 380 patients with MDR TB and 376 patients with non–MDR TB were enrolled at 23 centers in 16 countries in Europe during 2010–2011. A total of 52.4% of MDR TB patients had never been treated for TB, which suggests primary transmission of MDR M. tuberculosis. At initiation of treatment for MDR TB, 59.7% of M. tuberculosis strains tested were resistant to pyrazinamide, 51.1% were resistant to ≥1 second-line drug, 26.6% were resistant to second-line injectable drugs, 17.6% were resistant to fluoroquinolones, and 6.8% were extensively drug resistant. Previous treatment for TB was the strongest risk factor for MDR TB. High levels of primary transmission and advanced resistance to second-line drugs characterize MDR TB cases in Europe. PMID:25693485

  6. [Multidrug-resistant tuberculosis: current epidemiology, therapeutic regimens, new drugs].

    PubMed

    Gómez-Ayerbe, C; Vivancos, M J; Moreno, S

    2016-09-01

    Multidrug and extensively resistant tuberculosis are especially severe forms of the disease for which no efficacious therapy exists in many cases. All the countries in the world have registered cases, although most of them are diagnosed in resource-limited countries from Asia, Africa and South America. For adequate treatment, first- and second-line antituberculosis drugs have to be judiciously used, but the development of new drugs with full activity, good tolerability and little toxicity is urgently needed. There are some drugs in development, some of which are already available through expanded-access programs. PMID:27608311

  7. Vaccine Approaches for Multidrug Resistant Gram negative infections

    PubMed Central

    Campfield, Brian; Chen, Kong; Kolls, Jay K.

    2014-01-01

    Multidrug resistant (MDR) Gram negative bacterial infections are increasing in frequency and are associated with significant financial costs, morbidity and mortality. Current antibiotic therapies are associated with unacceptably poor clinical outcomes and toxicity. Unfortunately, the development of novel antimicrobials is stagnant leaving a significant clinical need for alternative treatments of MDR Gram negative rod infections. Recent preclinical studies have identified Th17 cells as critical mediators of broadly protective adaptive immunity, including protection against MDR infections. Studies of Th17 eliciting antigens, adjuvants and routes of immunization have identified potential vaccine strategies that may confer long-lived adaptive immunity against MDR Gram negative bacterial infections. PMID:24637162

  8. Multidrug-resistant tuberculosis in prison inmates, Azerbaijan.

    PubMed Central

    Pfyffer, G. E.; Strässle, A.; van Gorkum, T.; Portaels, F.; Rigouts, L.; Mathieu, C.; Mirzoyev, F.; Traore, H.; van Embden, J. D.

    2001-01-01

    In a tuberculosis (TB) program in the Central Penitentiary Hospital of Azerbaijan, we analyzed 65 isolates of Mycobacterium tuberculosis by IS6110-based restriction fragment-length polymorphism (RFLP) and spoligotyping. From 11 clusters associated with 33 patients, 31 isolates had an IS6110-based banding pattern characteristic of the Beijing genotype of M. tuberculosis. In addition, 15 M. tuberculosis isolates with similar RFLP patterns constituted a single group by spoligotyping, matching the Beijing genotype. Multidrug resistance, always involving isoniazid and rifampin, was seen in 34 (52.3%) of 65 isolates, with 28 belonging to the Beijing genotype. PMID:11747699

  9. Treatment for patients with multidrug resistant Acinetobacter baumannii pulmonary infection

    PubMed Central

    PAN, TAO; LIU, XIAOYUN; XIANG, SHOUGUI; JI, WENLI

    2016-01-01

    Bacterial infections are common but have become increasingly resistant to drugs. The aim of the present study was to examine the combined treatment of traditional Chinese and Western medicine in 30 cases of pulmonary infection with multidrug resistant Acinetobacter baumannii. Patients were divided into groups A and B according to drug treatments. Cefoperazone or sulbactam and tanreqing were administered in group A, and cefoperazone or sulbactam in group B. The curative effect and prognosis of the two groups were recorded and the remaining treatments were performed routinely in the clinic. For the combined therapy group, which was administered sulperazone and tanreqing, 8 patients were recovered, 6 patients had significant effects, 3 patients exhibited some improvement and 1 patient had no response. One of the patients did not survive after 28 days. By contrast, there were 4 patients that were successfully treated, 3 patients with significant effects, 2 patients with some improvement and 2 patients had no response in the sulperazone group, and 4 patients did not survive after 28 days. In conclusion, the combined therapy of cefoperazone or sulbactam supplemented with tanreqing was identified to be more effective than cefoperazone or sulbactam as monotherapy, for treating multidrug resistant Acinetobacter baumannii. PMID:27073447

  10. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections

    PubMed Central

    Thangamani, Shankar; Younis, Waleed; Seleem, Mohamed N.

    2015-01-01

    Novel antimicrobials and new approaches to developing them are urgently needed. Repurposing already-approved drugs with well-characterized toxicology and pharmacology is a novel way to reduce the time, cost, and risk associated with antibiotic innovation. Ebselen, an organoselenium compound, is known to be clinically safe and has a well-known pharmacology profile. It has shown potent bactericidal activity against multidrug-resistant clinical isolates of staphylococcus aureus, including methicillin- and vancomycin-resistant S. aureus (MRSA and VRSA). We demonstrated that ebselen acts through inhibition of protein synthesis and subsequently inhibited toxin production in MRSA. Additionally, ebselen was remarkably active and significantly reduced established staphylococcal biofilms. The therapeutic efficacy of ebselen was evaluated in a mouse model of staphylococcal skin infections. Ebselen 1% and 2% significantly reduced the bacterial load and the levels of the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and monocyte chemo attractant protein-1 (MCP-1) in MRSA USA300 skin lesions. Furthermore, it acts synergistically with traditional antimicrobials. This study provides evidence that ebselen has great potential for topical treatment of MRSA skin infections and lays the foundation for further analysis and development of ebselen as a potential treatment for multidrug-resistant staphylococcal infections. PMID:26111644

  11. Breaking the Spell: Combating Multidrug Resistant ‘Superbugs’

    PubMed Central

    Khan, Shahper N.; Khan, Asad U.

    2016-01-01

    Multidrug-resistant (MDR) bacteria have become a severe threat to community wellbeing. Conventional antibiotics are getting progressively more ineffective as a consequence of resistance, making it imperative to realize improved antimicrobial options. In this review we emphasized the microorganisms primarily reported of being resistance, referred as ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa, and Enterobacteriaceae) accentuating their capacity to “escape” from routine antimicrobial regimes. The upcoming antimicrobial agents showing great potential and can serve as alternative therapeutic options are discussed. We also provided succinct overview of two evolving technologies; specifically network pharmacology and functional genomics profiling. Furthermore, In vivo imaging techniques can provide novel targets and a real time tool for potential lead molecule assessment. The employment of such approaches at prelude of a drug development process, will enables more informed decisions on candidate drug selection and will maximize or predict therapeutic potential before clinical testing. PMID:26925046

  12. Multidrug-resistant tuberculosis in the United Kingdom and Lithuania.

    PubMed

    Gonzalo, X; Hutchison, D C S; Drobniewski, F A; Pimkina, E; Davidaviciene, E

    2014-06-01

    Rates of resistance to first- and second-line drugs in multidrug-resistant tuberculosis (MDR-TB) cases in the United Kingdom were studied during 2010-2012. The highest rates for ethambutol, pyrazinamide and aminoglycosides occurred among patients originating in Eastern Europe, of whom 47% were Lithuanian. Rates of resistance to kanamycin were significantly lower (P < 0.0001) in the Lithuanian National TB Register than among Lithuanian patients resident in the United Kingdom (5% vs. 78%). In 2010, the majority of UK patients of Eastern European origin were located within the London region, whereas in 2011 the majority were located outside this region, a significant change (P = 0.01). PMID:24903935

  13. Nanodrug delivery in reversing multidrug resistance in cancer cells.

    PubMed

    Kapse-Mistry, Sonali; Govender, Thirumala; Srivastava, Rohit; Yergeri, Mayur

    2014-01-01

    Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. "Theragnostics" combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome MDR in

  14. Nanodrug delivery in reversing multidrug resistance in cancer cells

    PubMed Central

    Kapse-Mistry, Sonali; Govender, Thirumala; Srivastava, Rohit; Yergeri, Mayur

    2014-01-01

    Different mechanisms in cancer cells become resistant to one or more chemotherapeutics is known as multidrug resistance (MDR) which hinders chemotherapy efficacy. Potential factors for MDR includes enhanced drug detoxification, decreased drug uptake, increased intracellular nucleophiles levels, enhanced repair of drug induced DNA damage, overexpression of drug transporter such as P-glycoprotein(P-gp), multidrug resistance-associated proteins (MRP1, MRP2), and breast cancer resistance protein (BCRP). Currently nanoassemblies such as polymeric/solid lipid/inorganic/metal nanoparticles, quantum dots, dendrimers, liposomes, micelles has emerged as an innovative, effective, and promising platforms for treatment of drug resistant cancer cells. Nanocarriers have potential to improve drug therapeutic index, ability for multifunctionality, divert ABC-transporter mediated drug efflux mechanism and selective targeting to tumor cells, cancer stem cells, tumor initiating cells, or cancer microenvironment. Selective nanocarrier targeting to tumor overcomes dose-limiting side effects, lack of selectivity, tissue toxicity, limited drug access to tumor tissues, high drug doses, and emergence of multiple drug resistance with conventional or combination chemotherapy. Current review highlights various nanodrug delivery systems to overcome mechanism of MDR by neutralizing, evading, or exploiting the drug efflux pumps and those independent of drug efflux pump mechanism by silencing Bcl-2 and HIF1α gene expressions by siRNA and miRNA, modulating ceramide levels and targeting NF-κB. “Theragnostics” combining a cytotoxic agent, targeting moiety, chemosensitizing agent, and diagnostic imaging aid are highlighted as effective and innovative systems for tumor localization and overcoming MDR. Physical approaches such as combination of drug with thermal/ultrasound/photodynamic therapies to overcome MDR are focused. The review focuses on newer drug delivery systems developed to overcome

  15. Multiwavelength videomicrofluorometry for multiparametric investigations of multidrug resistance

    NASA Astrophysics Data System (ADS)

    Rocchi, Emmanuelle; Salmon, Jean-Marie; Vigo, Jean; Viallet, Pierre M.

    1996-05-01

    A major problem in the cancer chemotherapy is the development of resistance to a whole range of drugs not only similar to the drugs used for resistance induction but also to some functionally and structurally unrelated. It's one of the multifactorial causes of failure of chemotherapy. Thus it appears essential to evaluate the multi-drug resistance (MDR) in living cells populations to: detect the MDR phenotype, to discriminate between resistant and sensitive cells, to identify mechanisms which are involved in the induction or the reversion of resistance and to study the cytotoxic process. Such a challenge implies the use of multiparametric approach that has been possible using a protocol involving microfluorometry connected to numerical image analysis on single living cells. This protocol relays on the correlation existing between the decreased intracellular accumulation of some fluorescent probes such as Hoechst 33342 (Ho342) and Rhodamine 123 (R123) in resistant cells. The simultaneous estimation of the fluorescence intensities of these probes has required the use of a third probe, the Nile Red, for cell contour delineation. The analysis of parameters related to Ho342 and R123 allows the discrimination of sensitive and resistant cells. So the multiparametric approach using multi-wavelength image analysis, which appears to be a powerful technique, has allowed us to show on human lymphoblastoid CCRF-CEM cells lines that the cytotoxic effects could be different depending on the cell resistance or on the cytotoxic drug used: Adriamycine, Vinblastine and the different cell behavior could be used for cell differentiation.

  16. Multidrug resistance ABC transporter structure predictions by homology modeling approaches.

    PubMed

    Honorat, Mylène; Falson, Pierre; Terreux, Raphael; Di Pietro, Attilio; Dumontet, Charles; Payen, Léa

    2011-03-01

    Human multidrug resistance ABC transporters are ubiquitous membrane proteins responsible for the efflux of multiple, endogenous or exogenous, compounds out of the cells, and therefore they are involved in multi-drug resistance phenotype (MDR). They thus deeply impact the pharmacokinetic parameters and toxicity properties of drugs. A great pressure to develop inhibitors of these pumps is carried out, by either ligand-based drug design or (more ideally) structure-based drug design. In that goal, many biochemical studies have been carried out to characterize their transport functions, and many efforts have been spent to get high-resolution structures. Currently, beside the 3D-structures of bacterial ABC transporters Sav1866 and MsbA, only the mouse ABCB1 complete structure has been published at high-resolution, illustrating the tremendous difficulty in getting such information, taking into account that the human genome accounts for 48 ABC transporters encoding genes. Homology modeling is consequently a reasonable approach to overcome this obstacle. The present review describes, in the first part, the different approaches which have been published to set up human ABC pump 3D-homology models allowing the localization of binding sites for drug candidates, and the identification of critical residues therein. In a second part, the review proposes a more accurate strategy and practical keys to use such biological tools for initiating structure-based drug design. PMID:21470105

  17. Emergence of Multidrug-resistant Salmonella Paratyphi B dT+, Canada

    PubMed Central

    Boyd, David; Cloeckaert, Axel; Ahmed, Rafiq; Ng, Lai-King

    2004-01-01

    We document an increase in the number of multidrug-resistant Salmonella enterica serovar Paratyphi B dT+ identified in Canada. Most of these strains harbor Salmonella genomic island 1 (SGI1). Further studies are needed to determine factors contributing to the observed emergence of this multidrug-resistant strain. PMID:15324556

  18. Human Multidrug-Resistant Salmonella Newport Infections, Wisconsin, 2003–2005

    PubMed Central

    Archer, John R.; Sotir, Mark J.; Monson, Timothy A.; Kazmierczak, James J.

    2007-01-01

    We conducted a retrospective study of Salmonella Newport infections among Wisconsin residents during 2003–2005. Multidrug resistance prevalence was substantially greater in Wisconsin than elsewhere in the United States. Persons with multidrug-resistant infections were more likely than persons with susceptible infections to report exposure to cattle, farms, and unpasteurized milk. PMID:18217570

  19. [Epidemiology of multi-drug resistant gramnegative bacilli].

    PubMed

    Ruiz-Garbajosa, P; Cantón, R

    2016-09-01

    Current antimicrobial resistance in Gram negative bacilli is particularly worrisome due to development of resistance to all available antimicrobial agents. This situation dramatically limits therapeutic options. The microorganisms acquire a multiresistance phenotype as a consequence of different complex processes in which the antimicrobials acts as selective driver of resistance. Dissemination of multiresistant bacteria is driven by the expansion of the high-risk clones. These clones can be selected in the presence of antimicrobials allowing their persistence over time. PMID:27608308

  20. Nanomedicinal strategies to treat multidrug-resistant tumors: current progress

    PubMed Central

    Dong, Xiaowei; Mumper, Russell J

    2010-01-01

    Multidrug resistance (MDR) is a major impediment to the success of cancer chemotherapy. P-glycoprotein is an important and the best-known membrane transporter involved in MDR. Several strategies have been used to address MDR, especially P-glycoprotein-mediated drug resistance in tumors. However, clinical success has been limited, largely due to issues regarding lack of efficacy and/or safety. Nanoparticles have shown the ability to target tumors based on their unique physical and biological properties. To date, nanoparticles have been investigated primarily to address P-glycoprotein and the observed improved anticancer efficacy suggests that nanomedicinal strategies provide a new opportunity to overcome MDR. This article focuses on nanotechnology-based formulations and current nanomedicine approaches to address MDR in tumors and discusses the proposed mechanisms of action. PMID:20528455

  1. Cell biological mechanisms of multidrug resistance in tumors.

    PubMed Central

    Simon, S M; Schindler, M

    1994-01-01

    Multidrug resistance (MDR) is a generic term for the variety of strategies tumor cells use to evade the cytotoxic effects of anticancer drugs. MDR is characterized by a decreased sensitivity of tumor cells not only to the drug employed for chemotherapy but also to a broad spectrum of drugs with neither obvious structural homology nor common targets. This pleiotropic resistance is one of the major obstacles to the successful treatment of tumors. MDR may result from structural or functional changes at the plasma membrane or within the cytoplasm, cellular compartments, or nucleus. Molecular mechanisms of MDR are discussed in terms of modifications in detoxification and DNA repair pathways, changes in cellular sites of drug sequestration, decreases in drug-target affinity, synthesis of specific drug inhibitors within cells, altered or inappropriate targeting of proteins, and accelerated removal or secretion of drugs. PMID:7909602

  2. How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps.

    PubMed

    Blair, Jessica M A; Piddock, Laura J V

    2016-01-01

    Bacterial multidrug resistance (MDR) efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i) those that directly measure efflux and (ii) those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity. PMID:27381291

  3. Cell Biological Mechanisms of Multidrug Resistance in Tumors

    NASA Astrophysics Data System (ADS)

    Simon, Sanford M.; Schindler, Melvin

    1994-04-01

    Multidrug resistance (MDR) is a generic term for the variety of strategies tumor cells use to evade the cytotoxic effects of anticancer drugs. MDR is characterized by a decreased sensitivity of tumor cells not only to the drug employed for chemotherapy but also to a broad spectrum of drugs with neither obvious structural homology nor common targets. This pleotropic resistance is one of the major obstacles to the successful treatment of tumors. MDR may result from structural or functional changes at the plasma membrane or within the cytoplasm, cellular compartments, or nucleus. Molecular mechanisms of MDR are discussed in terms of modifications in detoxification and DNA repair pathways, changes in cellular sites of drug sequestration, decreases in drug-target affinity, synthesis of specific drug inhibitors within cells, altered or inappropriate targeting of proteins, and accelerated removal or secretion of drugs.

  4. How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps

    PubMed Central

    Blair, Jessica M. A.

    2016-01-01

    ABSTRACT Bacterial multidrug resistance (MDR) efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i) those that directly measure efflux and (ii) those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity. PMID:27381291

  5. Global evolution of multidrug-resistant Acinetobacter baumannii clonal lineages.

    PubMed

    Zarrilli, Raffaele; Pournaras, Spyros; Giannouli, Maria; Tsakris, Athanassios

    2013-01-01

    The rapid expansion of Acinetobacter baumannii clinical isolates exhibiting resistance to carbapenems and most or all available antibiotics during the last decade is a worrying evolution. The apparent predominance of a few successful multidrug-resistant lineages worldwide underlines the importance of elucidating the mode of spread and the epidemiology of A. baumannii isolates in single hospitals, at a country-wide level and on a global scale. The evolutionary advantage of the dominant clonal lineages relies on the capability of the A. baumannii pangenome to incorporate resistance determinants. In particular, the simultaneous presence of divergent strains of the international clone II and their increasing prevalence in international hospitals further support the ongoing adaptation of this lineage to the hospital environment. Indeed, genomic and genetic studies have elucidated the role of mobile genetic elements in the transfer of antibiotic resistance genes and substantiate the rate of genetic alterations associated with acquisition in A. baumannii of various resistance genes, including OXA- and metallo-β-lactamase-type carbapenemase genes. The significance of single nucleotide polymorphisms and transposon mutagenesis in the evolution of A. baumannii has been also documented. Establishment of a network of reference laboratories in different countries would generate a more complete picture and a fuller understanding of the importance of high-risk A. baumannii clones in the international dissemination of antibiotic resistance. PMID:23127486

  6. Centromere anatomy in the multidrug-resistant pathogen Enterococcus faecium

    PubMed Central

    Derome, Andrew; Hoischen, Christian; Bussiek, Malte; Grady, Ruth; Adamczyk, Malgorzata; Kędzierska, Barbara; Diekmann, Stephan; Barillà, Daniela; Hayes, Finbarr

    2008-01-01

    Multidrug-resistant variants of the opportunistic human pathogen Enterococcus have recently emerged as leading agents of nosocomial infection. The acquisition of plasmid-borne resistance genes is a driving force in antibiotic-resistance evolution in enterococci. The segregation locus of a high-level gentamicin-resistance plasmid, pGENT, in Enterococcus faecium was identified and dissected. This locus includes overlapping genes encoding PrgP, a member of the ParA superfamily of segregation proteins, and PrgO, a site-specific DNA binding homodimer that recognizes the cenE centromere upstream of prgPO. The centromere has a distinctive organization comprising three subsites, CESII separates CESI and CESIII, each of which harbors seven TATA boxes spaced by half-helical turns. PrgO independently binds both CESI and CESIII, but with different affinities. The topography of the complex was probed by atomic force microscopy, revealing discrete PrgO foci positioned asymmetrically at the CESI and CESIII subsites. Bending analysis demonstrated that cenE is intrinsically curved. The organization of the cenE site and of certain other plasmid centromeres mirrors that of yeast centromeres, which may reflect a common architectural requirement during assembly of the mitotic apparatus in yeast and bacteria. Moreover, segregation modules homologous to that of pGENT are widely disseminated on vancomycin and other resistance plasmids in enterococci. An improved understanding of segrosome assembly may highlight new interventions geared toward combating antibiotic resistance in these insidious pathogens. PMID:18245388

  7. Selective Conditions for a Multidrug Resistance Plasmid Depend on the Sociality of Antibiotic Resistance

    PubMed Central

    Wood, A. Jamie; Brockhurst, Michael A.

    2016-01-01

    Multidrug resistance (MDR) plasmids frequently carry antibiotic resistance genes conferring qualitatively different mechanisms of resistance. We show here that the antibiotic concentrations selecting for the RK2 plasmid in Escherichia coli depend upon the sociality of the drug resistance: the selection for selfish drug resistance (efflux pump) occurred at very low drug concentrations, just 1.3% of the MIC of the plasmid-free antibiotic-sensitive strain, whereas selection for cooperative drug resistance (modifying enzyme) occurred at drug concentrations exceeding the MIC of the plasmid-free strain. PMID:26787694

  8. Effects of Efflux Pump Inhibitors on Colistin Resistance in Multidrug-Resistant Gram-Negative Bacteria.

    PubMed

    Ni, Wentao; Li, Yanjun; Guan, Jie; Zhao, Jin; Cui, Junchang; Wang, Rui; Liu, Youning

    2016-05-01

    We tested the effects of various putative efflux pump inhibitors on colistin resistance in multidrug-resistant Gram-negative bacteria. Addition of 10 mg/liter cyanide 3-chlorophenylhydrazone (CCCP) to the test medium could significantly decrease the MICs of colistin-resistant strains. Time-kill assays showed CCCP could reverse colistin resistance and inhibit the regrowth of the resistant subpopulation, especially in Acinetobacter baumannii and Stenotrophomonas maltophilia These results suggest colistin resistance in Gram-negative bacteria can be suppressed and reversed by CCCP. PMID:26953203

  9. Population genetics study of isoniazid resistance mutations and evolution of multidrug-resistant Mycobacterium tuberculosis.

    PubMed

    Hazbón, Manzour Hernando; Brimacombe, Michael; Bobadilla del Valle, Miriam; Cavatore, Magali; Guerrero, Marta Inírida; Varma-Basil, Mandira; Billman-Jacobe, Helen; Lavender, Caroline; Fyfe, Janet; García-García, Lourdes; León, Clara Inés; Bose, Mridula; Chaves, Fernando; Murray, Megan; Eisenach, Kathleen D; Sifuentes-Osornio, José; Cave, M Donald; Ponce de León, Alfredo; Alland, David

    2006-08-01

    The molecular basis for isoniazid resistance in Mycobacterium tuberculosis is complex. Putative isoniazid resistance mutations have been identified in katG, ahpC, inhA, kasA, and ndh. However, small sample sizes and related potential biases in sample selection have precluded the development of statistically valid and significant population genetic analyses of clinical isoniazid resistance. We present the first large-scale analysis of 240 alleles previously associated with isoniazid resistance in a diverse set of 608 isoniazid-susceptible and 403 isoniazid-resistant clinical M. tuberculosis isolates. We detected 12 mutant alleles in isoniazid-susceptible isolates, suggesting that these alleles are not involved in isoniazid resistance. However, mutations in katG, ahpC, and inhA were strongly associated with isoniazid resistance, while kasA mutations were associated with isoniazid susceptibility. Remarkably, the distribution of isoniazid resistance-associated mutations was different in isoniazid-monoresistant isolates from that in multidrug-resistant isolates, with significantly fewer isoniazid resistance mutations in the isoniazid-monoresistant group. Mutations in katG315 were significantly more common in the multidrug-resistant isolates. Conversely, mutations in the inhA promoter were significantly more common in isoniazid-monoresistant isolates. We tested for interactions among mutations and resistance to different drugs. Mutations in katG, ahpC, and inhA were associated with rifampin resistance, but only katG315 mutations were associated with ethambutol resistance. There was also a significant inverse association between katG315 mutations and mutations in ahpC or inhA and between mutations in kasA and mutations in ahpC. Our results suggest that isoniazid resistance and the evolution of multidrug-resistant strains are complex dynamic processes that may be influenced by interactions between genes and drug-resistant phenotypes. PMID:16870753

  10. Characterization of a human colorectal carcinoma cell line with acquired resistance to flavopiridol.

    PubMed

    Smith, V; Raynaud, F; Workman, P; Kelland, L R

    2001-11-01

    Flavopiridol is a broad-spectrum inhibitor of cyclin-dependent kinases (cdks) and represents the first in this anticancer class to enter clinical trials. In anticipation of the likelihood that, as with other cancer drugs, acquired resistance may limit the drug's efficacy, an acquired resistance model has been established by in vitro drug exposure of the human colon carcinoma cell line HCT116. This stably resistant line, possessing 8-fold resistance to flavopiridol, showed a lack of cross-resistance to the anticancer agents etoposide, doxorubicin, paclitaxel, topotecan, and cisplatin, and notably to other chemical classes of cdk inhibitors: the aminopurines roscovitine and purvalanol A, 9-nitropaullone, and hymenialdisine. Resistance did not seem to be related to differences in the levels of multidrug resistance drug efflux proteins, P-glycoprotein, and MRP1. Moreover, there were no changes in overall drug accumulation between the resistant and sensitive cell lines. Flavopiridol induced cell cycle arrest, apoptosis, and inhibition of retinoblastoma gene product phosphorylation on serine 780 in both parental and resistant lines, but the latter required 8-fold higher concentrations to achieve these effects. Cyclin E protein levels and cyclin E-associated kinase activity were increased in the resistant line, suggesting that overexpression of cyclin E may be the mechanism of resistance to flavopiridol. However, transfection of cyclin E to increase expression of this protein did not result in an increase in resistance to flavopiridol. Thus, up-regulation of cyclin E alone does not seem to cause resistance to this cdk inhibitor. PMID:11641415

  11. Molecular Analysis of Antibiotic Resistance Determinants and Plasmids in Malaysian Isolates of Multidrug Resistant Klebsiella pneumoniae

    PubMed Central

    Al-Marzooq, Farah; Mohd Yusof, Mohd Yasim; Tay, Sun Tee

    2015-01-01

    Infections caused by multidrug resistant Klebsiella pneumoniae have been increasingly reported in many parts of the world. A total of 93 Malaysian multidrug resistant K. pneumoniae isolated from patients attending to University of Malaya Medical Center, Kuala Lumpur, Malaysia from 2010-2012 were investigated for antibiotic resistance determinants including extended-spectrum beta-lactamases (ESBLs), aminoglycoside and trimethoprim/sulfamethoxazole resistance genes and plasmid replicons. CTX-M-15 (91.3%) was the predominant ESBL gene detected in this study. aacC2 gene (67.7%) was the most common gene detected in aminoglycoside-resistant isolates. Trimethoprim/sulfamethoxazole resistance (90.3%) was attributed to the presence of sul1 (53.8%) and dfrA (59.1%) genes in the isolates. Multiple plasmid replicons (1-4) were detected in 95.7% of the isolates. FIIK was the dominant replicon detected together with 13 other types of plasmid replicons. Conjugative plasmids (1-3 plasmids of ~3-100 kb) were obtained from 27 of 43 K. pneumoniae isolates. An ESBL gene (either CTX-M-15, CTX-M-3 or SHV-12) was detected from each transconjugant. Co-detection with at least one of other antibiotic resistance determinants [sul1, dfrA, aacC2, aac(6ˊ)-Ib, aac(6ˊ)-Ib-cr and qnrB] was noted in most conjugative plasmids. The transconjugants were resistant to multiple antibiotics including β-lactams, gentamicin and cotrimoxazole, but not ciprofloxacin. This is the first study describing the characterization of plasmids circulating in Malaysian multidrug resistant K. pneumoniae isolates. The results of this study suggest the diffusion of highly diverse plasmids with multiple antibiotic resistance determinants among the Malaysian isolates. Effective infection control measures and antibiotic stewardship programs should be adopted to limit the spread of the multidrug resistant bacteria in healthcare settings. PMID:26203651

  12. Role of old antibiotics in multidrug resistant bacterial infections.

    PubMed

    Maviglia, R; Nestorini, R; Pennisi, M

    2009-09-01

    Multidrug resistant bacteria infections are associated with an increase in attributable mortality and morbidity in ICU patients. Unfortunately, an emerging resistance to novel antibiotics used in the therapy of gram negative and gram positive bacteria infections is often reported in literature. Old antibiotics have been reintroduced in clinical practice. In this review we report the efficacy and safety use of older antimicrobial agents in critically ill patients. Polymyxins are used for nosocomial infection caused by Pseudomonas aeruginosa and Acinetobacter baumannii resistant strains. Patients with polymyxin-only susceptible gram-negative nosocomial pneumonia are reported to be successfully treated with inhaled colistin. Isepamicin can probably be used in intensive care units that harbor Gram-negative bacteria resistant to other aminoglycosides. Fosfomycin may be a useful alternative to linezolid and quinupristin-dalfopristin in the treatment of Vancomycin Resistant Enterococci (VRE) infections in certain clinical situations, e.g. uncomplicated urinary tract infections. Chloramphenicol has a wide antimicrobial spectrum and excellent tissue penetration; though it is sometimes used empirically in the hospital setting for the treatment of patients with unknown source of fever, its role is still a matter of controversy. The colistin/rifampicin combination might have a synergistic effect in Acinetobacter baumannii and Pseudomonas aeruginosa infections. Fusidic acid is active against staphylococcal strains. PMID:19799544

  13. Emerging cephalosporin and multidrug-resistant gonorrhoea in Europe.

    PubMed

    Cole, M J; Spiteri, G; Chisholm, S A; Hoffmann, S; Ison, C A; Unemo, M; Van de Laar, M

    2014-01-01

    Neisseria gonorrhoeae has consistently developed resistance to antimicrobials used therapeutically for gonorrhoea and few antimicrobials remain for effective empiric first-line therapy. Since 2009 the European gonococcal antimicrobial surveillance programme (Euro-GASP) has been running as a sentinel surveillance system across Member States of the European Union (EU) and European Economic Area (EEA) to monitor antimicrobial susceptibility in N. gonorrhoeae. During 2011, N. gonorrhoeae isolates were collected from 21 participating countries, and 7.6% and 0.5% of the examined gonococcal isolates had in vitro resistance to cefixime and ceftriaxone, respectively. The rate of ciprofloxacin and azithromycin resistance was 48.7% and 5.3%, respectively. Two (0.1%) isolates displayed high-level resistance to azithromycin, i.e. a minimum inhibitory concentration (MIC) ≥256 mg/L. The current report further highlights the public health need to implement the European response plan, including further strengthening of Euro-GASP, to control and manage the threat of multidrug resistant N. gonorrhoeae. PMID:25411689

  14. Purification of a Multidrug Resistance Transporter for Crystallization Studies

    PubMed Central

    Alegre, Kamela O.; Law, Christopher J.

    2015-01-01

    Crystallization of integral membrane proteins is a challenging field and much effort has been invested in optimizing the overexpression and purification steps needed to obtain milligram amounts of pure, stable, monodisperse protein sample for crystallography studies. Our current work involves the structural and functional characterization of the Escherichia coli multidrug resistance transporter MdtM, a member of the major facilitator superfamily (MFS). Here we present a protocol for isolation of MdtM to increase yields of recombinant protein to the milligram quantities necessary for pursuit of structural studies using X-ray crystallography. Purification of MdtM was enhanced by introduction of an elongated His-tag, followed by identification and subsequent removal of chaperonin contamination. For crystallization trials of MdtM, detergent screening using size exclusion chromatography determined that decylmaltoside (DM) was the shortest-chain detergent that maintained the protein in a stable, monodispersed state. Crystallization trials of MdtM performed using the hanging-drop diffusion method with commercially available crystallization screens yielded 3D protein crystals under several different conditions. We contend that the purification protocol described here may be employed for production of high-quality protein of other multidrug efflux members of the MFS, a ubiquitous, physiologically and clinically important class of membrane transporters. PMID:27025617

  15. Purification of a Multidrug Resistance Transporter for Crystallization Studies.

    PubMed

    Alegre, Kamela O; Law, Christopher J

    2015-01-01

    Crystallization of integral membrane proteins is a challenging field and much effort has been invested in optimizing the overexpression and purification steps needed to obtain milligram amounts of pure, stable, monodisperse protein sample for crystallography studies. Our current work involves the structural and functional characterization of the Escherichia coli multidrug resistance transporter MdtM, a member of the major facilitator superfamily (MFS). Here we present a protocol for isolation of MdtM to increase yields of recombinant protein to the milligram quantities necessary for pursuit of structural studies using X-ray crystallography. Purification of MdtM was enhanced by introduction of an elongated His-tag, followed by identification and subsequent removal of chaperonin contamination. For crystallization trials of MdtM, detergent screening using size exclusion chromatography determined that decylmaltoside (DM) was the shortest-chain detergent that maintained the protein in a stable, monodispersed state. Crystallization trials of MdtM performed using the hanging-drop diffusion method with commercially available crystallization screens yielded 3D protein crystals under several different conditions. We contend that the purification protocol described here may be employed for production of high-quality protein of other multidrug efflux members of the MFS, a ubiquitous, physiologically and clinically important class of membrane transporters. PMID:27025617

  16. Multidrug resistant commensal Escherichia coli in animals and its impact for public health

    PubMed Central

    Szmolka, Ama; Nagy, Béla

    2013-01-01

    After the era of plentiful antibiotics we are alarmed by the increasing number of antibiotic resistant strains. The genetic flexibility and adaptability of Escherichia coli to constantly changing environments allows to acquire a great number of antimicrobial resistance mechanisms. Commensal strains of E. coli as versatile residents of the lower intestine are also repeatedly challenged by antimicrobial pressures during the lifetime of their host. As a consequence, commensal strains acquire the respective resistance genes, and/or develop resistant mutants in order to survive and maintain microbial homeostasis in the lower intestinal tract. Thus, commensal E. coli strains are regarded as indicators of antimicrobial load on their hosts. This chapter provides a short historic background of the appearance and presumed origin and transfer of antimicrobial resistance genes in commensal intestinal E. coli of animals with comparative information on their pathogenic counterparts. The dynamics, development, and ways of evolution of resistance in the E. coli populations differ according to hosts, resistance mechanisms, and antimicrobial classes used. The most frequent tools of E. coli against a variety of antimicrobials are the efflux pumps and mobile resistance mechanisms carried by plasmids and/or other transferable elements. The emergence of hybrid plasmids (both resistance and virulence) among E. coli is of further concern. Co-existence and co-transfer of these “bad genes” in this huge and most versatile in vivo compartment may represent an increased public health risk in the future. Significance of multidrug resistant (MDR) commensal E. coli seem to be highest in the food animal industry, acting as reservoir for intra- and interspecific exchange and a source for spread of MDR determinants through contaminated food to humans. Thus, public health potential of MDR commensal E. coli of food animals can be a concern and needs monitoring and more molecular analysis in the

  17. Susceptibility of Multidrug-Resistant Gram-Negative Urine Isolates to Oral Antibiotics.

    PubMed

    Hirsch, Elizabeth B; Zucchi, Paola C; Chen, Alice; Raux, Brian R; Kirby, James E; McCoy, Christopher; Eliopoulos, George M

    2016-05-01

    Increasing resistance among Gram-negative uropathogens limits treatment options, and susceptibility data for multidrug-resistant isolates are limited. We assessed the activity of five oral agents against 91 multidrug-resistant Gram-negative urine isolates that were collected from emergency department/hospitalized patients. Fosfomycin and nitrofurantoin were most active (>75% susceptibility). Susceptibilities to sulfamethoxazole-trimethoprim, ciprofloxacin, and ampicillin were ≤40%; empirical use of these agents likely provides inadequate coverage in areas with a high prevalence of multidrug-resistant uropathogens. PMID:26883704

  18. Characterization of multidrug-resistant Escherichia coli by antimicrobial resistance profiles, plasmid replicon typing, and pulsed-field gel electrophoresis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Aim: Plasmid characterization has particular clinical importance because genes encoding significant traits including antimicrobial resistance are frequently carried on plasmids. The objective of this study was to examine the distribution of multidrug resistance (MDR) in Escherichia coli in relation ...

  19. Clinical management of infections caused by multidrug-resistant Enterobacteriaceae

    PubMed Central

    Delgado-Valverde, Mercedes; Sojo-Dorado, Jesús; Pascual, Álvaro

    2013-01-01

    Enterobacteriaceae showing resistance to cephalosporins due to extended-spectrum β-lactamases (ESBLs) or plasmid-mediated AmpC enzymes, and those producing carbapenemases have spread worldwide during the last decades. Many of these isolates are also resistant to other first-line agents such as fluoroquinolones or aminoglycosides, leaving few available options for therapy. Thus, older drugs such as colistin and fosfomycin are being increasingly used. Infections caused by these bacteria are associated with increased morbidity and mortality compared with those caused by their susceptible counterparts. Most of the evidence supporting the present recommendations is from in vitro data, animal studies, and observational studies. While carbapenems are considered the drugs of choice for ESBL and AmpC producers, recent data suggest that certain alternatives may be suitable for some types of infections. Combined therapy seems superior to monotherapy in the treatment of invasive infections caused by carbapenemase-producing Enterobacteriaceae. Optimization of dosage according to pharmacokinetics/pharmacodynamics data is important for the treatment of infections caused by isolates with borderline minimum inhibitory concentration due to low-level resistance mechanisms. The increasing frequency and the rapid spread of multidrug resistance among the Enterobacteriaceae is a true and complex public health problem. PMID:25165544

  20. Preparation of silver nanoparticles fabrics against multidrug-resistant bacteria

    NASA Astrophysics Data System (ADS)

    Hanh, Truong Thi; Thu, Nguyen Thi; Hien, Nguyen Quoc; An, Pham Ngoc; Loan, Truong Thi Kieu; Hoa, Phan Thi

    2016-04-01

    The silver nanoparticles (AgNPs)/peco fabrics were prepared by immobilization of AgNPs on fabrics in which AgNPs were synthesized by γ-irradiation of the 10 mM AgNO3 chitosan solution at the dose of 17.6 kGy. The AgNPs size has been estimated to be about 11 nm from TEM image. The AgNPs content onto peco fabrics was of 143±6 mg/kg at the initial AgNPs concentration of 100 ppm. The AgNPs colloidal solution was characterized by UV-vis spectroscopy and TEM image. The antibacterial activity of AgNPs/peco fabrics after 60 washings against Staphylococcus aureus and Klebsiella pneumoniae was found to be over 99%. Effects of AgNPs fabics on multidrug-resistant pathogens from the clinical specimens were also tested.

  1. An outbreak of multidrug-resistant tuberculosis among a family.

    PubMed

    Iliaz, Sinem; Caglar, Emel; Koksalan, Orhan Kaya; Chousein, Efsun Gonca Ugur

    2016-04-01

    Tuberculosis is a major public health problem and it may be complicated by multidrug-resistant tuberculosis (MDR-TB). Wide transmission among immunocompetent contacts of the index case is possible. If you detect tuberculosis in two contacts of the index case, it is called an outbreak. The aim of our paper is to evaluate the characteristics of a MDR-TB outbreak affecting 7 people in a family treated during 2012-2014 in Istanbul Yedikule Training and Research Hospital for Chest Disease and Thoracic Surgery, Turkey. The cultures, spoligotyping, and DNA fingerprinting revealed the same Mycobacterium tuberculosis species as T1 genotype and ST53 subtype. All patients were negative for human immunodeficiency virus and free of other underlying diseases. PMID:27451825

  2. Functional expression of murine multidrug resistance in Xenopus laevis oocytes

    SciTech Connect

    Castillo, G.; Vera, J.C.; Rosen, O.M. ); Yang, Chiaping Huang; Horwitz, S.B. )

    1990-06-01

    The development of multidrug resistance (MDR) is associated with the overproduction of a plasma membrane glycoprotein, P glycoprotein. Here the authors report the functional expression of a member of the murine MDR family of proteins and show that Xenopus oocytes injected with RNA encoding the mouse mdr1b P glycoprotein develop a MDR-like phenotype. Immunological analysis indicated that oocytes injected with the mdr1b RNA synthesized a protein with the size and immunological characteristics of the mouse mdr1b P glycoprotein. These oocytes exhibited a decreased accumulation of ({sup 3}H)vinblastine and showed an increased capacity to extrude the drug compared to control oocytes not expressing the P glycoprotein. In addition, competition experiments indicated that verapamil, vincristine, daunomycin, and quinidine, but not colchicine, can overcome the rapid drug efflux conferred by the expression of the mouse P glycoprotein.

  3. Biomimetic RNA Silencing Nanocomplexes Overcome Multidrug Resistance in Cancer Cells**

    PubMed Central

    Wang, Zhongliang; Wang, Zhe; Liu, Dingbin; Yan, Xuefeng; Wang, Fu; Niu, Gang

    2015-01-01

    RNA interference (RNAi) is an RNA-dependent gene silencing approach controlled by RNA-induced silencing complex (RISC). Here we represent a synthetic RISC-mimic nanocomplex, which can actively cleave its target RNA in a sequence-specific manner. With high enzymatic stability and efficient self-delivery to target cells, the designed nanocomplex can selectively and potently induce gene silencing without cytokine activation. The nanocomplexes targeting to multidrug resistance are able to not only bypass P-glycoprotein (Pgp) transporter due to their nano-size effect, but also effectively suppress the Pgp expression, thus resulting in successful restoration of drug sensitivity of OVCAR8/ADR cells to Pgp-transportable cytotoxic agents. This nanocomplex approach has the potential for both functional genomics and cancer therapy. PMID:24446433

  4. Molecular characterization of clinical multidrug-resistant Klebsiella pneumoniae isolates

    PubMed Central

    2014-01-01

    Background Klebsiella pneumoniae is a frequent nosocomial pathogen, with the multidrug-resistant (MDR) K. pneumoniae being a major public health concern, frequently causing difficult-to-treat infections worldwide. The aim of this study was to investigate the molecular characterization of clinical MDR Klebsiella pneumoniae isolates. Methods A total of 27 non-duplicate MDR K. pneumoniae isolates with a CTX-CIP-AK resistance pattern were investigated for the prevalence of antimicrobial resistance genes including extended spectrum β-lactamase genes (ESBLs), plasmid-mediated quinolone resistance (PMQR) genes, 16S rRNA methylase (16S-RMTase) genes, and integrons by polymerase chain reaction (PCR) amplification and DNA sequencing. Plasmid replicons were typed by PCR-based replicon typing (PBRT). Multi-locus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were carried out to characterize the strain relatedness. Results All the isolates co-harbored 3 or more resistance determinants. OqxAB, CTX-M-type ESBLs and RmtB were the most frequent determinants, distributed among19 (70.4%),18 (66.7%) and 8 (29.6%) strains. Fourteen isolates harbored class 1 integrons, with orfD-aacA4 being the most frequent gene cassette array. Class 3 integrons were less frequently identified and contained the gene cassette array of blaGES-1-blaOXA-10-aac(6′)-Ib. IncFII replicon was most commonly found in this collection. One cluster was observed with ≥80% similarity among profiles obtained by PFGE, and one sequence type (ST) by MLST, namely ST11, was observed in the cluster. Conclusion K. pneumoniae carbapenemase (KPC)–producing ST11 was the main clone detected. Of particular concern was the high prevalence of multiple resistance determinants, classs I integrons and IncFII plasmid replicon among these MDR strains, which provide advantages for the rapid development of MDR strains. PMID:24884610

  5. ATP7B expression confers multidrug resistance through drug sequestration

    PubMed Central

    Moinuddin, F M; Shinsato, Yoshinari; Komatsu, Masaharu; Mitsuo, Ryoichi; Minami, Kentaro; Yamamoto, Masatatsu; Kawahara, Kohich; Hirano, Hirofumi; Arita, Kazunori; Furukawa, Tatsuhiko

    2016-01-01

    We previously reported that ATP7B is involved in cisplatin resistance and ATP7A confers multidrug resistance (MDR) in cancer cells. In this study, we show that ATP7B expressing cells also are resistant to doxorubicin, SN-38, etoposide, and paclitaxel as well as cisplatin. In ATP7B expressing cells, doxorubicin relocated from the nuclei to the late-endosome at 4 hours after doxorubicin exposure. EGFP-ATP7B mainly colocalized with doxorubicin. ATP7B has six metal binding sites (MBSs) in the N-terminal cytoplasmic region. To investigate the role of the MBSs of ATP7B in doxorubicin resistance, we used three mutant ATP7B (Cu0, Cu6 and M6C/S) expressing cells. Cu0 has no MBSs, Cu6 has only the sixth MBS and M6C/S carries CXXC to SXXS mutation in the sixth MBS. Cu6 expressing cells were less resistance to the anticancer agents than wild type ATP7B expressing cells, and had doxorubicin sequestration in the late-endosome. Cu0- and M6C/S-expressing cells were sensitive to doxorubicin. In these cells, doxorubicin did not relocalize to the late-endosome. EGFP-M6C/S mainly localized to the trans-Golgi network (TGN) even in the presence of copper. Thus the cysteine residues in the sixth MBS of ATP7B are essential for MDR phenotype. Finally, we found that ammonium chloride and tamoxifen suppressed late endosomal sequestration of doxorubicin, thereby attenuating drug resistance. These results suggest that the sequestration depends on the acidity of the vesicles partly. We here demonstrate that ATP7B confers MDR by facilitating nuclear drug efflux and late endosomal drug sequestration. PMID:26988911

  6. Sensitive, resistant and multi-drug resistant Acinetobacter baumanii at Saudi Arabia hospital eastern region.

    PubMed

    Ahmed, Mughis Uddin; Farooq, Reshma; Al-Hawashim, Nadia; Ahmed, Motasim; Yiannakou, Nearchos; Sayeed, Fatima; Sayed, Ali Rifat; Lutfullah, Sualiha

    2015-05-01

    Since the Physicians start use of antibiotics long ago with un-notice drug resistance. However actual problem was recognized about 85 years ago. Antibiotic resistant and Multi-drug resistant bacterial strains are at rise throughout the world. It is physicians and researchers to take scientific research based appropriate action to overcome this ever-spreading problem. This study is designed to find out sensitive (S), resistant (R) and multi-drug resistant (MDR) Acinetobacter baumanii strain along with other isolates in the resident patients of Eastern Region of Saudi Arabia. Pseudomonas aeruginosa is excluded from other gram-negative organisms isolated from different sites as it will be dealt separately. This study is based in was retrospective observations designed to collect data of different stains of Acinetobacter baumanii with reference to their Sensitivity (S), Resistance (R), Multi-Drug Resistance (MDR) along with other Gram negative isolated from different sites (from 1st January 2004 to 31st December 2011) at King Abdulaziz Hospital located Eastern Region of Kingdom of Saudi Arabia (KSA). All necessary techniques were used to culture and perform sensitivity of these isolates. There were 4532 isolates out of which 3018 (67%) were from patients. Out of Acinetobacter baumanii infected were 906 (20%) while other 3626 (80%) isolates were miscellaneous. Numbers of patients or cases were 480 (53%) out of 906 isolates and numbers of patients or cases in other organisms were 2538 (70%) out of 3626 isolates. Acinetobacter baumanii infected patients 221 (46%) were male and 259 (54%) were female and the male and female ratio of 1:1.2. In other organisms this male female ratio was almost same. There was steady rise in number of patients and the hence the isolates from 2004 to 2011. Majority of the bacterial strains were isolated as single organism but some were isolated as double or triple or quadruple or more organisms from different sites. Sensitive, Resistant and

  7. [Multidrug-resistant tuberculosis: challenges of a global emergence].

    PubMed

    Comolet, T

    2015-10-01

    Drug-resistant tuberculosis, in particular Multi-Drug Resistant (MDR-TB) is an increasing global concern and a major burden for some developing countries, especially the BRICS. It is assumed that every year roughly 350 000 new MDR-TB cases occur in the world, on average in 20.5% of TB patients that have been previously treated but also in 3.5% of persons that have never been on TB treatment before. The global distribution of cases is very heterogeneous and is now better understood thanks to a growing number of specific surveys and routine surveillance systems: incidence is much higher in southern Africa and in all countries formerly part of the USSR. Countries with weak health systems and previously inefficient TB control programs are highly vulnerable to MDR epidemics because program failures do help creating, maintaining and spreading resistances. Global response is slowly rolled out and diagnosis capacities are on the rise (mostly with genotypic methods) but adequate and successful treatment and care is still limited to a minority of global cases. From a public health perspective the MDR-TB growing epidemics will not be controlled merely by the introduction of few new antibiotics because it is also linked to patient's compliance and adequate case management supported by efficient TB program. In depth quality improvement will only be achieved after previous errors are thoroughly analyzed and boldly corrected. PMID:26289547

  8. Facing the challenge of multidrug-resistant gram-negative bacilli in Australia.

    PubMed

    Harris, Patrick; Paterson, David; Rogers, Benjamin

    2015-03-16

    Multidrug-resistant (MDR) gram-negative bacilli (GNB) are now globally widespread and present a major challenge to modern medical practice. Resistance to common antibiotics such as ceftriaxone is becoming more frequent in Australia, primarily mediated by extended-spectrum β-lactamase enzymes in common organisms such as Escherichia coli, and may occur in both hospital- and community-acquired infections. Carbapenem-resistant Enterobacteriaceae have emerged rapidly in recent years and are well established in many countries in the Asia-Pacific region. Although rare at present in Australia, they have caused significant nosocomial outbreaks. GNB have numerous mechanisms by which they can develop antibiotic resistance. Genes that encode extended-spectrum β-lactamases or carbapenemases are frequently co-located with multiple other resistance determinants on highly transmissible genetic structures such as plasmids. A key risk factor for infection with MDR GNB is travel to countries with high rates of resistance, especially with health care exposure. With limited prospects for new antibiotics in late-stage development that are active against MDR GNB, our national response to these challenges will require a multifaceted approach, including widespread implementation of antimicrobial stewardship, enhanced surveillance, targeted screening of at-risk patients and improved infection control practices. In the longer term, restriction of agricultural use of antibiotic classes critical to human medicine, removal of barriers to new drug development, and technological advances in rapid microbiological diagnostics will be required. PMID:25758692

  9. Reversal effect of Dioscin on multidrug resistance in human hepatoma HepG2/adriamycin cells.

    PubMed

    Sun, Bu Tong; Zheng, Li Hua; Bao, Yong Li; Yu, Chun Lei; Wu, Yin; Meng, Xiang Ying; Li, Yu Xin

    2011-03-01

    Multidrug resistance is a serious obstacle encountered in cancer treatment. Since drug resistance in human cancer is mainly associated with overexpression of the multidrug resistance gene 1 (MDR1), the promoter of the human MDR1 gene may be a target for multidrug resistance reversion drug screening. In the present study, HEK293T cells were transfected with pGL3 reporter plasmids containing the 2kb of MDR1 promoter, and the transfected cells were used as models to screen for candidate multidrug resistance inhibitors from over 300 purified naturally occurring compounds extracted from plants and animals. Dioscin was found to have an inhibiting effect on MDR1 promoter activity. The resistant HepG2 cell line (HepG2/adriamycin) was used to validate the activity of multidrug resistance reversal by Dioscin. Results showed that Dioscin could decrease the resistance degree of HepG2/adriamycin cells, and significantly inhibit P-glycoprotein expression, as well as increase the accumulation of adriamycin in HepG2/adriamycin cells as measured by Flow Cytometric analysis. These results suggest that Dioscin is a potent multidrug resistance reversal agent and may be a potential adjunctive agent for tumor chemotherapy. PMID:21195709

  10. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

    PubMed

    Frappier, F; Jossang, A; Soudon, J; Calvo, F; Rasoanaivo, P; Ratsimamanga-Urverg, S; Saez, J; Schrevel, J; Grellier, P

    1996-06-01

    Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells. PMID:8726022

  11. Bisbenzylisoquinolines as modulators of chloroquine resistance in Plasmodium falciparum and multidrug resistance in tumor cells.

    PubMed Central

    Frappier, F; Jossang, A; Soudon, J; Calvo, F; Rasoanaivo, P; Ratsimamanga-Urverg, S; Saez, J; Schrevel, J; Grellier, P

    1996-01-01

    Ten naturally occurring bisbenzylisoquinolines (BBIQ) and two dihydro derivatives belonging to five BBIQ subgroups were evaluated in vitro for their ability to inhibit Plasmodium falciparum growth and, in drug combination, to reverse the resistance to chloroquine of strain FcB1. The same alkaloids were also assessed in vitro for their potentiating activity against vinblastine with the multidrug-resistant clone CCRF-CEM/VLB, established from lymphoblastic acute leukemia. Three of the BBIQ tested had 50% inhibitory concentrations of less than 1 microM. The most potent antimalarial agent was cocsoline (50% inhibitory concentration, 0.22 microM). Regarding the chloroquine-potentiating effect, fangchinoline exhibited the highest biological activity whereas the remaining compounds displayed either antagonistic or slight synergistic effects. Against the multidrug-resistant cancer cell line, fangchinoline was also by far the most active compound. Although there were clear differences between the activities of tested alkaloids, no relevant structure-activity relationship could be established. Nevertheless, fangchinoline appears to be a new biochemical tool able to help in the comprehension of the mechanism of both chloroquine resistance in P. falciparum and multidrug resistance in tumor cells. PMID:8726022

  12. A new class of nifuroxazide analogues: synthesis of 5-nitrothiophene derivatives with antimicrobial activity against multidrug-resistant Staphylococcus aureus.

    PubMed

    Masunari, Andrea; Tavares, Leoberto Costa

    2007-06-15

    Hospital-acquired methicillin-resistant Staphylococcus aureus (MRSA) has been an increasing problem worldwide since the initial reports over 40 years ago. To examine new drug leads with potential antibacterial activities, 14 p-substituted benzoic acid [(5-nitro-thiophen-2-yl)-methylene]-hydrazides were designed, synthesized, and tested against standard and multidrug-resistant S. aureus strains by serial dilution tests. All compounds exhibited significant bacteriostatic activity and some of them also showed bactericidal activity. The results confirmed the potential of this class of compounds as an alternative for the development of selective antimicrobial agents. PMID:17419064

  13. Human multidrug-resistant Mycobacterium bovis infection in Mexico.

    PubMed

    Vazquez-Chacon, Carlos A; Martínez-Guarneros, Armando; Couvin, David; González-Y-Merchand, Jorge A; Rivera-Gutierrez, Sandra; Escobar-Gutierrez, Alejandro; De-la-Cruz López, Juan J; Gomez-Bustamante, Adriana; Gonzalez-Macal, Gabriela A; Gonçalves Rossi, Livia Maria; Muñiz-Salazar, Raquel; Rastogi, Nalin; Vaughan, Gilberto

    2015-12-01

    Here, we describe the molecular characterization of six human Mycobacterium bovis clinical isolates, including three multidrug resistant (MDR) strains, collected in Mexico through the National Survey on Tuberculosis Drug Resistance (ENTB-2008), a nationally representative survey conducted during 2008-2009 in nine states with a stratified cluster sampling design. The genetic background of bovine M. bovis strains identified in three different states of Mexico was studied in parallel to assess molecular relatedness of bovine and human strains. Additionally, resistance to first and second line anti-tuberculosis (TB) drugs and molecular identification of mutations conferring drug resistance was also performed. All strains were characterized by spoligotyping and 24-loci MIRU-VNTRs, and analyzed using the SITVIT2 (n = 112,000 strains) and SITVITBovis (n = 25,000 strains) proprietary databases of Institut Pasteur de la Guadeloupe. Furthermore, data from this study (n = 55 isolates), were also compared with genotypes recorded for M. bovis from USA (n = 203), Argentina (n = 726), as well as other isolates from Mexico (independent from the present study; n = 147), to determine any evidence for genetic relatedness between circulating M. bovis strains. The results showed that all human M. bovis cases were not genetically related between them or to any bovine strain. Interestingly, a high degree of genetic variability was observed among bovine strains. Several autochthonous and presumably imported strains were identified. The emergence of drug-resistant M. bovis is an important public health problem that jeopardizes the success of TB control programs in the region. PMID:26299906

  14. Antimicrobial resistance determinant microarray for analysis of multi-drug resistant isolates

    NASA Astrophysics Data System (ADS)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  15. Effects of the multidrug resistance modulator HZ08 on the apoptosis pathway in human chronic leukaemia cell line K562/A02.

    PubMed

    Cen, Juan; Zhu, Yi-Lin; Yang, Yu; Zhu, Jun-Rong; Fang, Wei-Rong; Huang, Wen-Long; Li, Yun-Man; Tao, Yi-Fu

    2011-01-01

    ōancer falls to respond to chemotherapy by acquiring multidrug resistance in over 90% of patients. A previous study revealed that multidrug resistance modulator HZ08 had great multidrug resistance reversal effect in vitro and in vivo. It could enhance adriamycin (doxorubicin) induced intrinsic apoptosis pathway and rectify cell cycle and some apoptosis related proteins in human breast resistant cancer MCF-7/ADM cells. This study detected Rh123 accumulation to assess the effect of HZ08 on P-glycoprotein function in human chronic leukaemia cell line K562/A02. Moreover, mitochondria membrane potential, cytochrome c release and caspase-3 activity were analyzed for HZ08 treatment with or without vincristine. Since pretreatment with HZ08 could also reverse the multidrug resistance to vincristine in K562/A02 cells, the individual influence of HZ08 was further detected on apoptotic regulator like Bcl-2, Bax, p53, cell cycle checkpoints and proliferation regulatory factors like survivin, hTERT, c-Myc, c-Fos, c-Jun. Finally, it revealed that HZ08 increased vincristine induced activation in intrinsic apoptosis pathway by inhibition of P-gp mediated efflux. In addition, the outstanding reversal effect of HZ08 should also attribute to its individual effect on apoptosis and proliferation related regulatory factors. It renders HZ08 possibility of application in pretreatment to reverse multidrug resistance while avoiding unexpected drug interactions and accumulative toxicity. PMID:22232851

  16. Case of bronchoesophageal fistula with gastric perforation due to multidrug-resistant tuberculosis

    PubMed Central

    Park, Chan Sung; Seo, Kwang won; Park, Chang Ryul; Nah, Yang Won; Suh, Jae Hee

    2014-01-01

    Gastric perforation and tuberculous bronchoesophageal fistula (TBEF) are very rare complications of extrapulmonary tuberculosis (TB). We present a case of pulmonary TB with TBEF and gastric perforation caused by a multidrug-resistant tuberculosis strain in a non-acquired immune deficiency syndrome male patient. The patient underwent total gastrectomy with Roux-en-Y end-to-side esophagojejunostomy and feeding jejunostomy during intravenous treatment with anti-TB medication, and esophageal reconstruction with colonic interposition and jejunocolostomy were performed successfully after a full course of anti-TB medication. Though recent therapies for TBEF have favored medication, patients with severe stenosis or perforation require surgery and medication with anti-TB drugs based upon adequate culture and drug susceptibility testing. PMID:25548611

  17. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates.

    PubMed

    Hou, Xiang-hua; Song, Xiu-yu; Ma, Xiao-bo; Zhang, Shi-yang; Zhang, Jia-qin

    2015-01-01

    Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR) K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs) at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL) producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38) and class II integrons (10/38). All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX' and aadA1 genes. β-lactam resistance was conferred through bla SHV (22/38), bla TEM (10/38), and bla CTX-M (7/38). The highly conserved bla KPC-2 (37/38) and bla OXA-23(1/38) alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38) and the plasmid-mediated qnrB gene (13/38) were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR) fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  18. Molecular characterization of multidrug-resistant Klebsiella pneumoniae isolates

    PubMed Central

    Hou, Xiang-hua; Song, Xiu-yu; Ma, Xiao-bo; Zhang, Shi-yang; Zhang, Jia-qin

    2015-01-01

    Klebsiella pneumoniae is an important cause of healthcare-associated infections worldwide. Selective pressure, the extensive use of antibiotics, and the conjugational transmission of antibiotic resistance genes across bacterial species and genera facilitate the emergence of multidrug-resistant (MDR) K. pneumoniae. Here, we examined the occurrence, phenotypes and genetic features of MDR K. pneumoniae isolated from patients in intensive care units (ICUs) at the First Affiliated Hospital of Xiamen University in Xiamen, China, from January to December 2011. Thirty-eight MDR K. pneumoniae strains were collected. These MDR K. pneumoniae isolates possessed at least seven antibiotic resistance determinants, which contribute to the high-level resistance of these bacteria to aminoglycosides, macrolides, quinolones and β-lactams. Among these isolates, 24 strains were extended-spectrum β-lactamase (ESBL) producers, 2 strains were AmpC producers, and 12 strains were both ESBL and AmpC producers. The 38 MDR isolates also contained class I (28/38) and class II integrons (10/38). All 28 class I-positive isolates contained aacC1, aacC4, orfX, orfX’ and aadA1 genes. β-lactam resistance was conferred through bla SHV (22/38), bla TEM (10/38), and bla CTX-M (7/38). The highly conserved bla KPC-2 (37/38) and bla OXA-23(1/38) alleles were responsible for carbapenem resistance, and a gyrAsite mutation (27/38) and the plasmid-mediated qnrB gene (13/38) were responsible for quinolone resistance. Repetitive-sequence-based PCR (REP-PCR) fingerprinting of these MDR strains revealed the presence of five groups and sixteen patterns. The MDR strains from unrelated groups showed different drug resistance patterns; however, some homologous strains also showed different drug resistance profiles. Therefore, REP-PCR-based analyses can provide information to evaluate the epidemic status of nosocomial infection caused by MDR K. pneumoniae; however, this test lacks the power to discriminate some

  19. PEITC reverse multi-drug resistance of human gastric cancer SGC7901/DDP cell line.

    PubMed

    Tang, Tao; Song, Xin; Liu, Yu-Fen; Wang, Wen-Yue

    2014-04-01

    Gastric cancer is one of the leading causes of cancer death in the world and nearly all patients who respond initially to cisplatin later develop drug resistance, indicating multi-drug resistance is an essential aspect of the failure of treatment. Phenethyl isothiocyanate (PEITC) has been implicated in inhibiting metastasis of several types of human cancer. However, the effect and potential mechanism of PEITC reversed multi-drug resistance of human gastric cancer is not fully clear. We have identified the role of PEITC in multi-drug resistance reversal of human gastric cancer SGC7901/DDP cell line. PEITC inhibited cisplatin-resistant human SGC7901/DDP cell growth in a dose-dependent manner, causing increased apoptosis, ROS generation, glutathione depletion, accumulation of Rhodamine-123, decreased expression of P-glycoprotein and cell cycle arrest. mRNA and protein expression of the multi-drug resistance gene (MDR1), multi-drug resistance-associated protein (MRP1), excision repair cross-complementing gene 1 (ERCC1), survivin, and Mad2 was decreased, and phosphorylation of Akt and transcriptional activation of NF-κB were suppressed. PEITC may be useful as the therapeutic strategy for overcoming multi-drug resistance through suppressing the PI3K-Akt pathway in human gastric cancer. PMID:23956061

  20. Multidrug Resistance in Quinolone-Resistant Gram-Negative Bacteria Isolated from Hospital Effluent and the Municipal Wastewater Treatment Plant.

    PubMed

    Vaz-Moreira, Ivone; Varela, Ana Rita; Pereira, Thamiris V; Fochat, Romário C; Manaia, Célia M

    2016-03-01

    This study is aimed to assess if hospital effluents represent an important supplier of multidrug-resistant (MDR) Gram-negative bacteria that, being discharged in the municipal collector, may be disseminated in the environment and bypassed in water quality control systems. From a set of 101 non-Escherichia coli Gram-negative bacteria with reduced susceptibility to quinolones, was selected a group of isolates comprised by those with the highest indices of MDR (defined as nonsusceptibility to at least one agent in six or more antimicrobial categories, MDR ≥6) or resistance to meropenem or ceftazidime (n = 25). The isolates were identified and characterized for antibiotic resistance phenotype, plasmid-mediated quinolone resistance (PMQR) genes, and other genetic elements and conjugative capacity. The isolates with highest MDR indices were mainly from hospital effluent and comprised ubiquitous bacterial groups of the class Gammaproteobacteria, of the genera Aeromonas, Acinetobacter, Citrobacter, Enterobacter, Klebsiella, and Pseudomonas, and of the class Flavobacteriia, of the genera Chryseobacterium and Myroides. In this group of 25 strains, 19 identified as Gammaproteobacteria harbored at least one PMQR gene (aac(6')-Ib-cr, qnrB, qnrS, or oqxAB) or a class 1 integron gene cassette encoding aminoglycoside, sulfonamide, or carbapenem resistance. Most of the E. coli J53 transconjugants with acquired antibiotic resistance resulted from conjugation with Enterobacteriaceae. These transconjugants demonstrated acquired resistance to a maximum of five classes of antibiotics, one or more PMQR genes and/or a class 1 integron gene cassette. This study shows that ubiquitous bacteria, other than those monitored in water quality controls, are important vectors of antibiotic resistance and can be disseminated from hospital effluent to aquatic environments. This information is relevant to support management options aiming at the control of this public health problem. PMID

  1. ‘Old’ antibiotics for emerging multidrug-resistant bacteria

    PubMed Central

    Bergen, Phillip J.; Landersdorfer, Cornelia B.; Lee, Hee Ji; Li, Jian; Nation, Roger L.

    2014-01-01

    Purpose of review Increased emergence of bacterial resistance and the decline in newly developed antibiotics have necessitated the reintroduction of previously abandoned antimicrobial agents active against multidrug-resistant bacteria. Having never been subjected to contemporary drug development procedures, these ‘old’ antibiotics require redevelopment in order to optimize therapy. This review focuses on colistin as an exemplar of a successful redevelopment process and briefly discusses two other old antibiotics, fusidic acid and fosfomycin. Recent findings Redevelopment of colistin led to an improved understanding of its chemistry, pharmacokinetics and pharmacodynamics, enabling important steps towards optimizing its clinical use in different patient populations. A scientifically based dosing algorithm was developed for critically ill patients, including those with renal impairment. As nephrotoxicity is a dose-limiting adverse event of colistin, rational combination therapy with other antibiotics needs to be investigated. Summary The example of colistin demonstrated that state-of-the-art analytical, microbiological and pharmacokinetic/pharmacodynamic methods can facilitate optimized use of ‘old’ antibiotics in the clinic. Similar methods are now being applied to fosfomycin and fusidic acid in order to optimize therapy. To improve and preserve the usefulness of these antibiotics rational approaches for redevelopment need to be followed. PMID:23041772

  2. Multidrug-resistant tuberculosis in an adult with cystic fibrosis.

    PubMed

    Manika, K; Giouleka, P; Zarogoulidis, K; Kioumis, I

    2013-01-01

    Mycobacterium tuberculosis infection in patients with cystic fibrosis (CF) is rare. We report a 22-year-old CF patient with high fever, dyspnea and weight loss that progressively worsened over 2 weeks before admission. The patient suffered from liver cirrhosis, was colonized with Pseudomonas aeruginosa and had been repeatedly hospitalized for pulmonary infections. The patient was treated initially as for an exacerbation of P. aeruginosa infection, but tuberculosis (TBC) was suspected due to lack of improvement. A CT of the chest revealed enlarged bilateral cavities in the upper and middle lobes. A tuberculin skin test was positive, and M. tuberculosis nucleic acid was isolated from sputum samples. After receiving first-line anti-TBC drugs for 1 month, the patient's condition continued to worsen so molecular drug susceptibility testing was performed. Multidrug-resistant TBC was discovered, leading to a change in regimen. The patient was treated with ethionamide, moxifloxacin, linezolid, amikacin, imipenem/cilastatin and rifabutin and showed a remarkable clinical improvement. Although nontuberculous mycobacteria are more common in CF, the possibility of TBC should not be ignored. In that setting, early suspicion of infection due to resistant M. tuberculosis can be life saving. PMID:22869452

  3. Multidrug resistance after inappropriate tuberculosis treatment: a meta-analysis

    PubMed Central

    van der Werf, Marieke J.; Langendam, Miranda W.; Huitric, Emma; Manissero, Davide

    2012-01-01

    We conducted a systematic review and meta-analysis to assess the evidence for the postulation that inappropriate tuberculosis (TB) regimens are a risk for development of multidrug-resistant (MDR)-TB. MEDLINE, EMBASE and other databases were searched for relevant articles in January 2011. Cohort studies including TB patients who received treatment were selected and data on treatment regimen, drug susceptibility testing results and genotyping results before treatment and at failure or relapse were abstracted from the articles. Four studies were included in the systematic review and two were included in the meta-analysis. In these two studies the risk of developing MDR-TB in patients who failed treatment and used an inappropriate treatment regimen was increased 27-fold (RR 26.7, 95% CI 5.0–141.7) when compared with individuals who received an appropriate treatment regimen. This review provides evidence that supports the general opinion that the development of MDR-TB can be caused by inadequate treatment, given the drug susceptibility pattern of the Mycobacterium tuberculosis bacilli. It should be noted that only two studies provided data for the meta-analysis. The information can be used to advocate for adequate treatment for patients based on drug resistance profiles. PMID:22005918

  4. Effects of Mefloquine Use on Plasmodium vivax Multidrug Resistance

    PubMed Central

    Khim, Nimol; Andrianaranjaka, Voahangy; Popovici, Jean; Kim, Saorin; Ratsimbasoa, Arsene; Benedet, Christophe; Barnadas, Celine; Durand, Remy; Thellier, Marc; Legrand, Eric; Musset, Lise; Menegon, Michela; Severini, Carlo; Nour, Bakri Y.M.; Tichit, Magali; Bouchier, Christiane; Mercereau-Puijalon, Odile

    2014-01-01

    Numerous studies have indicated a strong association between amplification of the multidrug resistance-1 gene and in vivo and in vitro mefloquine resistance of Plasmodium falciparum. Although falciparum infection usually is not treated with mefloquine, incorrect diagnosis, high frequency of undetected mixed infections, or relapses of P. vivax infection triggered by P. falciparum infections expose non–P. falciparum parasites to mefloquine. To assess the consequences of such unintentional treatments on P. vivax, we studied variations in number of Pvmdr-1 (PlasmoDB accession no. PVX_080100, NCBI reference sequence NC_009915.1) copies worldwide in 607 samples collected in areas with different histories of mefloquine use from residents and from travelers returning to France. Number of Pvmdr-1 copies correlated with drug use history. Treatment against P. falciparum exerts substantial collateral pressure against sympatric P. vivax, jeopardizing future use of mefloquine against P. vivax. A drug policy is needed that takes into consideration all co-endemic species of malaria parasites. PMID:25272023

  5. Global dissemination of a multidrug resistant Escherichia coli clone

    PubMed Central

    Petty, Nicola K.; Ben Zakour, Nouri L.; Stanton-Cook, Mitchell; Skippington, Elizabeth; Totsika, Makrina; Forde, Brian M.; Phan, Minh-Duy; Gomes Moriel, Danilo; Peters, Kate M.; Davies, Mark; Rogers, Benjamin A.; Dougan, Gordon; Rodriguez-Baño, Jesús; Pascual, Alvaro; Pitout, Johann D. D.; Upton, Mathew; Paterson, David L.; Walsh, Timothy R.; Schembri, Mark A.; Beatson, Scott A.

    2014-01-01

    Escherichia coli sequence type 131 (ST131) is a globally disseminated, multidrug resistant (MDR) clone responsible for a high proportion of urinary tract and bloodstream infections. The rapid emergence and successful spread of E. coli ST131 is strongly associated with several factors, including resistance to fluoroquinolones, high virulence gene content, the possession of the type 1 fimbriae FimH30 allele, and the production of the CTX-M-15 extended spectrum β-lactamase (ESBL). Here, we used genome sequencing to examine the molecular epidemiology of a collection of E. coli ST131 strains isolated from six distinct geographical locations across the world spanning 2000–2011. The global phylogeny of E. coli ST131, determined from whole-genome sequence data, revealed a single lineage of E. coli ST131 distinct from other extraintestinal E. coli strains within the B2 phylogroup. Three closely related E. coli ST131 sublineages were identified, with little association to geographic origin. The majority of single-nucleotide variants associated with each of the sublineages were due to recombination in regions adjacent to mobile genetic elements (MGEs). The most prevalent sublineage of ST131 strains was characterized by fluoroquinolone resistance, and a distinct virulence factor and MGE profile. Four different variants of the CTX-M ESBL–resistance gene were identified in our ST131 strains, with acquisition of CTX-M-15 representing a defining feature of a discrete but geographically dispersed ST131 sublineage. This study confirms the global dispersal of a single E. coli ST131 clone and demonstrates the role of MGEs and recombination in the evolution of this important MDR pathogen. PMID:24706808

  6. Incidence and Diversity of Antimicrobial Multidrug Resistance Profiles of Uropathogenic Bacteria

    PubMed Central

    Linhares, Inês; Raposo, Teresa; Rodrigues, António

    2015-01-01

    The aim of this study was to assess the most frequent multidrug resistant (MDR) profiles of the main bacteria implicated in community-acquired urinary tract infections (UTI). Only the MDR profiles observed in, at least, 5% of the MDR isolates were considered. A quarter of the bacteria were MDR and the most common MDR profile, including resistance to penicillins, quinolones, and sulfonamides (antibiotics with different mechanisms of action, all mainly recommended by the European Association of Urology for empirical therapy of uncomplicated UTI), was observed, alone or in association with resistance to other antimicrobial classes, in the main bacteria implicated in UTI. The penicillin class was included in all the frequent MDR profiles observed in the ten main bacteria and was the antibiotic with the highest prescription during the study period. The sulfonamides class, included in five of the six more frequent MDR profiles, was avoided between 2000 and 2009. The results suggest that the high MDR percentage and the high diversity of MDR profiles result from a high prescription of antibiotics but also from antibiotic-resistant genes transmitted with other resistance determinants on mobile genetic elements and that the UTI standard treatment guidelines must be adjusted for the community of Aveiro District. PMID:25834814

  7. Incidence and diversity of antimicrobial multidrug resistance profiles of uropathogenic bacteria.

    PubMed

    Linhares, Inês; Raposo, Teresa; Rodrigues, António; Almeida, Adelaide

    2015-01-01

    The aim of this study was to assess the most frequent multidrug resistant (MDR) profiles of the main bacteria implicated in community-acquired urinary tract infections (UTI). Only the MDR profiles observed in, at least, 5% of the MDR isolates were considered. A quarter of the bacteria were MDR and the most common MDR profile, including resistance to penicillins, quinolones, and sulfonamides (antibiotics with different mechanisms of action, all mainly recommended by the European Association of Urology for empirical therapy of uncomplicated UTI), was observed, alone or in association with resistance to other antimicrobial classes, in the main bacteria implicated in UTI. The penicillin class was included in all the frequent MDR profiles observed in the ten main bacteria and was the antibiotic with the highest prescription during the study period. The sulfonamides class, included in five of the six more frequent MDR profiles, was avoided between 2000 and 2009. The results suggest that the high MDR percentage and the high diversity of MDR profiles result from a high prescription of antibiotics but also from antibiotic-resistant genes transmitted with other resistance determinants on mobile genetic elements and that the UTI standard treatment guidelines must be adjusted for the community of Aveiro District. PMID:25834814

  8. [New Drugs for the Treatment of Multidrug-resistant Tuberculosis (MDR-TB)].

    PubMed

    Schaberg, T; Otto-Knapp, R; Bauer, T

    2015-05-01

    This article summarizes the state of development of new drugs for the treatment of multidrug-resistant tuberculosis. We focused on delamanid, bedaquiline, pretomanid, SQ 109 and sutezolid. PMID:25970122

  9. Reversal effect of vitamin D on different multidrug-resistant cells.

    PubMed

    Yan, M; Nuriding, H

    2014-01-01

    We investigated the reversal effect of vitamin D on the multidrug-resistant leukemic Jurkat/ADR and K562/ADR cell lines and conducted a preliminary investigation of its reversal mechanism. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method was used to detect the reversal effect of vitamin D on multidrug-resistant cells. Real-time polymerase chain reaction was used to determine the effect of vitamin D on intracellular expression of mRNA of the multidrug-resistant gene (MDRI) and the multidrug-resistance-related gene (MRP1). A protein quantitative analysis method was used to determine the effect of vitamin D on intracellular glutathione content. After treatment of Jurkat/ADR and K562/ADR cells with vitamin D, multidrug resistance was reversed in a dose-dependent manner, which may have reduced mRNA expression of the MDR1 and MRP1 genes, the P-glycoprotein content on the cell surface, and the intracellular glutathione level. Different concentrations of vitamin D showed varying reversal effects on different multidrug-resistant cells. The resistance mechanism may be related to the inhibition of the expression of MDR1 and MRP1 genes. PMID:25158250

  10. Engineering Nanomedicines to Overcome Multidrug Resistance in Cancer Therapy.

    PubMed

    Beretta, Giovanni L; Cavalieri, Francesca

    2016-01-01

    Drug resistance to conventional antitumor drugs represents one of the major causes of treatment failure in patients affected by tumors. Two main types of drug resistance to anticancer drugs are found in tumors, namely intrinsic resistance, in which tumor cells are inherently resistant to chemotherapy, and acquired resistance, which results from previous drug exposure. Tumor cells resistant to a chemotherapeutic agent become cross-resistant to both similar and structurally unrelated classes of antitumor drugs, a biological mechanism known as multi drug resistance (MDR). Among the strategies considered to overcome MDR, nanovector-mediated drug administration represents an innovative and promising alternative. In this review, we report a number of nanovectors including polymer-drug conjugates, polymeric micelles, nanotubes, LbL nanocapsules, and silica and gold nanoparticles. These systems are designed for the efficient delivery of anthracyclines, vinca alkaloids, taxanes, and others drugs. The development of these nanovectos to specifically overcome MDR and their mechanisms of action are covered and discussed. Finally, we discuss challenges and opportunities for further development of nanodevices-based chemotherapies to circumvent MDR through the design of nanovectors for the delivery of multiple cargoes. PMID:26438248

  11. Hospital costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition

    PubMed Central

    2012-01-01

    Background We aimed to assess the hospital economic costs of nosocomial multi-drug resistant Pseudomonas aeruginosa acquisition. Methods A retrospective study of all hospital admissions between January 1, 2005, and December 31, 2006 was carried out in a 420-bed, urban, tertiary-care teaching hospital in Barcelona (Spain). All patients with a first positive clinical culture for P. aeruginosa more than 48 h after admission were included. Patient and hospitalization characteristics were collected from hospital and microbiology laboratory computerized records. According to antibiotic susceptibility, isolates were classified as non-resistant, resistant and multi-drug resistant. Cost estimation was based on a full-costing cost accounting system and on the criteria of clinical Activity-Based Costing methods. Multivariate analyses were performed using generalized linear models of log-transformed costs. Results Cost estimations were available for 402 nosocomial incident P. aeruginosa positive cultures. Their distribution by antibiotic susceptibility pattern was 37.1% non-resistant, 29.6% resistant and 33.3% multi-drug resistant. The total mean economic cost per admission of patients with multi-drug resistant P. aeruginosa strains was higher than that for non-resistant strains (15,265 vs. 4,933 Euros). In multivariate analysis, resistant and multi-drug resistant strains were independently predictive of an increased hospital total cost in compared with non-resistant strains (the incremental increase in total hospital cost was more than 1.37-fold and 1.77-fold that for non-resistant strains, respectively). Conclusions P. aeruginosa multi-drug resistance independently predicted higher hospital costs with a more than 70% increase per admission compared with non-resistant strains. Prevention of the nosocomial emergence and spread of antimicrobial resistant microorganisms is essential to limit the strong economic impact. PMID:22621745

  12. Cellular functions of vaults and their involvement in multidrug resistance.

    PubMed

    Steiner, E; Holzmann, K; Elbling, L; Micksche, M; Berger, W

    2006-08-01

    Vaults are evolutionary highly conserved ribonucleoprotein (RNP) particles with a hollow barrel-like structure. They are 41 x 73 nm in size and are composed of multiple copies of three proteins and small untranslated RNA (vRNA). The main component of vaults represents the 110 kDa major vault protein (MVP), whereas the two minor vault proteins comprise the 193 kDa vault poly(ADP-ribose) polymerase (VPARP) and the 240 kDa telomerase-associated protein-1 (TEP1). Vaults are abundantly present in the cytoplasm of eukaryotic cells and they were found to be associated with cytoskeletal elements as well as occasionally with the nuclear envelope. Vaults and MVP have been associated with several cellular processes which are also involved in cancer development like cell motility and differentiation. Due to the over-expression of MVP (also termed lung resistance-related protein or LRP) in several P-glycoprotein (P-gp)-negative chemoresistant cancer cell lines, vaults have been linked to multidrug resistance (MDR). Accordingly, high levels of MVP were found in tissues chronically exposed to xenobiotics. In addition, the expression of MVP correlated with the degree of malignancy in certain cancer types, suggesting a direct involvement in tumor development and/or progression. Based on the finding that MVP binds several phosphatases and kinases including PTEN, SHP-2 as well as Erk, evidence is accumulating that MVP might be involved in the regulation of important cell signalling pathways including the PI3K/Akt and the MAPK pathways. In this review we summarize the current knowledge concerning the vault particle and discuss its possible cellular functions, focusing on the role of vaults in chemotherapy resistance. PMID:16918321

  13. Multidrug-Resistant Organism Infections in Patients with Left Ventricular Assist Devices

    PubMed Central

    Donahey, Elisabeth E.; Polly, Derek M.; Vega, J. David; Lyon, Marshall; Butler, Javed; Nguyen, Duc; Pekarek, Ann; Wittersheim, Kristin; Kilgo, Patrick

    2015-01-01

    Left ventricular assist devices improve survival prospects in patients with end-stage heart failure; however, infection complicates up to 59% of implantation cases. How many of these infections are caused by multidrug-resistant organisms is unknown. We sought to identify the incidence, risk factors, and outcomes of multidrug-resistant organism infection in patients who have left ventricular assist devices. We retrospectively evaluated the incidence of multidrug-resistant organisms and the independent risk factors associated with them in 57 patients who had permanent left ventricular assist devices implanted at our institution from May 2007 through October 2011. Outcomes included death, transplantation, device explantation, number of subsequent hospital admissions, and number of subsequent admissions related to infection. Infections were categorized in accordance with criteria from the Infectious Diseases Council of the International Society for Heart and Lung Transplantation. Multidrug-resistant organism infections developed in 18 of 57 patients (31.6%)—a high incidence. We found 3 independent risk factors: therapeutic goal (destination therapy vs bridging), P=0.01; body mass index, P=0.04; and exposed velour at driveline exit sites, P=0.004. We found no significant differences in mortality, transplantation, or device explantation rates; however, there was a statistically significant increase in postimplantation hospital admissions in patients with multidrug-resistant organism infection. To our knowledge, this is the first report in the medical literature concerning multidrug-resistant organism infection in patients who have permanent left ventricular assist devices. PMID:26664303

  14. Bloodstream infections caused by multi-drug resistant Proteus mirabilis: Epidemiology, risk factors and impact of multi-drug resistance.

    PubMed

    Korytny, Alexander; Riesenberg, Klaris; Saidel-Odes, Lisa; Schlaeffer, Fransisc; Borer, Abraham

    2016-06-01

    Background The prevalence of antimicrobial co-resistance among ESBL-producing Enterobactereaceae is extremely high in Israel. Multidrug-resistant Proteus mirabilis strains (MDR-PM), resistant to almost all antibiotic classes have been described. The aim was to determine the risk factors for bloodstream infections caused by MDR-PM and clinical outcomes. Methods A retrospective case-control study. Adult patients with PM bacteremia during 7 years were identified retrospectively and their files reviewed for demographics, underlying diseases, Charlson Comorbidity Index, treatment and outcome. Results One hundred and eighty patients with PM-bloodstream infection (BSI) were included; 90 cases with MDR-PM and 90 controls with sensitive PM (S-PM). Compared to controls, cases more frequently were from nursing homes, had recurrent hospital admissions in the past year and received antibiotic therapy in the previous 3 months, were bedridden and suffered from peripheral vascular disease and peptic ulcer disease (p < 0.001). Two-thirds of the MDR-PM isolates were ESBL-producers vs 4.4% of S-PM isolates (p < 0.001, OR = 47.6, 95% CI = 15.9-142.6). In-hospital crude mortality rate of patients with MDR-PM BSI was 37.7% vs 23.3% in those with S-PM BSI (p = 0.0359, OR = 2, 95% CI = 1.4-3.81). Conclusions PM bacteremia in elderly and functionally-dependent patients is likely to be caused by nearly pan-resistant PM strains in the institution; 51.8% of the patients received inappropriate empiric antibiotic treatment. The crude mortality rate of patients with MDR-PM BSI was significantly higher than that of patients with S-PM BSI. PMID:26763474

  15. The emergence and outbreak of multidrug-resistant typhoid fever in China.

    PubMed

    Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao

    2016-01-01

    Typhoid fever remains a severe public health problem in developing countries. The emergence of resistant typhoid, particularly multidrug-resistant typhoid infections, highlights the necessity of monitoring the resistance characteristics of this invasive pathogen. In this study, we report a typhoid fever outbreak caused by multidrug-resistant Salmonella enterica serovar Typhi strains with an ACSSxtT pattern. Resistance genes conferring these phenotypes were harbored by a large conjugative plasmid, which increases the threat of Salmonella Typhi and thus requires close surveillance for dissemination of strains containing such genes. PMID:27329848

  16. The emergence and outbreak of multidrug-resistant typhoid fever in China

    PubMed Central

    Yan, Meiying; Li, Xinlan; Liao, Qiaohong; Li, Fang; Zhang, Jing; Kan, Biao

    2016-01-01

    Typhoid fever remains a severe public health problem in developing countries. The emergence of resistant typhoid, particularly multidrug-resistant typhoid infections, highlights the necessity of monitoring the resistance characteristics of this invasive pathogen. In this study, we report a typhoid fever outbreak caused by multidrug-resistant Salmonella enterica serovar Typhi strains with an ACSSxtT pattern. Resistance genes conferring these phenotypes were harbored by a large conjugative plasmid, which increases the threat of Salmonella Typhi and thus requires close surveillance for dissemination of strains containing such genes. PMID:27329848

  17. Evolution of acquired resistance to anti-cancer therapy

    PubMed Central

    Foo, Jasmine; Michor, Franziska

    2014-01-01

    Acquired drug resistance is a major limitation for the successful treatment of cancer. Resistance can emerge due to a variety of reasons including host environmental factors as well as genetic or epigenetic alterations in the cancer cells. Evolutionary theory has contributed to the understanding of the dynamics of resistance mutations in a cancer cell population, the risk of resistance pre-existing before the initiation of therapy, the composition of drug cocktails necessary to prevent the emergence of resistance, and optimum drug administration schedules for patient populations at risk of evolving acquired resistance. Here we review recent advances towards elucidating the evolutionary dynamics of acquired drug resistance and outline how evolutionary thinking can contribute to outstanding questions in the field. PMID:24681298

  18. Trametinib modulates cancer multidrug resistance by targeting ABCB1 transporter

    PubMed Central

    Qiu, Jian-Ge; Zhang, Yao-Jun; Li, Yong; Zhao, Jin-Ming; Zhang, Wen-Ji; Jiang, Qi-Wei; Mei, Xiao-Long; Xue, You-Qiu; Qin, Wu-Ming; Yang, Yang; Zheng, Di-Wei; Chen, Yao; Wei, Meng-Ning; Shi, Zhi

    2015-01-01

    Overexpression of adenine triphosphate (ATP)-binding cassette (ABC) transporters is one of the main reasons of multidrug resistance (MDR) in cancer cells. Trametinib, a novel specific small-molecule mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor, is currently used for the treatment of melanoma in clinic. In this study, we investigated the effect of trametinib on MDR mediated by ABC transporters. Trametinib significantly potentiated the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in cancer cells overexpressed ABCB1, but not ABCC1 and ABCG2. Furthermore, trametinib did not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, trametinib potently blocked the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. Importantly, trametinib remarkably enhanced the effect of vincristine against the xenografts of ABCB1-overexpressing cancer cells in nude mice. The predicted binding mode showed the hydrophobic interactions of trametinib within the large drug binding cavity of ABCB1. Consequently, our findings may have important implications for use of trametinib in combination therapy for cancer treatment. PMID:25915534

  19. Multidrug resistant citrobacter: an unusual cause of liver abscess

    PubMed Central

    Kumar, Prabhat; Ghosh, Soumik; Rath, Deepak; Gadpayle, A K

    2013-01-01

    Liver abscesses are infectious, space occupying lesions in the liver, the two most common abscesses being pyogenic and amoebic. A pyogenic liver abscess (PLA) is a rare condition with a reported incidence of 20 per 100 000 hospital admissions in the western population. The right lobe of the liver is the most common site in both types of liver abscess. Clinical presentation is elusive with complaints of fever, right upper quadrant pain in the abdomen and hepatomegaly with or without jaundice. The aetiology of PLA has changed in the past few decades and may be of biliary, portal, arterial or traumatic origin, but many cases are still cryptogenic. The most common organisms causing PLA are Gram-negative aerobes, especially Escherichia coli and Klebsiella pneumoniae. Studies have shown a high degree of antimicrobial susceptibility of isolated organism resulting in an overall lower mortality in PLA. Here, we present a case of PLA caused by multidrug-resistant Citrobacter freundii, which is an unusual organism to be isolated. PMID:23608848

  20. Wallichinine reverses ABCB1-mediated cancer multidrug resistance.

    PubMed

    Lv, Min; Qiu, Jian-Ge; Zhang, Wen-Ji; Jiang, Qi-Wei; Qin, Wu-Ming; Yang, Yang; Zheng, Di-Wei; Chen, Yao; Huang, Jia-Rong; Wang, Kun; Wei, Meng-Ning; Cheng, Ke-Jun; Shi, Zhi

    2016-01-01

    Overexpression of ABCB1 in cancer cells is one of the main reasons of cancer multidrug resistance (MDR). Wallichinine is a compound isolated from piper wallichii and works as an antagonist of platelet activiating factor receptor to inhibit the gathering of blood platelet. In this study, we investigate the effect of wallichinine on cancer MDR mediated by ABCB1 transporter. Wallichinine significantly potentiates the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in ABCB1 overexpressing cancer cells. Furthermore, wallichinine do not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, wallichinine blocks the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. The predicted binding mode shows the hydrophobic interactions of wallichinine within the large drug binding cavity of ABCB1. At all, our study of the interaction of wallichinine with ABCB1 presented herein provides valuable clues for the development of novel MDR reversal reagents from natural products. PMID:27508017

  1. Intracellular pH and the Control of Multidrug Resistance

    NASA Astrophysics Data System (ADS)

    Simon, Sanford; Roy, Deborshi; Schindler, Melvin

    1994-02-01

    Many anticancer drugs are classified as either weak bases or molecules whose binding to cellular structures is pH dependent. Accumulation of these drugs within tumor cells should be affected by transmembrane pH gradients. Indeed, development of multidrug resistance (MDR) in tumor cells has been correlated with an alkaline shift of cytosolic pH. To examine the role of pH in drug partitioning, the distribution of two drugs, doxorubicin and daunomycin, was monitored in fibroblasts and myeloma cells. In both cell types the drugs rapidly accumulated within the cells. The highest concentrations were measured in the most acidic compartments-e.g., lysosomes. Modifying the cellular pH in drug-sensitive cells to mimic reported shifts in MDR caused an immediate change in the cellular drug concentration. Drug accumulation was enhanced by acidic shifts and reversed by alkaline shifts. All of these effects were rapid and reversible. These results demonstrate that the alkaline shift observed in MDR is sufficient to prevent the accumulation of chemotherapeutic drugs independent of active drug efflux.

  2. Multidrug-resistant tuberculosis: Treatment and outcomes of 93 patients

    PubMed Central

    Brode, Sarah K; Varadi, Robert; McNamee, Jane; Malek, Nina; Stewart, Sharon; Jamieson, Frances B; Avendano, Monica

    2015-01-01

    BACKGROUND: Tuberculosis (TB) remains a leading cause of death worldwide and the emergence of multidrug-resistant TB (MDR TB) poses a threat to its control. There is scanty evidence regarding optimal management of MDR TB. The majority of Canadian cases of MDR TB are diagnosed in Ontario; most are managed by the Tuberculosis Service at West Park Healthcare Centre in Toronto. The authors reviewed 93 cases of MDR TB admitted from January 1, 2000 to December 31, 2011. RESULTS: Eighty-nine patients were foreign born. Fifty-six percent had a previous diagnosis of TB and most (70%) had only pulmonary involvement. Symptoms included productive cough, weight loss, fever and malaise. The average length of inpatient stay was 126 days. All patients had a peripherally inserted central catheter for the intensive treatment phase because medications were given intravenously. Treatment lasted for 24 months after bacteriologic conversion, and included a mean (± SD) of 5±1 drugs. A successful outcome at the end of treatment was observed in 84% of patients. Bacteriological conversion was achieved in 98% of patients with initial positive sputum cultures; conversion occurred by four months in 91%. CONCLUSIONS: MDR TB can be controlled with the available anti-TB drugs. PMID:25493698

  3. Wallichinine reverses ABCB1-mediated cancer multidrug resistance

    PubMed Central

    Lv, Min; Qiu, Jian-Ge; Zhang, Wen-Ji; Jiang, Qi-Wei; Qin, Wu-Ming; Yang, Yang; Zheng, Di-Wei; Chen, Yao; Huang, Jia-Rong; Wang, Kun; Wei, Meng-Ning; Cheng, Ke-Jun; Shi, Zhi

    2016-01-01

    Overexpression of ABCB1 in cancer cells is one of the main reasons of cancer multidrug resistance (MDR). Wallichinine is a compound isolated from piper wallichii and works as an antagonist of platelet activiating factor receptor to inhibit the gathering of blood platelet. In this study, we investigate the effect of wallichinine on cancer MDR mediated by ABCB1 transporter. Wallichinine significantly potentiates the effects of two ABCB1 substrates vincristine and doxorubicin on inhibition of growth, arrest of cell cycle and induction of apoptosis in ABCB1 overexpressing cancer cells. Furthermore, wallichinine do not alter the sensitivity of non-ABCB1 substrate cisplatin. Mechanistically, wallichinine blocks the drug-efflux activity of ABCB1 to increase the intracellular accumulation of rhodamine 123 and doxorubicin and stimulates the ATPase of ABCB1 without alteration of the expression of ABCB1. The predicted binding mode shows the hydrophobic interactions of wallichinine within the large drug binding cavity of ABCB1. At all, our study of the interaction of wallichinine with ABCB1 presented herein provides valuable clues for the development of novel MDR reversal reagents from natural products. PMID:27508017

  4. Phenothiazinium antimicrobial photosensitizers are substrates of bacterial multidrug resistance pumps.

    PubMed

    Tegos, George P; Hamblin, Michael R

    2006-01-01

    Antimicrobial photodynamic therapy (PDT) combines a nontoxic photoactivatable dye, or photosensitizer (PS), with harmless visible light to generate singlet oxygen and free radicals that kill microbial cells. Although the light can be focused on the diseased area, the best selectivity is achieved by choosing a PS that binds and penetrates microbial cells. Cationic phenothiazinium dyes, such as methylene blue and toluidine blue O, have been studied for many years and are the only PSs used clinically for antimicrobial PDT. Multidrug resistance pumps (MDRs) are membrane-localized proteins that pump drugs out of cells and have been identified for a wide range of organisms. We asked whether phenothiazinium salts with structures that are amphipathic cations could potentially be substrates of MDRs. We used MDR-deficient mutants of Staphylococcus aureus (NorA), Escherichia coli (TolC), and Pseudomonas aeruginosa (MexAB) and found 2 to 4 logs more killing than seen with wild-type strains by use of three different phenothiazinium PSs and red light. Mutants that overexpress MDRs were protected from killing compared to the wild type. Effective antimicrobial PSs of different chemical structures showed no difference in light-mediated killing depending on MDR phenotype. Differences in uptake of phenothiazinium PS by the cells depending on level of MDR expression were found. We propose that specific MDR inhibitors could be used in combination with phenothiazinium salts to enhance their photodestructive efficiency. PMID:16377686

  5. Marine Natural Products as Models to Circumvent Multidrug Resistance.

    PubMed

    Long, Solida; Sousa, Emília; Kijjoa, Anake; Pinto, Madalena M M

    2016-01-01

    Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds. PMID:27399665

  6. Demonstrating a Multi-drug Resistant Mycobacterium tuberculosis Amplification Microarray

    PubMed Central

    Linger, Yvonne; Kukhtin, Alexander; Golova, Julia; Perov, Alexander; Qu, Peter; Knickerbocker, Christopher; Cooney, Christopher G.; Chandler, Darrell P.

    2014-01-01

    Simplifying microarray workflow is a necessary first step for creating MDR-TB microarray-based diagnostics that can be routinely used in lower-resource environments. An amplification microarray combines asymmetric PCR amplification, target size selection, target labeling, and microarray hybridization within a single solution and into a single microfluidic chamber. A batch processing method is demonstrated with a 9-plex asymmetric master mix and low-density gel element microarray for genotyping multi-drug resistant Mycobacterium tuberculosis (MDR-TB). The protocol described here can be completed in 6 hr and provide correct genotyping with at least 1,000 cell equivalents of genomic DNA. Incorporating on-chip wash steps is feasible, which will result in an entirely closed amplicon method and system. The extent of multiplexing with an amplification microarray is ultimately constrained by the number of primer pairs that can be combined into a single master mix and still achieve desired sensitivity and specificity performance metrics, rather than the number of probes that are immobilized on the array. Likewise, the total analysis time can be shortened or lengthened depending on the specific intended use, research question, and desired limits of detection. Nevertheless, the general approach significantly streamlines microarray workflow for the end user by reducing the number of manually intensive and time-consuming processing steps, and provides a simplified biochemical and microfluidic path for translating microarray-based diagnostics into routine clinical practice. PMID:24796567

  7. Gatifloxacin for short, effective treatment of multidrug-resistant tuberculosis.

    PubMed

    Chiang, C-Y; Van Deun, A; Rieder, H L

    2016-09-01

    The 9-month regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) piloted in Bangladesh and used, with modifications, in Cameroon and Niger, has achieved treatment success in a very large proportion of patients; gatifloxacin (GFX) is likely to have played a critical role in this success. Two months after the publication of a study reporting that GFX and not moxifloxacin (MFX) was associated with dysglycaemia, the manufacturer announced the withdrawal of GFX from the market. The findings of that study may have less significance for the majority of MDR-TB patients living in high-incidence countries who are much younger, have a lower risk of dysglycaemia and suffer from a highly fatal condition. The problem of dysglycaemia is not limited to GFX use and may occur with other fluoroquinolones; furthermore, GFX-associated dysglycemia was manageable among those MDR-TB patients in Bangladesh and Niger in whom it occurred. GFX has now become unavailable in Bangladesh, Cameroon, Niger and other countries piloting the shorter MDR-TB regimens, depriving resource-poor countries of an efficacious, effective and inexpensive drug with a demonstrated good safety profile for the given indication. There is little reason not to make GFX available for MDR-TB treatment as long as the superiority of non-GFX-based MDR-TB regimens is not demonstrated. PMID:27510237

  8. Revisiting the ABCs of multidrug resistance in cancer chemotherapy.

    PubMed

    Tiwari, Amit K; Sodani, Kamlesh; Dai, Chun-Ling; Ashby, Charles R; Chen, Zhe-Sheng

    2011-04-01

    The adenosine tri-phosphate binding cassette (ABC) transporters are one of the largest transmembrane gene families in humans. The ABC transporters are present in a number of tissues, providing protection against xenobiotics and certain endogenous molecules. Unfortunately, their presence produces suboptimal chemotherapeutic outcomes in cancer patient tumor cells. It is well established that they actively efflux antineoplastic agents from cancer cells, producing the multidrug resistance (MDR) phenotype. The inadequate response to chemotherapy and subsequent poor prognosis in cancer patients can be in part the result of the clinical overexpression of ABC transporters. In fact, one of the targeted approaches for overcoming MDR in cancer cells is that directed towards blocking or inhibiting ABC transporters. Indeed, for almost three decades, research has been conducted to overcome MDR through pharmacological inhibition of ABC transporters with limited clinical success. Therefore, contemporary strategies to identify or to synthesize selective "resensitizers" of ABC transporters with limited nonspecific toxicity have been undertaken. Innovative approaches en route to understanding specific biochemical role of ABC transporters in MDR and tumorigenesis will prove essential to direct our knowledge towards more effective targeted therapies. This review briefly discusses the current knowledge regarding the clinical involvement of ABC transporters in MDR to antineoplastic drugs and highlights approaches undertaken so far to overcome ABC transporter-mediated MDR in cancer. PMID:21118094

  9. The multidrug resistant modulator HZ08 reverses multidrug resistance via P-glycoprotein inhibition and apoptosis sensitization in human epidermoid carcinoma cell line KBV200.

    PubMed

    Zhu, Y-L; Cen, J; Zhang, Y-Y; Feng, Y-D; Yang, Y; Li, Y-M; Huang, W-L

    2012-05-01

    Previous studies have demonstrated that the multidrug resistance modulator HZ08 has a strong multidrug resistance reversal effect in vitro and in vivo by inhibiting P-glycoprotein and multidrug resistance-associated protein 1 in K562/A02 and MCF-7/ADM cells, respectively. However, there are many other mechanisms responsible for resistance. In this study, MTT assay was used to examine the cytotoxicity and multidrug resistance reversal of HZ08 in KBV200 cells. It was also used to detect Rh123 and adriamycin accumulation in the presence of HZ08 to assess the effect on P-glycoprotein. Caspase-3 activity was analyzed under the incubation of HZ08 per se and in combination with vincristine. Results showed that HZ08 could increase the activity of caspase-3 with P-glycoprotein inhibition. Further studies revealed that HZ08 increased vincristine-induced apoptosis, characterized as an intrinsic apoptosis pathway with enhanced G2/M phase arrest, since HZ08 had an effect on the intrinsic apoptotic regulator Bcl-2 and Bax. Therefore, the outstanding reversal effect of HZ08 occurs not only through suppressing the P-glycoprotein function but also through activating the intrinsic apoptosis pathway. PMID:22344570

  10. Detection of Multi-drug Resistant Acinetobacter Lwoffii Isolated from Soil of Mink Farm.

    PubMed

    Sun, Na; Wen, Yong Jun; Zhang, Shu Qin; Zhu, Hong Wei; Guo, Li; Wang, Feng Xue; Chen, Qiang; Ma, Hong Xia; Cheng, Shi Peng

    2016-07-01

    There were 4 Acinetobacter lwoffii obtained from soil samples. The antimicrobial susceptibility of the strains to 16 antimicrobial agents was investigated using K-B method. Three isolates showed the multi-drug resistance. The presence of resistance genes and integrons was determined using PCR. The aadA1, aac(3')-IIc, aph(3')-VII, aac(6')-Ib, sul2, cat2, floR, and tet(K) genes were detected, respectively. Three class 1 integrons were obtained. The arr-3-aacA4 and blaPSE-1 gene cassette, which cause resistance to aminoglycoside and beta-lactamase antibiotics. Our results reported the detection of multi-drug resistant and carried resistant genes Acinetobacter lwoffii from soil. The findings suggested that we should pay close attention to the prevalence of multi-drug resistant bacterial species of environment. PMID:27554122

  11. [Significance of efflux pumps in multidrug resistance of Gram-negative bacteria].

    PubMed

    Wiercińska, Olga; Chojecka, Agnieszka; Kanclerski, Krzysztof; Rőhm-Rodowald, Ewa; Jakimiak, Bożenna

    2015-01-01

    The phenomenon of multidrug. resistance of bacteria is a serious problem of modern medicine. This resistance largely is a consequence of abuse and improper use of antibacterial substances, especially antibiotics and chemotherapeutics in hospital settings. Multidrug resistance is caused by a number of interacting mechanisms of resistance. Recent studies have indicated that efflux pumps and systems of efflux pumps are an important determinant of this phenomenon. Contribute to this particular RND efflux systems of Gram-negative bacteria, which possess a wide range of substrates such as antibiotics, dyes, detergents, toxins and active substances of disinfectants and antiseptics. These transporters are usually encoded on bacterial chromosomes. Genes encoding efflux pumps' proteins may also be carried on plasmids and other mobile genetic elements. Such pumps are usually specific to a small group of substrates, but as an additional mechanism of resistance may contribute to the multidrug resistance. PMID:26084076

  12. CD44-engineered mesoporous silica nanoparticles for overcoming multidrug resistance in breast cancer

    NASA Astrophysics Data System (ADS)

    Wang, Xin; Liu, Ying; Wang, Shouju; Shi, Donghong; Zhou, Xianguang; Wang, Chunyan; Wu, Jiang; Zeng, Zhiyong; Li, Yanjun; Sun, Jing; Wang, Jiandong; Zhang, Longjiang; Teng, Zhaogang; Lu, Guangming

    2015-03-01

    Multidrug resistance is a major impediment for the successful chemotherapy in breast cancer. CD44 is over-expressed in multidrug resistant human breast cancer cells. CD44 monoclonal antibody exhibits anticancer potential by inhibiting proliferation and regulating P-glycoprotein-mediated drug efflux activity in multidrug resistant cells. Thereby, CD44 monoclonal antibody in combination with chemotherapeutic drug might be result in enhancing chemosensitivity and overcoming multidrug resistance. The purpose of this study is to investigate the effects of the CD44 monoclonal antibody functionalized mesoporous silica nanoparticles containing doxorubicin on human breast resistant cancer MCF-7 cells. The data showed that CD44-modified mesoporous silica nanoparticles increased cytotoxicity and enhanced the downregulation of P-glycoprotein in comparison to CD44 antibody. Moreover, CD44-engineered mesoporous silica nanoparticles provided active target, which promoted more cellular uptake of DOX in the resistant cells and more retention of DOX in tumor tissues than unengineered counterpart. Animal studies of the resistant breast cancer xenografts demonstrated that CD44-engineered drug delivery system remarkably induced apoptosis and inhibited the tumor growth. Our results indicated that the CD44-engineered mesoporous silica nanoparticle-based drug delivery system offers an effective approach to overcome multidrug resistance in human breast cancer.

  13. National action plan to combat multidrug-resistant tuberculosis.

    PubMed

    1992-06-19

    At no time in recent history has tuberculosis (TB) been as great a concern as it is today. TB cases are on the increase, and the most serious aspect of the problem is the recent occurrence of outbreaks of multidrug-resistant (MDR) TB, which pose an urgent public health problem and require rapid intervention. A Task Force composed of representatives of many federal agencies has developed a National Action Plan for addressing this problem. The Task Force identified a number of objectives to be met if MDR-TB is to be successfully combatted. These objectives fall under the categories of a) surveillance and epidemiology--determining the magnitude and nature of the problem; b) laboratory diagnosis--improving the rapidity, sensitivity, and reliability of diagnostic methods for MDR-TB; c) patient management--effectively managing patients who have MDR-TB and preventing patients with drug-susceptible TB from developing drug-resistant disease; d) screening and preventive therapy--identifying persons who are infected with or at risk of developing MDR-TB and preventing them from developing clinically active TB; e) infection control--minimizing the risk of transmission of MDR-TB to patients, workers, and others in institutional settings; f) outbreak control; g) program evaluation--ensuring that TB programs are effective in managing patients and preventing MDR-TB; h) information dissemination/training and education; and i) research to provide new, more effective tools with which to combat MDR-TB. The Action Plan lays out a series of activities to be undertaken at the national level. For each category, the Plan presents statements of problems to be overcome, followed by a summary of the objective to be achieved and steps to be carried out. For each implementation step, responsibility is assigned to the appropriate organization and start-up dates are listed. PMID:1640920

  14. A Novel Way of Treating Multidrug-resistant Enterococci

    PubMed Central

    Desai, Hem; Wong, Ryan; Pasha, Ahmed Khurshid

    2016-01-01

    Context: Daptomycin is the only antibiotic available with in vitro bactericidal activity against vancomycin-resistant enterococci (VRE). Its increased use has resulted in cases of decreased daptomycin efficacy. Recent in vitro studies have shown effective use of beta (β)-lactam and daptomycin antibiotics, as a combination therapy, in the treatment of VRE. We describe a case of effective treatment in a patient with VRE infection using dual ampicillin and daptomycin therapy that shows bench-to-bedside application of the abovementioned finding. Case Report: A 76-year-old gentleman with a history of bilateral arthroplasty was admitted with a swollen left knee. Blood cultures were positive for Enterococcus faecium. Left knee joint aspiration showed leukocytosis and alpha defensins. Extensive imaging did not show any other source of infection. Culture sensitivity results showed multidrug-resistant enterococci sensitive to daptomycin. The patient was started on intravenous (IV) daptomycin. His left knee prosthesis was explanted and a spacer was placed. The patient continued to be bacteremic for 10 days after removing the knee prosthesis. The patient was trialed on combination IV ampicillin and daptomycin. His blood culture turned negative 2 days later. The patient was discharged home to continue 6 weeks of IV ampicillin and daptomycin. Conclusion: The exact mechanism of the daptomycin/ampicillin synergy effect is unclear. Current hypothesis suggests that ampicillin causes a reduction in the net positive charge of the bacterial surface, possibly by releasing lipoteichoic acid (LTA) from the cell wall. This process increases the ability of the cationic daptomycin/calcium complex to bind to the cell wall more effectively. Our case shows the clinical application of the same. A prospective randomized control trial to explore the effectiveness of dual antibiotic therapy in vivo is needed. If proven, daptomycin/β-lactam can become a standard of care to treat VRE and decrease

  15. Interleukin-6: A Critical Cytokine in Cancer Multidrug Resistance.

    PubMed

    Ghandadi, Morteza; Sahebkar, Amirhossein

    2016-01-01

    Multidrug resistance (MDR) is a phenomenon through which tumor cells develop resistance against the cytotoxic effects of various structurally and mechanistically unrelated chemotherapeutic agents. The most consistent feature in MDR is overexpression and/or overactivity of ATP-dependent drug efflux transporters. Other mechanisms such as overexpression of drug-detoxifying enzymes and alterations in pro-survival or pro-death signaling pathways are also responsible for MDR. Inflammatory mediators including interleukin-6 (IL-6) play important roles in various events during inflammation and are also involved in development and progression of several types of cancers. Mounting evidence has suggested a crosstalk between IL-6 and MDR in cancer, highlighting the role of IL-6 in chemotherapy response, and the potential opportunity to control MDR through modulation of IL-6 expression. Upregulation of IL-6 has been shown to promote MDR through activation of Janus kinases (JAK)/signal transducer and activator of transcription 3 (STAT3), phosphatidylinositol-3 kinase (PI3K)/protein kinase B (Akt), and Ras-MAPK (mitogen-activated protein kinase) pathways. Activation of the aforementioned pathways changes the expression pattern of several genes involved in proliferation, survival and cell cycle regulation, thus facilitating MDR. Conversely, IL-6 inhibition using different strategies (antibodies, siRNA, and antisense transfection) has been shown to improve tumor responsiveness and mitigate MDR in different cancer cell lines. This review focuses on the in vitro, experimental and clinical findings on the role of IL-6 in MDR, and potential therapeutic opportunities arising from this role of IL-6. PMID:26601970

  16. Multidrug-Resistant Nontuberculous Mycobacteria Isolated from Cystic Fibrosis Patients

    PubMed Central

    Cândido, Pedro Henrique Campanini; Nunes, Luciana de Souza; Marques, Elizabeth Andrade; Folescu, Tânia Wrobel; Coelho, Fábrice Santana; de Moura, Vinicius Calado Nogueira; da Silva, Marlei Gomes; Gomes, Karen Machado; Lourenço, Maria Cristina da Silva; Aguiar, Fábio Silva; Chitolina, Fernanda; Armstrong, Derek T.; Leão, Sylvia Cardoso; Neves, Felipe Piedade Gonçalves; Mello, Fernanda Carvalho de Queiroz

    2014-01-01

    Worldwide, nontuberculous mycobacteria (NTM) have become emergent pathogens of pulmonary infections in cystic fibrosis (CF) patients, with an estimated prevalence ranging from 5 to 20%. This work investigated the presence of NTM in sputum samples of 129 CF patients (2 to 18 years old) submitted to longitudinal clinical supervision at a regional reference center in Rio de Janeiro, Brazil. From June 2009 to March 2012, 36 NTM isolates recovered from 10 (7.75%) out of 129 children were obtained. Molecular identification of NTM was performed by using PCR restriction analysis targeting the hsp65 gene (PRA-hsp65) and sequencing of the rpoB gene, and susceptibility tests were performed that followed Clinical and Laboratory Standards Institute recommendations. For evaluating the genotypic diversity, pulsed-field gel electrophoresis (PFGE) and/or enterobacterial repetitive intergenic consensus sequence PCR (ERIC-PCR) was performed. The species identified were Mycobacterium abscessus subsp. bolletii (n = 24), M. abscessus subsp. abscessus (n = 6), Mycobacterium fortuitum (n = 3), Mycobacterium marseillense (n = 2), and Mycobacterium timonense (n = 1). Most of the isolates presented resistance to five or more of the antimicrobials tested. Typing profiles were mainly patient specific. The PFGE profiles indicated the presence of two clonal groups for M. abscessus subsp. abscessus and five clonal groups for M. abscesssus subsp. bolletii, with just one clone detected in two patients. Given the observed multidrug resistance patterns and the possibility of transmission between patients, we suggest the implementation of continuous and routine investigation of NTM infection or colonization in CF patients, including countries with a high burden of tuberculosis disease. PMID:24920766

  17. Draft genome sequence of a multidrug-resistant Chryseobacterium indologenes isolate from Malaysia

    PubMed Central

    Yu, Choo Yee; Ang, Geik Yong; Cheng, Huey Jia; Cheong, Yuet Meng; Yin, Wai-Fong; Chan, Kok-Gan

    2015-01-01

    Chryseobacterium indologenes is an emerging pathogen which poses a threat in clinical healthcare setting due to its multidrug-resistant phenotype and its common association with nosocomial infections. Here, we report the draft genome of a multidrug-resistant C. indologenes CI_885 isolated in 2014 from Malaysia. The 908,704-kb genome harbors a repertoire of putative antibiotic resistance determinants which may elucidate the molecular basis and underlying mechanisms of its resistant to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number LJOD00000000. PMID:26981402

  18. Draft genome sequence of a multidrug-resistant Chryseobacterium indologenes isolate from Malaysia.

    PubMed

    Yu, Choo Yee; Ang, Geik Yong; Cheng, Huey Jia; Cheong, Yuet Meng; Yin, Wai-Fong; Chan, Kok-Gan

    2016-03-01

    Chryseobacterium indologenes is an emerging pathogen which poses a threat in clinical healthcare setting due to its multidrug-resistant phenotype and its common association with nosocomial infections. Here, we report the draft genome of a multidrug-resistant C. indologenes CI_885 isolated in 2014 from Malaysia. The 908,704-kb genome harbors a repertoire of putative antibiotic resistance determinants which may elucidate the molecular basis and underlying mechanisms of its resistant to various classes of antibiotics. The genome sequence has been deposited in DDBJ/EMBL/GenBank under the accession number LJOD00000000. PMID:26981402

  19. ATP-dependent transport of vinblastine in vesicles from human multidrug-resistant cells

    SciTech Connect

    Horio, M.; Gottesman, M.M.; Pastan, I. )

    1988-05-01

    Resistance of human cancer cells to multiple cytotoxic hydrophobic agents (multidrug resistance) is due to overexpression of the MDR1 gene, whose product is the plasma membrane P-glycoprotein. Plasma membrane vesicles partially purified from multidrug-resistant human KB carcinoma cells, but not from drug-sensitive cells, accumulate ({sup 3}H)vinblastine in an ATP-dependent manner. This transport is osmotically sensitive, with an apparent K{sub m} of 38 {mu}M for ATP and of {approx} 2 {mu}M for vinblastine. The nonhydrolyzable analog adenosine 5{prime}-({beta},{gamma}-imido)triphosphate does not substitute for ATP but is a competitive inhibitor of ATP for the transport process. Vanadate, and ATPase inhibitor, is a potent noncompetitive inhibitor of transport. These results indicate that hydrolysis of ATP is probably required for active transport vinblastine. Several other drugs to which multidrug-resistant cell lines are resistant inhibit transport, with relative potencies as follows: vincristine > actinomycin D > daunomycin > colchicine = puromycin. Verapamil and quinidine, which reverse the multidrug-resistance phenotype, are good inhibitors of the transport process. These results confirm that multidrug-resistant cells express an energy-dependent plasma membrane transporter for hydrophobic drugs, and establish a system for the detailed biochemical analysis of this transport process.

  20. Role of FKS Mutations in Candida glabrata: MIC values, echinocandin resistance, and multidrug resistance.

    PubMed

    Pham, Cau D; Iqbal, Naureen; Bolden, Carol B; Kuykendall, Randall J; Harrison, Lee H; Farley, Monica M; Schaffner, William; Beldavs, Zintars G; Chiller, Tom M; Park, Benjamin J; Cleveland, Angela A; Lockhart, Shawn R

    2014-08-01

    Candida glabrata is the second leading cause of candidemia in U.S. hospitals. Current guidelines suggest that an echinocandin be used as the primary therapy for the treatment of C. glabrata disease due to the high rate of resistance to fluconazole. Recent case reports indicate that C. glabrata resistance to echinocandins may be increasing. We performed susceptibility testing on 1,380 isolates of C. glabrata collected between 2008 and 2013 from four U.S. cities, Atlanta, Baltimore, Knoxville, and Portland. Our analysis showed that 3.1%, 3.3%, and 3.6% of the isolates were resistant to anidulafungin, caspofungin, and micafungin, respectively. We screened 1,032 of these isolates, including all 77 that had either a resistant or intermediate MIC value with respect to at least one echinocandin, for mutations in the hot spot regions of FKS1 and FKS2, the major mechanism of echinocandin resistance. Fifty-one isolates were identified with hot spot mutations, 16 in FKS1 and 35 in FKS2. All of the isolates with an FKS mutation except one were resistant to at least one echinocandin by susceptibility testing. Of the isolates resistant to at least one echinocandin, 36% were also resistant to fluconazole. Echinocandin resistance among U.S. C. glabrata isolates is a concern, especially in light of the fact that one-third of those isolates may be multidrug resistant. Further monitoring of U.S. C. glabrata isolates for echinocandin resistance is warranted. PMID:24890592

  1. Colonization of multidrug resistant pathogens in a hybrid pediatric cardiac surgery center

    PubMed Central

    Haponiuk, Ireneusz; Steffens, Mariusz; Arlukowicz, Elzbieta; Irga-Jaworska, Ninela; Chojnicki, Maciej; Kwasniak, Ewelina; Zielinski, Jacek

    2016-01-01

    Introduction The incidence of multidrug resistant microorganisms worldwide is increasing. The aim of the study was to present institutional experience with the multidrug resistant microorganism colonization patterns observed in children with congenital heart diseases hospitalized in a hybrid pediatric cardiac surgery center. Material and methods Microbiological samples were routinely collected in all children admitted to our department. All microbiological samples were analyzed with regard to multidrug resistant microorganisms: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), Gram-negative rods producing extended-spectrum beta-lactamases (ESBL), multidrug resistant Gram-negative rods (MDR-GNRs), carbapenemase-producing Klebsiella pneumoniae (KPC), carbapenem-resistant Acinetobacter baumannii (CRAB) and Pseudomonas aeruginosa (CRPA). Results In 30 (9%) swabs ‘alert’ pathogens from the above group of listed microorganisms were found. All positive swabs were isolated in 19 (16.1%) children. Multidrug resistant pathogen colonization was statistically significantly more often observed in children admitted from other medical facilities than in children admitted from home (38% vs. 10%, p = 0.0089). In the group of children younger than 6 months ‘alert’ pathogen were more often observed than in older children (34.1% vs. 5.4%, p < 0.001). Conclusions Preoperative multidrug resistant pathogen screening in children admitted and referred for congenital heart disease procedures may be of great importance since many of these patients are colonized with resistant bacteria. Knowledge of the patient's microbiome is important in local epidemiological control along with tailoring the most effective preoperative prophylactic antibiotic for each patient. The impact of preoperative screening on postoperative infections and other complications requires further analysis. PMID:27279859

  2. A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity.

    PubMed

    Zheng, Yan-Bo; Gong, Jian-Hua; Liu, Xiu-Jun; Wu, Shu-Ying; Li, Yi; Xu, Xian-Dong; Shang, Bo-Yang; Zhou, Jin-Ming; Zhu, Zhi-Ling; Si, Shu-Yi; Zhen, Yong-Su

    2016-01-01

    Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl-5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037-0.426 μM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug-resistant tumors. PMID:27510727

  3. A Novel Nitrobenzoate Microtubule Inhibitor that Overcomes Multidrug Resistance Exhibits Antitumor Activity

    PubMed Central

    Zheng, Yan-Bo; Gong, Jian-Hua; Liu, Xiu-Jun; Wu, Shu-Ying; Li, Yi; Xu, Xian-Dong; Shang, Bo-Yang; Zhou, Jin-Ming; Zhu, Zhi-Ling; Si, Shu-Yi; Zhen, Yong-Su

    2016-01-01

    Multidrug resistance is a major limitation for microtubule-binding agents in cancer treatment. Here we report a novel microtubule inhibitor (2-morpholin-4-yl-5-nitro-benzoic acid 4-methylsulfanyl-benzyl ester, IMB5046), its cytotoxicity against multidrug-resistant cell lines and its antitumor efficacy in animal models. IMB5046 disrupted microtubule structures in cells and inhibited purified tubulin polymerization in vitro. It bound to the colchicine pocket of tubulin. IMB5046 displayed potent cytotoxicity against multiple tumor cell lines with an IC50 range of 0.037–0.426 μM. Notably, several multidrug-resistant cell lines which were resistant to colchicine, vincristine and paclitaxel remained sensitive to IMB5046. IMB5046 was not a P-glycoprotein substrate. IMB5046 blocked cell cycle at G2/M phase and induced cell apoptosis. Microarray assay indicated that the differentially expressed genes after IMB5046 treatment were highly related to immune system, cell death and cancer. In a mouse xenograft model IMB5046 inhibited the growth of human lung tumor xenograft by 83% at a well-tolerated dose. It is concluded that IMB5046 is a tubulin polymerization inhibitor with novel chemical structure and can overcome multidrug resistance. It is a promising lead compound for cancer chemotherapy, especially for treatment of multidrug-resistant tumors. PMID:27510727

  4. Counting Pyrazinamide in Regimens for Multidrug-Resistant Tuberculosis

    PubMed Central

    Becerra, Mercedes C.; Tierney, Dylan B.; Rich, Michael L.; Bonilla, Cesar; Bayona, Jaime; McLaughlin, Megan M.; Mitnick, Carole D.

    2015-01-01

    Rationale: For treatment of multidrug-resistant tuberculosis, World Health Organization (WHO) guidelines recommend four likely effective drugs plus pyrazinamide (PZA), irrespective of the likely effectiveness of PZA in an individual patient. Whether this regimen should be supplemented in the absence of likely PZA effectiveness is an open question. Objectives: The objectives of this study were to examine (1) whether individuals receiving four likely effective drugs (based on documented susceptibility or no prior exposure) experienced higher mortality during the intensive phase of treatment than those receiving five likely effective drugs and (2) whether the WHO-recommended regimen (four likely effective drugs plus PZA) may be compromised in individuals in whom PZA is not likely effective. Methods: Among 668 patients, we compared the hazard of death across regimen groups characterized by the number of likely effective drugs and whether pyrazinamide was one of the likely effective drugs. Measurements and Main Results: Relative to five likely effective drugs, regimens of four likely effective drugs and the WHO-recommended regimen used in individuals in whom PZA was not likely effective were associated with higher mortality rates (respectively, adjusted hazard ratio [HR], 2.87; 95% confidence interval [CI], 1.35–6.09 and adjusted HR, 2.76; 95% CI, 0.92–8.27). The mortality rate for a regimen of five likely effective drugs with likely effective PZA was similar to that for the regimen of five likely effective drugs without PZA (HR, 1.00; 95% CI, 0.12–8.00). Conclusions: Mortality may be reduced by the inclusion of five likely effective drugs, including an injectable, during the intensive phase of treatment. If PZA is unlikely to be effective in an individual patient, these results suggest adding a different, likely effective drug. PMID:25664920

  5. [Adverse drug reactions in multidrug-resistant tuberculosis].

    PubMed

    Palmero, Domingo; Cruz, Víctor; Museli, Tomás; Pavlovsky, Hernán; Fernández, Juan; Waisman, Jaime

    2010-01-01

    Multidrug-resistant tuberculosis (MDRTB) poses difficulties in diagnosis and treatment, including increased frequency of adverse reactions to antituberculosis drugs (ADRAs), which compromise the effectiveness of treatment. This is specially complicated in the treatment of patients co-infected with HIV which includes the antiretroviral therapy plus the treatment of eventual comorbidities. A total of 121 MDRTB patients, 87 HIV-negative and 34 HIV positive, assisted in the Hospital F. J. Muñiz, Buenos Aires, during the period 2003-2007 were retrospectively studied. The incidence of ADRAs among the two groups of patients was compared. All the patients with adherence to treatment (no more than one abandon, recovered) were included in the study. Antituberculosis drugs used were: ethambutol, pyrazinamide, ofloxacin, moxifloxacin, cycloserine, ethionamide, PAS, streptomycin, kanamycin, amikacin and linezolid. The emergence of ADRAs and the proportion of severe reactions attributed to antituberculosis drugs were similar in both groups: 44.8% in HIV negative and 44.1% in HIV positive, but it was observed an additional 23.5% of adverse reactions to antiretroviral therapy in the second group. There were differences in the type of reactions and time of occurrence between the two groups. One HIV positive patient died of epidermolysis. The proportion of adverse reactions in HIV/AIDS patients increased 50% when those attributed to antiretroviral treatment were included. We conclude that the studied population showed a frequency of ADRAs higher than it would be expected in the treatment of susceptible TB, but there was no difference in its frequency among HIV-negative and positive patients. PMID:20920959

  6. Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

    PubMed Central

    Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.

    2013-01-01

    Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2–53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17–0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17–50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease. PMID:23223591

  7. Characteristics of multidrug-resistant tuberculosis in Namibia

    PubMed Central

    2012-01-01

    Background To describe the epidemiology and possible risk factors for the development of multidrug-resistant tuberculosis (MDR-TB) in Namibia. Methods Using medical records and patient questionnaires, we conducted a case-control study among patients diagnosed with TB between January 2007 and March 2009. Cases were defined as patients with laboratory-confirmed MDR-TB; controls had laboratory-confirmed drug-susceptible TB or were being treated with WHO Category I or Category II treatment regimens. Results We enrolled 117 MDR-TB cases and 251 TB controls, of which 100% and 2% were laboratory-confirmed, respectively. Among cases, 97% (113/117) had been treated for TB before the current episode compared with 46% (115/251) of controls (odds ratio [OR] 28.7, 95% confidence interval [CI] 10.3–80.5). Cases were significantly more likely to have been previously hospitalized (OR 1.9, 95% CI 1.1–3.5) and to have had a household member with MDR-TB (OR 5.1, 95% CI 2.1–12.5). These associations remained significant when separately controlled for being currently hospitalized or HIV-infection. Conclusions MDR-TB was associated with previous treatment for TB, previous hospitalization, and having had a household member with MDR-TB, suggesting that TB control practices have been inadequate. Strengthening basic TB control practices, including expanding laboratory confirmation, directly observed therapy, and infection control, are critical to the prevention of MDR-TB. PMID:23273024

  8. Molecular Characterization of Multidrug Resistant Hospital Isolates Using the Antimicrobial Resistance Determinant Microarray

    PubMed Central

    Leski, Tomasz A.; Vora, Gary J.; Barrows, Brian R.; Pimentel, Guillermo; House, Brent L.; Nicklasson, Matilda; Wasfy, Momtaz; Abdel-Maksoud, Mohamed; Taitt, Chris Rowe

    2013-01-01

    Molecular methods that enable the detection of antimicrobial resistance determinants are critical surveillance tools that are necessary to aid in curbing the spread of antibiotic resistance. In this study, we describe the use of the Antimicrobial Resistance Determinant Microarray (ARDM) that targets 239 unique genes that confer resistance to 12 classes of antimicrobial compounds, quaternary amines and streptothricin for the determination of multidrug resistance (MDR) gene profiles. Fourteen reference MDR strains, which either were genome, sequenced or possessed well characterized drug resistance profiles were used to optimize detection algorithms and threshold criteria to ensure the microarray's effectiveness for unbiased characterization of antimicrobial resistance determinants in MDR strains. The subsequent testing of Acinetobacter baumannii, Escherichia coli and Klebsiella pneumoniae hospital isolates revealed the presence of several antibiotic resistance genes [e.g. belonging to TEM, SHV, OXA and CTX-M classes (and OXA and CTX-M subfamilies) of β-lactamases] and their assemblages which were confirmed by PCR and DNA sequence analysis. When combined with results from the reference strains, ∼25% of the ARDM content was confirmed as effective for representing allelic content from both Gram-positive and –negative species. Taken together, the ARDM identified MDR assemblages containing six to 18 unique resistance genes in each strain tested, demonstrating its utility as a powerful tool for molecular epidemiological investigations of antimicrobial resistance in clinically relevant bacterial pathogens. PMID:23936031

  9. Recent independent emergence of multiple multidrug-resistant Serratia marcescens clones within the United Kingdom and Ireland

    PubMed Central

    Moradigaravand, Danesh; Boinett, Christine J.; Martin, Veronique; Peacock, Sharon J.; Parkhill, Julian

    2016-01-01

    Serratia marcescens, a member of the Enterobacteriaceae family, is a Gram-negative bacterium responsible for a wide range of nosocomial infections. The emergence of multidrug-resistant strains is an increasing danger to public health. To design effective means to control the dissemination of S. marcescens, an in-depth analysis of the population structure and variation is required. Utilizing whole-genome sequencing, we characterized the population structure and variation, as well as the antimicrobial resistance determinants, of a systematic collection of antimicrobial-resistant S. marcescens associated with bloodstream infections in hospitals across the United Kingdom and Ireland between 2001 and 2011. Our results show that S. marcescens is a diverse species with a high level of genomic variation. However, the collection was largely composed of a limited number of clones that emerged from this diverse background within the past few decades. We identified potential recent transmissions of these clones, within and between hospitals, and showed that they have acquired antimicrobial resistance determinants for different beta-lactams, ciprofloxacin, and tetracyclines on multiple occasions. The expansion of these multidrug-resistant clones suggests that the treatment of S. marcescens infections will become increasingly difficult in the future. PMID:27432456

  10. The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons

    PubMed Central

    Ravi, Anuradha; Avershina, Ekaterina; Foley, Steven L.; Ludvigsen, Jane; Storrø, Ola; Øien, Torbjørn; Johnsen, Roar; McCartney, Anne L.; L’Abée-Lund, Trine M.; Rudi, Knut

    2015-01-01

    Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance. PMID:26507767

  11. The commensal infant gut meta-mobilome as a potential reservoir for persistent multidrug resistance integrons.

    PubMed

    Ravi, Anuradha; Avershina, Ekaterina; Foley, Steven L; Ludvigsen, Jane; Storrø, Ola; Øien, Torbjørn; Johnsen, Roar; McCartney, Anne L; L'Abée-Lund, Trine M; Rudi, Knut

    2015-01-01

    Despite the accumulating knowledge on the development and establishment of the gut microbiota, its role as a reservoir for multidrug resistance is not well understood. This study investigated the prevalence and persistence patterns of an integrase gene (int1), used as a proxy for integrons (which often carry multiple antimicrobial resistance genes), in the fecal microbiota of 147 mothers and their children sampled longitudinally from birth to 2 years. The study showed the int1 gene was detected in 15% of the study population, and apparently more persistent than the microbial community structure itself. We found int1 to be persistent throughout the first two years of life, as well as between mothers and their 2-year-old children. Metagenome sequencing revealed integrons in the gut meta-mobilome that were associated with plasmids and multidrug resistance. In conclusion, the persistent nature of integrons in the infant gut microbiota makes it a potential reservoir of mobile multidrug resistance. PMID:26507767

  12. A Research-Inspired Laboratory Sequence Investigating Acquired Drug Resistance

    ERIC Educational Resources Information Center

    Taylor, Elizabeth Vogel; Fortune, Jennifer A.; Drennan, Catherine L.

    2010-01-01

    Here, we present a six-session laboratory exercise designed to introduce students to standard biochemical techniques in the context of investigating a high impact research topic, acquired resistance to the cancer drug Gleevec. Students express a Gleevec-resistant mutant of the Abelson tyrosine kinase domain, the active domain of an oncogenic…

  13. Emergence of multidrug-resistant Salmonella enterica serotype Newport infections resistant to expanded-spectrum cephalosporins in the United States.

    PubMed

    Gupta, Amita; Fontana, John; Crowe, Colleen; Bolstorff, Barbara; Stout, Alison; Van Duyne, Susan; Hoekstra, Mike P; Whichard, Jean M; Barrett, Timothy J; Angulo, Frederick J

    2003-12-01

    We describe a field investigation in New England that identified the emergence and epidemiology of new strains of multidrug-resistant Salmonella, Newport-MDRAmpC, and summarize the Center for Disease Control and Prevention's surveillance data for these infections. In Massachusetts, the prevalence of Newport-MDRAmpC among Salmonella serotype Newport isolates obtained from humans increased from 0% (0/14) in 1998 to 53% (32/60) in 2001 (P<.001). In a retrospective case-control study, infection with Newport-MDRAmpC was domestically acquired and was associated with exposure to a dairy farm. Isolates from both humans and cattle had indistinguishable or closely related antibiograms and pulsed-field gel electrophoresis patterns. Nationally, the prevalence of ceftriaxone-resistant Salmonella increased from 0.5% in 1998 to 2.4% in 2001; 85% of the isolates in 2001 were Newport-MDRAmpC, and at least 27 states have isolated these strains from humans, cattle, or ground beef. These data document the widespread emergence of Newport-MDRAmpC strains in the United States and show that the 5-fold increase in the prevalence of Salmonella resistant to expanded-spectrum cephalosporins, between 1998 and 2001, is primarily due to the emergence of Newport-MDRAmpC strains. PMID:14639542

  14. [Relevance of animal models in the development of compounds targeting multidrug resistant cancer].

    PubMed

    Füredi, András; Tóth, Szilárd; Hámori, Lilla; Nagy, Veronika; Tóvári, József; Szakács, Gergely

    2015-12-01

    Anticancer compounds are typically identified in in vitro screens. Unfortunately, the in vitro drug sensitivity of cell lines does not reflect treatment efficiency in animal models, and neither show acceptable correlation to clinical results. While cell lines and laboratory animals can be readily "cured", the treatment of malignancies remains hampered by the multidrug resistance (MDR) of tumors. Genetically engineered mouse models (GEMMs) giving rise to spontaneous tumors offer a new possibility to characterize the evolution of drug resistance mechanisms and to target multidrug resistant cancer. PMID:26665195

  15. Multidrug resistance-associated protein 4 is a determinant of arsenite resistance.

    PubMed

    Yuan, Bo; Yoshino, Yuta; Fukushima, Hisayo; Markova, Svetlana; Takagi, Norio; Toyoda, Hiroo; Kroetz, Deanna L

    2016-01-01

    Although arsenic trioxide (arsenite, As(III)) has shown a remarkable efficacy in the treatment of acute promyelocytic leukemia patients, multidrug resistance is still a major concern for its clinical use. Multidrug resistance-associated protein 4 (MRP4), which belongs to the ATP-binding cassette (ABC) superfamily of transporters, is localized to the basolateral membrane of hepatocytes and the apical membrane of renal proximal tubule cells. Due to its characteristic localization, MRP4 is proposed as a candidate in the elimination of arsenic and may contribute to resistance to As(III). To test this hypothesis, stable HEK293 cells overexpressing MRP4 or MRP2 were used to establish the role of these two transporters in As(III) resistance. The IC50 values of As(III) in MRP4 cells were approximately 6-fold higher than those in MRP2 cells, supporting an important role for MRP4 in resistance to As(III). The capacity of MRP4 to confer resistance to As(III) was further confirmed by a dramatic decrease in the IC50 values with the addition of MK571, an MRP4 inhibitor, and cyclosporine A, a well-known broad-spectrum inhibitor of ABC transporters. Surprisingly, the sensitivity of the MRP2 cells to As(III) was similar to that of the parent cells, although insufficient formation of glutathione and/or Se conjugated arsenic compounds in the MRP2 cells might limit transport. Given that MRP4 is a major contributor to arsenic resistance in vitro, further investigation into the correlation between MRP4 expression and treatment outcome of leukemia patients treated with arsenic-based regimens is warranted. PMID:26497925

  16. Effect of curcumin on human colon cancer multidrug resistance in vitro and in vivo

    PubMed Central

    Lu, Wei-Dong; Qin, Yong; Yang, Chuang; Li, Lei

    2013-01-01

    OBJECTIVE: To determine whether curcumin reverses the multidrug resistance of human colon cancer cells in vitro and in vivo. METHODS: In a vincristine-resistant cell line of human colon cancer, the cell viability of curcumin-treated cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Rhodamine123 efflux was evaluated to detect P-glycoprotein transporter activity, and expression of the multidrug resistance protein 1 and survivin genes was analyzed by reverse transcription polymerase chain reaction and western blotting. In addition, xenograft mouse tumors were grown and treated with curcumin. The morphology of the xenografts was investigated by hematoxylin-eosin staining. The in vivo expression of the multidrug resistance gene and P-glycoprotein and survivin genes and proteins was observed using reverse transcription-polymerase chain reaction and western blotting, respectively. RESULTS: Curcumin was not obviously toxic to the vincristine-resistant human colon cancer cells at concentrations less than 25 μM, but the growth of cells was significantly inhibited. At concentrations greater than 25 μM, curcumin was toxic in a concentration-dependent manner. The sensitivity of cells to vincristine, cisplatin, fluorouracil, and hydroxycamptothecin was enhanced, intracellular Rhodamine123 accumulation was increased (p<0.05), and the expression of the multidrug resistance gene and P-glycoprotein were significantly suppressed (p<0.05). The combination of curcumin and vincristine significantly inhibited xenograft growth. The expression of the multidrug resistance protein 1 and survivin genes was significantly reduced in xenografts of curcumin-treated mice and mice treated with both curcumin and vincristine relative to control mice. CONCLUSION: Curcumin has strong reversal effects on the multidrug resistance of human colon carcinoma in vitro and in vivo. PMID:23778405

  17. Modified live Edwardsiella ictaluri vaccine, AQUAVAC-ESC, lacks multidrug resistance plasmids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasmid mediated antibiotic resistance was first discovered in Edwardsiella ictaluri in the early 1990’s, and in 2007 an E. ictaluri isolate harboring an IncA/C plasmid was recovered from a moribund channel catfish infected with the bacterium. Due to the identification of multidrug resistance plasm...

  18. Multidrug-Resistant Bacteroides fragilis Bacteremia in a US Resident: An Emerging Challenge

    PubMed Central

    Parajuli, Sunita; Siegfried, Justin; Dubrovskaya, Yanina; Rahimian, Joseph

    2016-01-01

    We describe a case of Bacteroides fragilis bacteremia associated with paraspinal and psoas abscesses in the United States. Resistance to b-lactam/b-lactamase inhibitors, carbapenems, and metronidazole was encountered despite having a recent travel history to India as the only possible risk factor for multidrug resistance. Microbiological cure was achieved with linezolid, moxifloxacin, and cefoxitin. PMID:27418986

  19. Comparative genomics of the IncA/C multidrug resistance plasmid family

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multidrug resistance (MDR) plasmids belonging to the IncA/C plasmid family are widely distributed among Salmonella and other enterobacterial isolates from agricultural sources and have, at least once, also been identified in a drug resistant Yersinia pestis isolate (IP275) from Madagascar. Here, we...

  20. Genome Sequence of Riemerella anatipestifer Strain RCAD0122, a Multidrug-Resistant Isolate from Ducks

    PubMed Central

    Song, Xiao-Heng; Zhou, Wang-Shu; Wang, Jiang-Bo; Liu, Ma-Feng; Wang, Ming-Shu; Cheng, An-Chun; Jia, Ren-Yong; Chen, Shun; Sun, Kun-Feng; Yang, Qiao; Wu, Ying; Chen, Xiao-Yue

    2016-01-01

    Riemerella anatipestifer is an important pathogenic bacterium in waterfowl and other avian species. We present here the genome sequence of R. anatipestifer RCAD0122, a multidrug-resistant strain isolated from infected ducks. The isolate contains at least nine types of antibiotic resistance-associated genes. PMID:27151800

  1. ACSSuT Multi-Drug Resistance Among Salmonella Isolates of Animal Origin

    Technology Transfer Automated Retrieval System (TEKTRAN)

    BACKGROUND: Multi-drug resistant (MDR) Salmonella Typhimurium DT104 (DT104) emerged in the mid-1990’s in humans and animals with infection resulting in increased morbidity and mortality. DT104 was characterized by resistance to Ampicillin, Chloramphenicol, Streptomycin, Sulfa, and Tetracycline (AC...

  2. Whole-Genome Sequence of a Multidrug-Resistant Clinical Isolate of Acinetobacter lwoffii▿

    PubMed Central

    Hu, Yongfei; Zhang, Wei; Liang, Hui; Liu, Liping; Peng, Guojun; Pan, Yuanlong; Yang, Xi; Zheng, Beiwen; Gao, George F.; Zhu, Baoli; Hu, Hongyan

    2011-01-01

    Acinetobacter lwoffii has been considered an opportunistic pathogen that can cause nosocomial infections in humans. Here, we present the genome sequence of A. lwoffii WJ10621, a multidrug-resistant clinical isolate that carries a plasmid with the NDM-1 resistance gene. PMID:21742884

  3. Induction of apoptosis and reversal of permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM by ginsenoside Rh2

    PubMed Central

    Zhang, Hui; Gong, Jian; Zhang, Huilai; Kong, Di

    2015-01-01

    Multidrug resistance is a phenomenon that cancer cells develop a cross-resistant phenotype against several unrelated drugs, and permeability glycoprotein derived from the overexpression of multidrug resistance gene 1 has been taken as the most significant cause of multidrug resistance. In the present study, ginsenoside Rh2 was used to reverse permeability glycoprotein-mediated multidrug resistance of MCF-7/ADM cell line. Effects of ginsenoside Rh2 on the apoptotic process and caspase-3 activity of MCF-7 and MCF-7/ADM cell lines were determined using flow cytometry and microplate reader. Methyl thiazolyl tetrazolium test was conducted to assess the IC50 values of ginsenoside Rh2 and adriamycin on MCF-7 and MCF-7/ADM cultures; Rhodamin 123 assay was used to assess the retention of permeability glycoprotein after ginsenoside Rh2 treatment; flow cytometry and real time polymerase chain reaction were used to determine the expression levels of permeability glycoprotein and multidrug resistance gene 1 in drug-resistant cells and their parental cells after exposure to ginsenoside Rh2. The results showed that ginsenoside Rh2, except for inducing apoptosis, had the ability to reverse multidrug resistance in MCF-7/ADM cell line without changing the expression levels of permeability glycoprotein and multidrug resistance gene 1. Our findings provided some valuable information for the application of ginsenoside Rh2 in cancer therapy, especially for multidrug resistance reversal in clinic. PMID:26191135

  4. Acquired inducible antimicrobial resistance in Gram-positive bacteria

    PubMed Central

    Chancey, Scott T; Zähner, Dorothea; Stephens, David S

    2012-01-01

    A major contributor to the emergence of antibiotic resistance in Gram-positive bacterial pathogens is the expansion of acquired, inducible genetic elements. Although acquired, inducible antibiotic resistance is not new, the interest in its molecular basis has been accelerated by the widening distribution and often ‘silent’ spread of the elements responsible, the diagnostic challenges of such resistance and the mounting limitations of available agents to treat Gram-positive infections. Acquired, inducible antibiotic resistance elements belong to the accessory genome of a species and are horizontally acquired by transformation/recombination or through the transfer of mobile DNA elements. The two key, but mechanistically very different, induction mechanisms are: ribosome-sensed induction, characteristic of the macrolide–lincosamide–streptogramin B antibiotics and tetracycline resistance, leading to ribosomal modifications or efflux pump activation; and resistance by cell surface-associated sensing of β-lactams (e.g., oxacillin), glycopeptides (e.g., vancomycin) and the polypeptide bacitracin, leading to drug inactivation or resistance due to cell wall alterations. PMID:22913355

  5. Compensatory Mutations of Rifampin Resistance Are Associated with Transmission of Multidrug-Resistant Mycobacterium tuberculosis Beijing Genotype Strains in China.

    PubMed

    Li, Qin-Jing; Jiao, Wei-Wei; Yin, Qing-Qin; Xu, Fang; Li, Jie-Qiong; Sun, Lin; Xiao, Jing; Li, Ying-Jia; Mokrousov, Igor; Huang, Hai-Rong; Shen, A-Dong

    2016-05-01

    Mycobacterium tuberculosis can acquire resistance to rifampin (RIF) through mutations in the rpoB gene. This is usually accompanied by a fitness cost, which, however, can be mitigated by secondary mutations in the rpoA or rpoC gene. This study aimed to identify rpoA and rpoC mutations in clinical M. tuberculosis isolates in northern China in order to clarify their role in the transmission of drug-resistant tuberculosis (TB). The study collection included 332 RIF-resistant and 178 RIF-susceptible isolates. The majority of isolates belonged to the Beijing genotype (95.3%, 486/510 isolates), and no mutation was found in rpoA or rpoC of the non-Beijing genotype strains. Among the Beijing genotype strains, 27.8% (89/320) of RIF-resistant isolates harbored nonsynonymous mutations in the rpoA (n = 6) or rpoC (n = 83) gene. The proportion of rpoC mutations was significantly higher in new cases (P = 0.023) and in strains with the rpoB S531L mutation (P < 0.001). In addition, multidrug-resistant (MDR) strains with rpoC mutations were significantly associated with 24-locus mycobacterial interspersed repetitive-unit-variable-number tandem-repeat clustering (P = 0.016). In summary, we believe that these findings indirectly suggest an epistatic interaction of particular mutations related to RIF resistance and strain fitness and, consequently, the role of such mutations in the spread of MDR M. tuberculosis strains. PMID:26902762

  6. Nationwide outbreak of multidrug-resistant Salmonella Heidelberg infections associated with ground turkey: United States, 2011.

    PubMed

    Routh, J A; Pringle, J; Mohr, M; Bidol, S; Arends, K; Adams-Cameron, M; Hancock, W T; Kissler, B; Rickert, R; Folster, J; Tolar, B; Bosch, S; Barton Behravesh, C; Williams, I T; Gieraltowski, L

    2015-11-01

    On 23 May 2011, CDC identified a multistate cluster of Salmonella Heidelberg infections and two multidrug-resistant (MDR) isolates from ground turkey retail samples with indistinguishable pulsed-field gel electrophoresis patterns. We defined cases as isolation of outbreak strains in persons with illness onset between 27 February 2011 and 10 November 2011. Investigators collected hypothesis-generating questionnaires and shopper-card information. Food samples from homes and retail outlets were collected and cultured. We identified 136 cases of S. Heidelberg infection in 34 states. Shopper-card information, leftover ground turkey from a patient's home containing the outbreak strain and identical antimicrobial resistance profiles of clinical and retail samples pointed to plant A as the source. On 3 August, plant A recalled 36 million pounds of ground turkey. This outbreak increased consumer interest in MDR Salmonella infections acquired through United States-produced poultry and played a vital role in strengthening food safety policies related to Salmonella and raw ground poultry. PMID:25865382

  7. Phosphate-Containing Polyethylene Glycol Polymers Prevent Lethal Sepsis by Multidrug-Resistant Pathogens

    SciTech Connect

    Zaborin, Alexander; Defazio, Jennifer; Kade, Matthew; Kaiser, Brooke LD; Belogortseva, Natalia; Camp, David G.; Smith, Richard D.; Adkins, Joshua N.; Kim, Sangman M.; Alverdy, Alexandria; Goldfeld, David; Firestone, Millicent; Collier, Joel; Jabri, Bana; Tirrell, Matthew; Zaborina, Olga; Alverdy, John C.

    2014-02-01

    The gastrointestinal tract is the primary site of colonization for multi-drug resistant healthcare associated pathogens (HAPs) that are the principal source and cause of life-threatening infections in critically ill patients. We previously identified a high molecular weight co-polymer (PEG15-20) with mucoadhesive and cytoprotective actions on the intestinal epithelium. In this report we covalently bonded phosphate (Pi) to PEG15-20 ( termed Pi-PEG15-20) to enhance its cytoprotective activity against microbial virulence activation and invasion based on our previous work showing that Pi is a key environmental cue regulating microbial virulence across pathogens of clinical importance to hospitalized patients. We demonstrated that Pi-PEG15-20 can suppress phosphate-, iron-, and quorum sensing signal- mediated activation of bacterial virulence as well as inhibit intestinal epithelial IL-8 release during lipopolysaccharide (LPS) exposure. Pi-PEG15-20 also prevented mortality in C. elegans and mice exposed to several highly virulent and antibiotic(?)-resistant health care acquired pathogens (HAPs) while preserving the normal microbiota. Intestinal application Pi-PEG 15-20 has the potential to be a useful agent to prevent the pathogenic activation of microbes during critical illness where exposure to HAPs is ubiquitous.

  8. Glycosylation in Cancer: Interplay between Multidrug Resistance and Epithelial-to-Mesenchymal Transition?

    PubMed Central

    da Fonseca, Leonardo Marques; da Silva, Vanessa Amil; Freire-de-Lima, Leonardo; Previato, José Osvaldo; Mendonça-Previato, Lucia; Capella, Márcia Alves Marques

    2016-01-01

    The expression of unusual glycan structures is a hallmark of cancer progression, and their functional roles in cancer biology have been extensively investigated in epithelial-to-mesenchymal transition (EMT) models. EMT is a physiological process involved in embryonic development and wound healing. It is characterized by loss of epithelial cell polarity and cell adhesion, permitting cell migration, and thus formation of new epithelia. However, this process is unwanted when occurring outside their physiological limit, resulting in fibrosis of organs and progression of cancer and metastasis. Several studies observed that EMT is related to the acquisition of multidrug resistance (MDR) phenotype, a condition in which cancer cells acquire resistance to multiple different drugs, which has virtually nothing in common. However, although some studies suggested interplay between these two apparently distinct phenomena, almost nothing is known about this possible relationship. A common pathway to them is the need for glycosylation, a post-translational modification that can alter biological function. Thus, this review intends to compile the main facts obtained until now in these two areas, as an effort to unravel the relationship between EMT and MDR. PMID:27446804

  9. Description of genomic islands associated to the multidrug-resistant Pseudomonas aeruginosa clone ST277.

    PubMed

    Silveira, Melise Chaves; Albano, Rodolpho Mattos; Asensi, Marise Dutra; Carvalho-Assef, Ana Paula D'Alincourt

    2016-08-01

    Multidrug-resistant Pseudomonas aeruginosa clone ST277 is disseminated in Brazil where it is mainly associated with the presence of metallo-β-lactamase SPM-1. Furthermore, it carries the class I integron In163 and a 16S rRNA methylase rmtD that confers aminoglycoside resistance. To analyze the genetic characteristics that might be responsible for the success of this endemic clone, genomes of four P. aeruginosa strains that were isolated in distinct years and in different Brazilian states were sequenced. The strains differed regarding the presence of the genes blaSPM-1 and rmtD. Genomic comparisons that included genomes of other clones that have spread worldwide from this species were also performed. These analyses revealed a 763,863bp region in the P. aeruginosa chromosome that concentrates acquired genetic structures comprising two new genomic islands (PAGI-13 and PAGI-14), a mobile element that could be used for ST277 fingerprinting and a recently reported Integrative and Conjugative Element (ICE) associated to blaSPM-1. The genetic elements rmtD and In163 are inserted in PAGI-13 while PAGI-14 has genes encoding proteins related to type III restriction system and phages. The data reported in this study provide a basis for a clearer understanding of the genetic content of clone ST277 and illustrate the mechanisms that are responsible for the success of these endemic clones. PMID:27108807

  10. Surveillance of ESBL producing multidrug resistant Escherichia coli in a teaching hospital in India

    PubMed Central

    Rath, Shakti; Dubey, Debasmita; Sahu, Mahesh C.; Padhy, Rabindra N

    2014-01-01

    Objective To record nosocomial and community-acquired accounts of antibiotic resistance in Escherichia coli (E. coli) strains, isolated from clinical samples of a teaching hospital by surveillance, over a period of 39 months (November 2009-January 2013). Methods Clinical samples from nosocomial sources, i.e., wards and cabins, intensive care unit (ICU) and neonatal intensive care unit (NICU), and community (outpatient department, OPD) sources of the hospital, were used for isolating strains of E. coli, which were subjected for testing for production of ‘extended spectrum beta-lactamase’-(ESBL) enzyme as well as determining antibiotic sensitivity pattern with 23 antibiotics. Results Of the total 1642 (100%) isolates, 810 (49.33%) strains were from OPD and 832 (50.66%) were from hospital settings. Occurrence of infectious E. coli strains increased in a mathematical progression in community sources, but in nosocomial infections, such values remained almost constant in each quarter. A total of 395 (24.05%) ESBL strains were isolated from the total 810 isolates of community; of the total of 464 (28.25%) isolates of wards and cabins, 199 (12.11%) were ESBL strains; and among the total of 368 (22.41%) isolates of ICU and NICU, ESBLs were 170 (10.35%); the total nosocomial ESBL isolates, 369 (22.47%) were from the nosocomial total of 832 (50.66%) isolates. Statistically, it was confirmed that ESBL strains were equally distributed in community or hospital units. Antibiogram of 23 antibiotics revealed progressive increases of drug-resistance against each antibiotic with the maximum resistance values were recorded against gentamicin: 92% and 79%, oxacillin: 94% and 69%, ceftriaxone: 85% and 58%, and norfloxacin 97% and 69% resistance, in nosocomial and community isolates, respectively. Conclusions This study revealed the daunting state of occurrence of multidrug resistant E. coli and its infection dynamics in both community and hospital settings.

  11. Virulence Gene Profiles of Multidrug-Resistant Pseudomonas aeruginosa Isolated From Iranian Hospital Infections

    PubMed Central

    Fazeli, Nastaran; Momtaz, Hassan

    2014-01-01

    Background: The most common hospital-acquired pathogen is Pseudomonas aeruginosa. It is a multidrug resistant bacterium causing systemic infections. Objectives: The present study was carried out in order to investigate the distribution of virulence factors and antibiotic resistance properties of Pseudomonas aeruginosa isolated from various types of hospital infections in Iran. Patients and Methods: Two-hundred and seventeen human infection specimens were collected from Baqiyatallah and Payambaran hospitals in Tehran, Iran. The clinical samples were cultured immediately and samples positive for P. aeruginosa were analyzed for the presence of antibiotic resistance and bacterial virulence genes using PCR (polymerase chain reaction). Antimicrobial susceptibility testing was performed using disk diffusion methodology with Müeller–Hinton agar. Results: Fifty-eight out of 127 (45.66%) male infection specimens and 44 out of 90 (48.88%) female infection specimens harbored P. aeruginosa. Also, 65% (in male specimens) and 21% (in female specimens) of respiratory system infections were positive for P. aeruginosa, which was a high rate. The genes encoding exoenzyme S (67.64%) and phospholipases C (45.09%) were the most common virulence genes found among the strains. The incidences of various β-lactams encoding genes, including blaTEM, blaSHV, blaOXA, blaCTX-M, blaDHA, and blaVEB were 94.11%, 16.66%, 15.68%, 18.62%, 21.56%, and 17.64%, respectively. The most commonly detected fluoroquinolones encoding gene was gyrA (15. 68%). High resistance levels to penicillin (100%), tetracycline (90.19%), streptomycin (64.70%), and erythromycin (43.13%) were observed too. Conclusions: Our findings should raise awareness about antibiotic resistance in hospitalized patients in Iran. Clinicians should exercise caution in prescribing antibiotics, especially in cases of human infections. PMID:25763199

  12. In vivo uptake of carbon-14-colchicine for identification of tumor multidrug resistance

    SciTech Connect

    Mehta, B.M.; Rosa, E.; Biedler, J.L.

    1994-07-01

    A major limitation in the treatment of cancer with natural product chemotherapeutic agents is the development of multidrug resistance (MDR). Multidrug resistance is attributed to enhanced expression of the multidrug resistance gene MDR1. Colchicine (CHC) is known to be one of the MDR drugs. The authors have previously demonstrated that it is possible to distinguish multidrug resistant tumors from the multidrug-sensitive tumors in vivo on the basis of tritium ({sup 3}H) uptake following injection of {sup 3}H-CHC. The present studies were carried out in xenografted animals using {sup 14}C-CHC which may be more indicative of {sup 11}C-labeled CHC distribution with regard to circulating metabolites, since metabolic processes following injection of (ring C, methoxy-{sup 11}C)-CHC may produce significant amounts of circulating 1l-carbon fragments (i.e., methanol and/or formaldehyde). Experiments were carried out at a dose of 2 mg/kg. Activity concentration per injected dose was approximately twice as great in sensitive as in resistant tumors (p < 0.05) at 60 min following intravenous injection of {sup 14}C-CHC. About 75% of total activity was CHC in the sensitive tumors. The findings are further confirmed by the quantitative autoradiographic evaluation of resistant and sensitive tumors. These studies confirm our previous observations that it is possible to noninvasively distinguish multidrug-resistant tumors from sensitive tumors in vivo based on uptake of an injected MDR drug using a{sup 14}C-labeled CHC at the same position and of comparable specific activity to a {sup 11}C-CHC tracer used for PET imaging. 16 refs., 5 figs., 2 tabs.

  13. Applications of nanoparticle drug delivery systems for the reversal of multidrug resistance in cancer

    PubMed Central

    HUANG, YINGHONG; COLE, SUSAN P.C.; CAI, TIANGE; CAI, YU

    2016-01-01

    Multidrug resistance (MDR) to chemotherapy presents a major obstacle in the treatment of cancer patients, which directly affects the clinical success rate of cancer therapy. Current research aims to improve the efficiency of chemotherapy, whilst reducing toxicity to prolong the lives of cancer patients. As with good biocompatibility, high stability and drug release targeting properties, nanodrug delivery systems alter the mechanism by which drugs function to reverse MDR, via passive or active targeting, increasing drug accumulation in the tumor tissue or reducing drug elimination. Given the potential role of nanodrug delivery systems used in multidrug resistance, the present study summarizes the current knowledge on the properties of liposomes, lipid nanoparticles, polymeric micelles and mesoporous silica nanoparticles, together with their underlying mechanisms. The current review aims to provide a reliable basis and useful information for the development of new treatment strategies of multidrug resistance reversal using nanodrug delivery systems. PMID:27347092

  14. Multidrug resistance of DNA-mediated transformants is linked to transfer of the human mdr1 gene.

    PubMed Central

    Shen, D W; Fojo, A; Roninson, I B; Chin, J E; Soffir, R; Pastan, I; Gottesman, M M

    1986-01-01

    Mouse NIH 3T3 cells were transformed to multidrug resistance with high-molecular-weight DNA from multidrug-resistant human KB carcinoma cells. The patterns of cross resistance to colchicine, vinblastine, and doxorubicin hydrochloride (Adriamycin; Adria Laboratories Inc.) of the human donor cell line and mouse recipients were similar. The multidrug-resistant human donor cell line contains amplified sequences of the mdr1 gene which are expressed at high levels. Both primary and secondary NIH 3T3 transformants contained and expressed these amplified human mdr1 sequences. Amplification and expression of the human mdr1 sequences and amplification of cotransferred human Alu sequences in the mouse cells correlated with the degree of multidrug resistance. These data suggest that the mdr1 gene is likely to be responsible for multidrug resistance in cultured cells. Images PMID:3796599

  15. Does a multi-drug resistant Escherichia coli facilitate dissemination of resistance to Salmonella in dairy calves?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous research conducted by our laboratory investigated the incidence of multi-drug resistant (MDR) Salmonella in dairy cattle and reported that individual cattle, and most often calves, can shed multiple Salmonella serotypes that vary in the degree of antibiotic resistance. More recently, we di...

  16. Evaluation of the potential antimicrobial resistance transfer from a multi-drug resistant Escherichia coli to Salmonella in dairy calves

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous research conducted by our laboratory investigated the incidence of multi-drug resistant (MDR) Salmonella in dairy cattle and reported that individual cattle, and most often calves, shed multiple Salmonella serotypes that vary in the degree of antibiotic resistance. More recently, we invest...

  17. Scaling-up treatment for HIV/AIDS: lessons learned from multidrug-resistant tuberculosis.

    PubMed

    Gupta, Rajesh; Irwin, Alexander; Raviglione, Mario C; Kim, Jim Yong

    2004-01-24

    The UN has launched an initiative to place 3 million people in developing countries on antiretroviral AIDS treatment by end 2005 (the 3 by 5 target). Lessons for HIV/AIDS treatment scale-up emerge from recent experience with multidrug-resistant tuberculosis. Expansion of treatment for multidrug-resistant tuberculosis through the multipartner mechanism known as the Green Light Committee (GLC) has enabled gains in areas relevant to 3 by 5, including policy development, drug procurement, rational use of drugs, and the strengthening of health systems. The successes of the GLC and the obstacles it has encountered provide insights for building sustainable HIV/AIDS treatment programmes. PMID:14751708

  18. Long-term survival of patients with multidrug-resistant tuberculosis according to treatment outcomes.

    PubMed

    Kwak, Nakwon; Yoo, Chul-Gyu; Kim, Young Whan; Han, Sung Koo; Yim, Jae-Joon

    2016-07-01

    Survival times of 219 patients diagnosed with multidrug-resistant tuberculosis were calculated and treatment outcomes compared. Mean survival of 20 patients who failed to be cured was 109.8 months (95% confidence interval [CI], 87.4-132.1), shorter than that of 150 patients who were cured (140.4 months; 95% CI, 136.1-144.7; P < .01) and that of 28 patients classified as treatment completed (138.5 months; 95% CI, 131.0-146.1; P = .02). The results demonstrate that patients with multidrug-resistant tuberculosis with poor treatment outcomes live 9 years, on average. PMID:26922891

  19. Modulation of multidrug resistance gene expression in human breast cancer cells by (-)-gossypol-enriched cottonseed oil.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    P-glycoprotein, the product of the multidrug resistance 1 gene, acts as an efflux pump and prevents sufficient intracellular accumulation of several anticancer agents. Thus, it plays a major role in multidrug cancer resistance. Using the non-radioactive cell proliferation MTS assay, none of three ...

  20. Modulating cancer multidrug resistance by sertraline in combination with a nanomedicine.

    PubMed

    Drinberg, Velthe; Bitcover, Rivka; Rajchenbach, Wolf; Peer, Dan

    2014-11-28

    Inherent and acquired multiple drug resistance (MDR) to chemotherapeutic drugs is a major obstacle in cancer treatment. The ATP Binding Cassettes (ABC) transporter super family that act as extrusion pumps such as P-glycoprotein and multidrug-resistance-associated-proteins have prominent roles in cancer MDR. One of the most efficient strategies to modulate this active drug efflux from the cells is to physically block the pump proteins and thus change the balance between drug influx and efflux toward an accumulation of drug inside the cell, which eventually cumulates into cell death. MDR modulators (also known as chemosensitizers) were found among drugs approved for non-cancer indications. Yet, toxicity, adverse effects, and poor solubility at doses required for MDR reversal prevent their clinical application. Previous reports have shown that drugs belonging to the selective serotonin reuptake inhibitors (SSRI) family, which are clinically used as antidepressants, can act as effective chemosensitizers both in vitro and in vivo in tumor bearing mouse models. Here, we set out to explore whether sertraline (Zoloft®), a molecule belonging to the SSRI family, can be used as an MDR modulator. Combining sertraline with another FDA approved drug, Doxil® (pegylated liposomal doxorubicin), is expected to enhance the effect of chemotherapy while potentially reducing adverse effects. Our findings reveal that sertraline acts as a pump modulator in cellular models of MDR. In addition, in an aggressive and highly resistant human ovarian xenograft mouse model the use of sertraline in combination with Doxil® generated substantial reduction in tumor progression, with extension of the median survival of tumor-bearing mice. Taken together, our results show that sertraline could act as a clinically relevant cancer MDR inhibitor. Moreover, combining two FDA approved drugs, DOXIL®, which favor the influx of chemotherapy inside the malignant cell with sertraline, which blocks the

  1. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?

    PubMed Central

    2015-01-01

    Acquired drug resistance by Mycobacterium tuberculosis (MTB) may result in treatment failure and death. Bedaquiline was recently approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). This report examines the available data on this novel drug for the treatment of MDR-TB. PubMed searches, last updated 18 February 2015, using the terms bedaquiline, TMC 207 and R207910 identified pertinent English citations. Citation reference lists were reviewed to identify other relevant reports. Pertinent MDR-TB treatment reports on the US Food and Drug Administration, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and Cochrane websites were also evaluated. Bedaquiline is an adenosine triphosphate (ATP) synthase inhibitor specific for MTB and some nontuberculous mycobacteria. The early bactericidal activity (EBA) of bedaquiline is delayed until ATP stores are depleted but subsequently it is similar to the EBA of isoniazid and rifampin. Bedaquiline demonstrated excellent minimum inhibitory concentrations (MICs) against both drug-sensitive and MDR-TB. Adding it to the WHO-recommended MDR-TB regimen reduced the time for sputum culture conversion in pulmonary MDR-TB. Rifampin, other cytochrome oxidase 3A4 inducers or inhibitors alter its metabolism. Adverse effects are common with MDR-TB treatment regimens with or without bedaquiline. Nausea is more common with bedaquiline and it increases the QTcF interval. It is not recommended for children, pregnant or lactating women. More patients died in the bedaquiline-treatment arms despite better microbiological outcomes in two recent trials. The WHO and CDC published interim guidelines that recommend restricting its use to patients with MDR-TB or more complex drug resistance who cannot otherwise be treated with a minimum of three effective drugs. It should never be added to a regimen as a single drug nor should it be added to a failing regimen to prevent the emergence of bedaquiline-resistant

  2. Bedaquiline for the treatment of multidrug-resistant tuberculosis: great promise or disappointment?

    PubMed

    Field, Stephen K

    2015-07-01

    Acquired drug resistance by Mycobacterium tuberculosis (MTB) may result in treatment failure and death. Bedaquiline was recently approved for the treatment of multidrug-resistant tuberculosis (MDR-TB). This report examines the available data on this novel drug for the treatment of MDR-TB. PubMed searches, last updated 18 February 2015, using the terms bedaquiline, TMC 207 and R207910 identified pertinent English citations. Citation reference lists were reviewed to identify other relevant reports. Pertinent MDR-TB treatment reports on the US Food and Drug Administration, Centers for Disease Control and Prevention (CDC), World Health Organization (WHO) and Cochrane websites were also evaluated. Bedaquiline is an adenosine triphosphate (ATP) synthase inhibitor specific for MTB and some nontuberculous mycobacteria. The early bactericidal activity (EBA) of bedaquiline is delayed until ATP stores are depleted but subsequently it is similar to the EBA of isoniazid and rifampin. Bedaquiline demonstrated excellent minimum inhibitory concentrations (MICs) against both drug-sensitive and MDR-TB. Adding it to the WHO-recommended MDR-TB regimen reduced the time for sputum culture conversion in pulmonary MDR-TB. Rifampin, other cytochrome oxidase 3A4 inducers or inhibitors alter its metabolism. Adverse effects are common with MDR-TB treatment regimens with or without bedaquiline. Nausea is more common with bedaquiline and it increases the QTcF interval. It is not recommended for children, pregnant or lactating women. More patients died in the bedaquiline-treatment arms despite better microbiological outcomes in two recent trials. The WHO and CDC published interim guidelines that recommend restricting its use to patients with MDR-TB or more complex drug resistance who cannot otherwise be treated with a minimum of three effective drugs. It should never be added to a regimen as a single drug nor should it be added to a failing regimen to prevent the emergence of bedaquiline-resistant

  3. De-Differentiation Confers Multidrug Resistance Via Noncanonical PERK-Nrf2 Signaling

    PubMed Central

    Del Vecchio, Catherine A.; Feng, Yuxiong; Sokol, Ethan S.; Tillman, Erik J.; Sanduja, Sandhya; Reinhardt, Ferenc; Gupta, Piyush B.

    2014-01-01

    Malignant carcinomas that recur following therapy are typically de-differentiated and multidrug resistant (MDR). De-differentiated cancer cells acquire MDR by up-regulating reactive oxygen species (ROS)–scavenging enzymes and drug efflux pumps, but how these genes are up-regulated in response to de-differentiation is not known. Here, we examine this question by using global transcriptional profiling to identify ROS-induced genes that are already up-regulated in de-differentiated cells, even in the absence of oxidative damage. Using this approach, we found that the Nrf2 transcription factor, which is the master regulator of cellular responses to oxidative stress, is preactivated in de-differentiated cells. In de-differentiated cells, Nrf2 is not activated by oxidation but rather through a noncanonical mechanism involving its phosphorylation by the ER membrane kinase PERK. In contrast, differentiated cells require oxidative damage to activate Nrf2. Constitutive PERK-Nrf2 signaling protects de-differentiated cells from chemotherapy by reducing ROS levels and increasing drug efflux. These findings are validated in therapy-resistant basal breast cancer cell lines and animal models, where inhibition of the PERK-Nrf2 signaling axis reversed the MDR of de-differentiated cancer cells. Additionally, analysis of patient tumor datasets showed that a PERK pathway signature correlates strongly with chemotherapy resistance, tumor grade, and overall survival. Collectively, these results indicate that de-differentiated cells up-regulate MDR genes via PERK-Nrf2 signaling and suggest that targeting this pathway could sensitize drug-resistant cells to chemotherapy. PMID:25203443

  4. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants

    PubMed Central

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; de Almeida Nogueira Pinto, José Paes; dos Santos Bersot, Luciano

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp. PMID:26887244

  5. Multidrug resistance and ESBL-producing Salmonella spp. isolated from broiler processing plants.

    PubMed

    Ziech, Rosangela Estel; Lampugnani, Camila; Perin, Ana Paula; Sereno, Mallu Jagnow; Sfaciotte, Ricardo Antônio Pilegi; Viana, Cibeli; Soares, Vanessa Mendonça; Pinto, José Paes de Almeida Nogueira; Bersot, Luciano dos Santos

    2016-01-01

    The aim of this study was to investigate the occurrence of multidrug-resistant, extended spectrum beta-lactamase (ESBL) producing Salmonella spp. isolated from conveyor belts of broiler cutting rooms in Brazilian broiler processing plants. Ninety-eight strains of Salmonella spp. were analyzed. Multidrug resistance was determined by the disk diffusion test and the susceptibility of the isolated bacteria was evaluated against 18 antimicrobials from seven different classes. The double disk diffusion test was used to evaluate ESBL production. Of the 98 strains tested, 84 were multidrug resistant. The highest rates of resistance were against nalidixic acid (95%), tetracycline (91%), and the beta-lactams: ampicillin and cefachlor (45%), followed by streptomycin and gentamicin with 19% and 15% of strain resistance, respectively. By contrast, 97% of the strains were sensitive to chloramphenicol. 45% of the strains were positive for the presence of ESBL activity. In this study, high rates of multidrug resistance and ESBL production were observed in Salmonella spp. PMID:26887244

  6. [Prevalence of multidrug-resistant Proteus spp. strains in clinical specimens and their susceptibility to antibiotics].

    PubMed

    Reśliński, Adrian; Gospodarek, Eugenia; Mikucka, Agnieszka

    2005-01-01

    Proteus sp. are opportunistic microorganisms which cause urinary tract and wounds infections, bacteriaemia and sepsis. The aim of this study was analysis of prevalence of multidrug-resistant Proteus sp. strains in clinical specimens and evaluation of their susceptibility to selected antibiotics. The study was carried out of 1499 Proteus sp. strains were isolated in 2000-2003 from patients of departments and dispensaries of the University Hospital CM in Bydgoszcz UMK in Torun. The strains were identified on the basis of appearance of bacterial colonies on bloody and McConkey's agars, movement ability, indole and urease production and in questionable cases biochemical profile in ID GN or ID E (bio-Mérieux) tests was also included. Antibiotic susceptibility was tested by disk diffusion method. Isolated strains were regarded as multidrug-resistant when they were resistant to three kinds of antibiotics at least. Received Proteus sp. the most frequently belonged to P. mirabilis species (92.3%). Most of these bacteria were isolated from urine from patients of Rehabilitation Clinic. All of multidrug-resistant strains were resistant to penicillins and cephalosporins, 98.9% to co-trimoxazole, 77.7% to quinolones, 63.8% to tetracyclines, 38.5% to aminoglycosides, 19.3% to monobactams and 3.4% to carbapenems. Almost 25% multidrug-resistant Proteus sp. produced ESBL. PMID:16134389

  7. Fatal skin and soft tissue infection of multidrug resistant Acinetobacter baumannii: A case report

    PubMed Central

    Ali, Aqsa; Botha, John; Tiruvoipati, Ravindranath

    2014-01-01

    INTRODUCTION Acinetobacter baumannii is usually associated with respiratory tract, urinary tract and bloodstream infections. Recent reports suggest that it is increasingly causing skin and soft tissue infections. It is also evolving as a multidrug resistant organism that can be difficult to treat. We present a fatal case of multidrug resistant A. baumannii soft tissue infection and review of relevant literature. PRESENTATION OF CASE A 41 year old morbidly obese man, with history of alcoholic liver disease presented with left superficial pre-tibial abrasions and cellulitis caused by multidrug resistant (MDR) A. baumannii. In spite of early antibiotic administration he developed extensive myositis and fat necrosis requiring extensive and multiple surgical debridements. He deteriorated despite appropriate antibiotic therapy and multiple surgical interventions with development of multi-organ failure and died. DISCUSSION Managing Acinetobacter infections remains difficult due to the array of resistance and the pathogens ability to develop new and ongoing resistance. The early diagnosis of necrotizing soft tissue infection may be challenging, but the key to successful management of patients with necrotizing soft tissue infection are early recognition and complete surgical debridement. CONCLUSION A. baumannii is emerging as an important cause of severe, life-threatening soft tissue infections. Multidrug resistant A. baumannii soft tissue infections may carry a high mortality in spite of early and aggressive treatment. Clinicians need to consider appropriate early empirical antibiotic coverage or the use of combination therapy to include MDR A. baumannii as a cause of skin and soft tissue infections. PMID:25016080

  8. Multidrug-resistant Vibrio associated with an estuary affected by shrimp farming in Northeastern Brazil.

    PubMed

    Rocha, Rafael Dos Santos; Sousa, Oscarina Viana de; Vieira, Regine Helena Silva Dos Fernandes

    2016-04-15

    Bacteria of genus Vibrio with multidrug resistance in shrimp farm environment were recurrent. Thus, the aim of this study was to evaluate the antimicrobial resistance profile of 70 strains of Vibrio isolated from water and sediment of Acaraú estuary, Ceará, Brazil. In order to achieve this goal, disk diffusion technique was used with the following antimicrobial agents: ampicillin (Amp), aztreonam (Atm), cephalothin (Cef), cefotaxime (Ctx), ceftriaxone (Cro), ciprofloxacin (Cip), chloramphenicol (Clo), florfenicol (Flo), nitrofurantoin (Nit), gentamicin (Gen), oxytetracycline (Otc), tetracycline (Tet), streptomycin (Str), nalidixic acid (Nal), and sulfazotrim (Sut). All Vibrio strains were resistant to at least one antimicrobial agent, being verified as 17 multidrug-resistant profiles. All strains resistant to Otc and Tet were characterized to exhibit plasmidial resistance. Therefore, Vibrio strains from Acaraú estuary pose a risk to public health and aquatic culture. PMID:26876560

  9. A pilot study on water pollution and characterization of multidrug-resistant superbugs from Byramangala tank, Ramanagara district, Karnataka, India.

    PubMed

    Skariyachan, Sinosh; Lokesh, Priyanka; Rao, Reshma; Kumar, Arushi Umesh; Vasist, Kiran S; Narayanappa, Rajeswari

    2013-07-01

    Urbanization and industrialization has increased the strength and qualities of municipal sewage in Bangalore, India. The disposal of sewage into natural water bodies became a serious issue. Byramangala reservoir is one such habitat enormously polluted in South India. The water samples were collected from four hotspots of Byramangala tank in 3 months. The biochemical oxygen demand (BOD) and bacterial counts were determined. The fecal coliforms were identified by morphological, physiological, and biochemical studies. The antibiotics sensitivity profiling of isolated bacteria were further carried out. We have noticed that a high content of BOD in the tank in all the 3 months. The total and fecal counts were found to be varied from 1.6 × 10(6) to 8.2 × 10(6) colony forming unit/ml and >5,500/100 ml, respectively. The variations in BOD and total count were found to be statistically significant at p > 0.05. Many pathogenic bacteria were characterized and most of them were found to be multidrug resistant. Salmonella showed resistance to cefoperazone, cefotaxime, cefixime, moxifloxacin, piperacillin/tazobactam, co-trimoxazole, levofloxacin, trimethoprim, and ceftazidime. Escherichia coli showed resistance to chloramphenicol, trimethoprim, co-trimoxazole, rifampicin, and nitrofurantoin while Enterobacter showed resistant to ampicillin, cefepime, ceftazidime, cefoperazone, and cefotaxime. Klebsiella and Shigella exhibited multiple drug resistance to conventional antibiotics. Staphylococcus showed resistance to vancomycin, methicillin, oxacillin, and tetracycline. Furthermore, Salmonella and Klebsiella are on the verge of acquiring resistance to even the strongest carbapenems-imipenem and entrapenem. Present study revealed that Byramanagala tank has become a cesspool of multidrug-resistant "superbugs" and will be major health concern in South Bangalore, India. PMID:23114918

  10. Targets for Combating the Evolution of Acquired Antibiotic Resistance.

    PubMed

    Culyba, Matthew J; Mo, Charlie Y; Kohli, Rahul M

    2015-06-16

    Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal. PMID:26016604

  11. Targets for Combating the Evolution of Acquired Antibiotic Resistance

    PubMed Central

    2015-01-01

    Bacteria possess a remarkable ability to rapidly adapt and evolve in response to antibiotics. Acquired antibiotic resistance can arise by multiple mechanisms but commonly involves altering the target site of the drug, enzymatically inactivating the drug, or preventing the drug from accessing its target. These mechanisms involve new genetic changes in the pathogen leading to heritable resistance. This recognition underscores the importance of understanding how such genetic changes can arise. Here, we review recent advances in our understanding of the processes that contribute to the evolution of antibiotic resistance, with a particular focus on hypermutation mediated by the SOS pathway and horizontal gene transfer. We explore the molecular mechanisms involved in acquired resistance and discuss their viability as potential targets. We propose that additional studies into these adaptive mechanisms not only can provide insights into evolution but also can offer a strategy for potentiating our current antibiotic arsenal. PMID:26016604

  12. Role of OmpA in the Multidrug Resistance Phenotype of Acinetobacter baumannii

    PubMed Central

    Fàbrega, Anna; Roca, Ignasi; Sánchez-Encinales, Viviana; Vila, Jordi; Pachón, Jerónimo

    2014-01-01

    Acinetobacter baumannii has emerged as a nosocomial pathogen with an increased prevalence of multidrug-resistant strains. The role of the outer membrane protein A (OmpA) in antimicrobial resistance remains poorly understood. In this report, disruption of the ompA gene led to decreased MICs of chloramphenicol, aztreonam, and nalidixic acid. We have characterized, for the first time, the contribution of OmpA in the antimicrobial resistance phenotype of A. baumannii. PMID:24379205

  13. [AA-type amyloidosis secondary to multidrug resistant pulmonary tuberculosis: implications for therapy].

    PubMed

    Baux, E; Henard, S; Alauzet, C; Goehringer, F; Laurain, C; Champigneulle, J; Vaillant, P; Hardy, A; Rabaud, C; May, T

    2015-10-01

    Multidrug resistant pulmonary tuberculosis was diagnosed to a 32-year-old man. An AA-amyloidosis was subsequently diagnosed on the renal biopsy performed for nephrotic syndrome and macroscopic hematuria. A 6-drug antibiotic treatment was delivered quickly after first results of genotypic antibiogram given the renal failure, and was secondarily adapted to the phenotypic antibiogram. Multidrug therapy was fairly well tolerated. Clinical and biological improving were slow. Although tuberculosis is a classic cause of amyloidosis, this is the first case reporting an association between a multidrug resistant case and an amyloidosis in adults. This case also raises the question of MDR probabilistic treatments in situations whether a vital organ prognosis is engaged. PMID:26198876

  14. Primary Extrapulmonary Multidrug-Resistant Tuberculosis of the Sternum without HIV Infection

    PubMed Central

    Rawal, Gautam

    2016-01-01

    Skeletal tuberculosis (TB) accounts for about 9% of all TB cases. Tuberculosis of the sternum is not a common presentation. The case of primary multidrug-resistant (MDR) TB of the sternum is even rare. So far no such case has been reported in the medical literature. Herein, we present the very first case of primary extrapulmonary MDR TB of the sternum in a 21-year-old immunocompetent Indian female who presented with chest pain and an increased swelling over the anterior chest with an intermittently discharging sinus. She was diagnosed with multidrug-resistant tuberculosis of the sternum without the active pulmonary disease. Conservative management with oral multidrug antitubercular therapy (ATT) completely cured the patient. PMID:26894135

  15. An Autocrine Cytokine/JAK/STAT-Signaling Induces Kynurenine Synthesis in Multidrug Resistant Human Cancer Cells

    PubMed Central

    Campia, Ivana; Buondonno, Ilaria; Castella, Barbara; Rolando, Barbara; Kopecka, Joanna; Gazzano, Elena; Ghigo, Dario; Riganti, Chiara

    2015-01-01

    Background Multidrug resistant cancer cells are hard to eradicate for the inefficacy of conventional anticancer drugs. Besides escaping the cytotoxic effects of chemotherapy, they also bypass the pro-immunogenic effects induced by anticancer drugs: indeed they are not well recognized by host dendritic cells and do not elicit a durable anti-tumor immunity. It has not yet been investigated whether multidrug resistant cells have a different ability to induce immunosuppression than chemosensitive ones. We addressed this issue in human and murine chemosensitive and multidrug resistant cancer cells. Results We found that the activity and expression of indoleamine 2,3-dioxygenase 1 (IDO1), which catalyzes the conversion of tryptophan into the immunosuppressive metabolite kynurenine, was higher in all the multidrug resistant cells analyzed and that IDO1 inhibition reduced the growth of drug-resistant tumors in immunocompetent animals. In chemoresistant cells the basal activity of JAK1/STAT1 and JAK1/STAT3 signaling was higher, the STAT3 inhibitor PIAS3 was down-regulated, and the autocrine production of STAT3-target and IDO1-inducers cytokines IL-6, IL-4, IL-1β, IL-13, TNF-α and CD40L, was increased. The disruption of the JAK/STAT signaling lowered the IDO1 activity and reversed the kynurenine-induced pro-immunosuppressive effects, as revealed by the restored proliferation of T-lymphocytes in STAT-silenced chemoresistant cells. Conclusions Our work shows that multidrug resistant cells have a stronger immunosuppressive attitude than chemosensitive cells, due to the constitutive activation of the JAK/STAT/IDO1 axis, thus resulting chemo- and immune-evasive. Disrupting this axis may significantly improve the efficacy of chemo-immunotherapy protocols against resistant tumors. PMID:25955018

  16. Staphylococci in community-acquired infections: Increased resistance to penicillin.

    PubMed

    Hughes, G B; Chidi, C C; Macon, W L

    1976-04-01

    One hundred patients with community-acquired staphylococcal infections of the skin and soft tissues were treated in the Emergency Ward of Cleveland Metropolitan General Hospital from June to October of 1974. Each staphylococcal infection was considered community-acquired if, within two weeks prior to being treated for the first time, the patient had not received antibiotics, had not been hospitalized, and had not been in contact with other recently hospitalized persons. Of 100 community-acquired staphylococcal infections, 85 were resistant to penicillin. Almost no resistance to other tested antibiotics was observed. Unless indicated otherwise by bacteriologic testing, penicillin is a poor drug of choice in those skin and soft tissue infections suspected of harboring staphylococci. PMID:1267491

  17. Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants

    PubMed Central

    Cort, Aysegul; Ozben, Tomris; Saso, Luciano; De Luca, Chiara

    2016-01-01

    Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed. PMID:26881027

  18. Prevalence of multidrug resistant organisms in an intensive care burn unit.

    PubMed

    Ram, S; Gupta, R; Gaheer, M; Uppal, S

    2000-04-01

    During January to December, 1998, analysis of an outbreak of infections in the burn intensive care unit (BICU) of the hospital attached to the Dayanand Medical College, Ludhiana was carried out. A total of 868 clinical samples from 290 patients with more than 40 per cent thermal injury were investigated. These samples included 322 wound swabs, 325 blood and 221 urine samples. Bacterial pathogens were isolated from 80, 62 and 48 per cent samples of pus, blood and urine respectively. Among the nine different pathogens isolated, the more common were Pseudomona aeruginosa from pus, Staphylococcus aureus from blood and Escherichia coli from urine samples. Multidrug resistance was observed among these predominant pathogens. Identical drug susceptibility pattern was depicted by large number of isolates of Ps. aeruginosa, Staph. aureus, Esch. coli and Proteus mirabilis. Similar pathogens with identical drug sensitivity pattern were isolated from environmental samples of the BICU. The ongoing outbreak of hospital acquired infection (HAI) was significantly reduced after strictly adhering to the guidelines for control of HAI. PMID:10935317

  19. Redox Control of Multidrug Resistance and Its Possible Modulation by Antioxidants.

    PubMed

    Cort, Aysegul; Ozben, Tomris; Saso, Luciano; De Luca, Chiara; Korkina, Liudmila

    2016-01-01

    Clinical efficacy of anticancer chemotherapies is dramatically hampered by multidrug resistance (MDR) dependent on inherited traits, acquired defence against toxins, and adaptive mechanisms mounting in tumours. There is overwhelming evidence that molecular events leading to MDR are regulated by redox mechanisms. For example, chemotherapeutics which overrun the first obstacle of redox-regulated cellular uptake channels (MDR1, MDR2, and MDR3) induce a concerted action of phase I/II metabolic enzymes with a temporal redox-regulated axis. This results in rapid metabolic transformation and elimination of a toxin. This metabolic axis is tightly interconnected with the inducible Nrf2-linked pathway, a key switch-on mechanism for upregulation of endogenous antioxidant enzymes and detoxifying systems. As a result, chemotherapeutics and cytotoxic by-products of their metabolism (ROS, hydroperoxides, and aldehydes) are inactivated and MDR occurs. On the other hand, tumour cells are capable of mounting an adaptive antioxidant response against ROS produced by chemotherapeutics and host immune cells. The multiple redox-dependent mechanisms involved in MDR prompted suggesting redox-active drugs (antioxidants and prooxidants) or inhibitors of inducible antioxidant defence as a novel approach to diminish MDR. Pitfalls and progress in this direction are discussed. PMID:26881027

  20. Elucidating Emergence and Transmission of Multidrug-Resistant Tuberculosis in Treatment Experienced Patients by Whole Genome Sequencing

    PubMed Central

    Clark, Taane G.; Mallard, Kim; Coll, Francesc; Preston, Mark; Assefa, Samuel; Harris, David; Ogwang, Sam; Mumbowa, Francis; Kirenga, Bruce; O’Sullivan, Denise M.; Okwera, Alphonse; Eisenach, Kathleen D.; Joloba, Moses; Bentley, Stephen D.; Ellner, Jerrold J.; Parkhill, Julian; Jones-López, Edward C.; McNerney, Ruth

    2013-01-01

    Background Understanding the emergence and spread of multidrug-resistant tuberculosis (MDR-TB) is crucial for its control. MDR-TB in previously treated patients is generally attributed to the selection of drug resistant mutants during inadequate therapy rather than transmission of a resistant strain. Traditional genotyping methods are not sufficient to distinguish strains in populations with a high burden of tuberculosis and it has previously been difficult to assess the degree of transmission in these settings. We have used whole genome analysis to investigate M. tuberculosis strains isolated from treatment experienced patients with MDR-TB in Uganda over a period of four years. Methods and Findings We used high throughput genome sequencing technology to investigate small polymorphisms and large deletions in 51 Mycobacterium tuberculosis samples from 41 treatment-experienced TB patients attending a TB referral and treatment clinic in Kampala. This was a convenience sample representing 69% of MDR-TB cases identified over the four year period. Low polymorphism was observed in longitudinal samples from individual patients (2-15 SNPs). Clusters of samples with less than 50 SNPs variation were examined. Three clusters comprising a total of 8 patients were found with almost identical genetic profiles, including mutations predictive for resistance to rifampicin and isoniazid, suggesting transmission of MDR-TB. Two patients with previous drug susceptible disease were found to have acquired MDR strains, one of which shared its genotype with an isolate from another patient in the cohort. Conclusions Whole genome sequence analysis identified MDR-TB strains that were shared by more than one patient. The transmission of multidrug-resistant disease in this cohort of retreatment patients emphasises the importance of early detection and need for infection control. Consideration should be given to rapid testing for drug resistance in patients undergoing treatment to monitor the

  1. [Antimicrobial therapy in severe infections with multidrug-resistant Gram-negative bacterias].

    PubMed

    Duszyńska, Wiesława

    2010-01-01

    Multidrug-resistant Gram-negative bacteria pose a serious and rapidly emerging threat to patients in healthcare settings, and are especially prevalent and problematic in intensive therapy units. Recently, the emergence of pandrug-resistance in Gram-negative bacteria poses additional concerns. This review examines the clinical impact and epidemiology of multidrug-resistant Gram-negative bacteria as a cause of increased morbidity and mortality among ITU patients. Beta-lactamases, cephalosporinases and carbapenemases play the most important role in resistance to antibiotics. Despite the tendency to increased resistance, carbapenems administered by continuous infusion remain the most effective drugs in severe sepsis. Drug concentration monitoring, albeit rarely used in practice, is necessary to ensure an effective therapeutic effect. PMID:21413423

  2. Bacteraemia and antibiotic-resistant pathogens in community acquired pneumonia: risk and prognosis.

    PubMed

    Torres, Antoni; Cillóniz, Catia; Ferrer, Miquel; Gabarrús, Albert; Polverino, Eva; Villegas, Santiago; Marco, Francesc; Mensa, Josep; Menéndez, Rosario; Niederman, Michael

    2015-05-01

    The sensitivity of blood cultures in the diagnosis of bacteraemia for community-acquired pneumonia is low. Recommendations, by guidelines, to perform blood cultures are discordant. We aimed to determine the incidence, microbial aetiology, risk factors and outcomes of bacteraemic patients with community-acquired pneumonia, including cases with antibiotic-resistant pathogens (ARP). A prospective, observational study was undertaken on consecutive adult patients admitted to the Hospital Clinic of Barcelona (Barcelona, Spain) with community-acquired pneumonia and blood cultures were obtained. Of the 2892 patients included, bacteraemia was present in 297 (10%) patients; 30 (10%) of whom had ARP (multidrug-resistant Streptococcus pneumoniae, methicillin-resistant Staphylococcus aureus, Pseudomonas aeruginosa, and an extended spectrum of beta-lactamase producing Enterobacteriaceae). In multivariate analyses, pleuritic pain, C-reactive protein ≥21.6 mg·dL(-1) and intensive care unit admissions were independently associated with bacteraemia, while prior antibiotic treatment and pneumococcal vaccine were protective factors. The risk factors for ARP bacteraemia were previous antibiotics and C-reactive protein <22.2 mg·dL(-1), while pleuritic pain was the only protective factor in the multivariate analysis. Bacteraemia (excluding ARP), appropriate empiric treatment, neurological disease, arterial oxygen tension/inspiratory oxygen fraction <250, pneumonia severity index risk classes IV and V, and intensive care unit admission were independently associated with a 30-day hospital mortality in the multivariate analysis. Inappropriate therapy was more frequent in ARP bacteraemia, compared with other bacteraemias (27% versus 3%, respectively, p<0.001). Antibiotic therapy protected against bacteraemia, but increased specifically the risk of bacteraemia from ARP due to the inappropriate coverage of these pathogens. Identifying patients at risk of ARP bacteraemia would help in

  3. Molecular characterization of multidrug-resistant Shigella spp. of food origin.

    PubMed

    Ahmed, Ashraf M; Shimamoto, Tadashi

    2015-02-01

    Shigella spp. are the causative agents of food-borne shigellosis, an acute enteric infection. The emergence of multidrug-resistant clinical isolates of Shigella presents an increasing challenge for clinicians in the treatment of shigellosis. Several studies worldwide have characterized the molecular basis of antibiotic resistance in clinical Shigella isolates of human origin, however, to date, no such characterization has been reported for Shigella spp. of food origin. In this study, we characterized the genetic basis of multidrug resistance in Shigella spp. isolated from 1600 food samples (800 meat products and 800 dairy products) collected from different street venders, butchers, retail markets, and slaughterhouses in Egypt. Twenty-four out of 27 Shigella isolates (88.9%) showed multidrug resistance phenotypes to at least three classes of antimicrobials. The multidrug-resistant Shigella spp. were as follows: Shigella flexneri (66.7%), Shigella sonnei (18.5%), and Shigella dysenteriae (3.7%). The highest resistance was to streptomycin (100.0%), then to kanamycin (95.8%), nalidixic acid (95.8%), tetracycline (95.8%), spectinomycin (93.6%), ampicillin (87.5%), and sulfamethoxazole/trimethoprim (87.5%). PCR and DNA sequencing were used to screen and characterize integrons and antibiotic resistance genes. Our results indicated that 11.1% and 74.1% of isolates were positive for class 1 and class 2 integrons, respectively. Beta-lactamase-encoding genes were identified in 77.8% of isolates, and plasmid-mediated quinolone resistance genes were identified in 44.4% of isolates. These data provide useful information to better understand the molecular basis of antimicrobial resistance in Shigella spp. To the best of our knowledge, this is the first report of the molecular characterization of antibiotic resistance in Shigella spp. isolated from food. PMID:25485847

  4. Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India

    PubMed Central

    Padmavathy, Kesavaram; Padma, Krishnan; Rajasekaran, Sikhamani

    2016-01-01

    Extended Spectrum β-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients from South India were screened for blaCTX-M, AmpC production, multidrug resistance, and nine virulence associated genes (VAGs), fimH, pap, afa/dra, sfa/foc, iutA, fyuA, iroN, usp, and kpsMII. The majority (70.2%) of the ESBL producers harbored blaCTX-M and were AmpC coproducers. Among the CTX-M producers, 47.5% were found to be UPEC, 10% harbored as many as 7 VAGs, and 45% possessed kpsMII. Multidrug resistance (CIPRSXTRGENR) was significantly more common among the CTX-M producers compared to the nonproducers (70% versus 41.2%). However, 71.4% of the multidrug resistant CTX-M producers exhibited susceptibility to nitrofurantoin thereby making it an effective alternative to cephalosporins/fluoroquinolones. The emergence of CTX-M-producing highly virulent, multidrug resistant uropathogenic E. coli is of significant public health concern in countries like India with a high burden of HIV/AIDS. PMID:27123344

  5. Multidrug Resistant CTX-M-Producing Escherichia coli: A Growing Threat among HIV Patients in India.

    PubMed

    Padmavathy, Kesavaram; Padma, Krishnan; Rajasekaran, Sikhamani

    2016-01-01

    Extended Spectrum β-Lactamases (ESBLs) confer resistance to third-generation cephalosporins and CTX-M types have emerged as the most prominent ESBLs worldwide. This study was designed to determine the prevalence of CTX-M positive ESBL-producing urinary E. coli isolates from HIV patients and to establish the association of multidrug resistance, phylogeny, and virulence profile with CTX-M production. A total of 57 ESBL producers identified among 76 E. coli strains isolated from HIV patients from South India were screened for bla CTX-M, AmpC production, multidrug resistance, and nine virulence associated genes (VAGs), fimH, pap, afa/dra, sfa/foc, iutA, fyuA, iroN, usp, and kpsMII. The majority (70.2%) of the ESBL producers harbored bla CTX-M and were AmpC coproducers. Among the CTX-M producers, 47.5% were found to be UPEC, 10% harbored as many as 7 VAGs, and 45% possessed kpsMII. Multidrug resistance (CIP(R)SXT(R)GEN(R)) was significantly more common among the CTX-M producers compared to the nonproducers (70% versus 41.2%). However, 71.4% of the multidrug resistant CTX-M producers exhibited susceptibility to nitrofurantoin thereby making it an effective alternative to cephalosporins/fluoroquinolones. The emergence of CTX-M-producing highly virulent, multidrug resistant uropathogenic E. coli is of significant public health concern in countries like India with a high burden of HIV/AIDS. PMID:27123344

  6. Isolation and characterization of antimicrobial compounds in plant extracts against multidrug-resistant Acinetobacter baumannii.

    PubMed

    Miyasaki, Yoko; Rabenstein, John D; Rhea, Joshua; Crouch, Marie-Laure; Mocek, Ulla M; Kittell, Patricia Emmett; Morgan, Margie A; Nichols, Wesley Stephen; Van Benschoten, M M; Hardy, William David; Liu, George Y

    2013-01-01

    The number of fully active antibiotic options that treat nosocomial infections due to multidrug-resistant Acinetobacter baumannii (A. baumannii) is extremely limited. Magnolia officinalis, Mahonia bealei, Rabdosia rubescens, Rosa rugosa, Rubus chingii, Scutellaria baicalensis, and Terminalia chebula plant extracts were previously shown to have growth inhibitory activity against a multidrug-resistant clinical strain of A. baumannii. In this study, the compounds responsible for their antimicrobial activity were identified by fractionating each plant extract using high performance liquid chromatography, and determining the antimicrobial activity of each fraction against A. baumannii. The chemical structures of the fractions inhibiting >40% of the bacterial growth were elucidated by liquid chromatography/mass spectrometry analysis and nuclear magnetic resonance spectroscopy. The six most active compounds were identified as: ellagic acid in Rosa rugosa; norwogonin in Scutellaria baicalensis; and chebulagic acid, chebulinic acid, corilagin, and terchebulin in Terminalia chebula. The most potent compound was identified as norwogonin with a minimum inhibitory concentration of 128 µg/mL, and minimum bactericidal concentration of 256 µg/mL against clinically relevant strains of A. baumannii. Combination studies of norwogonin with ten anti-Gram negative bacterial agents demonstrated that norwogonin did not enhance the antimicrobial activity of the synthetic antibiotics chosen for this study. In conclusion, of all identified antimicrobial compounds, norwogonin was the most potent against multidrug-resistant A. baumannii strains. Further studies are warranted to ascertain the prophylactic and therapeutic potential of norwogonin for infections due to multidrug-resistant A. baumannii. PMID:23630600

  7. First Genome Sequence of a Mexican Multidrug-Resistant Acinetobacter baumannii Isolate

    PubMed Central

    Graña-Miraglia, Lucía; Lozano, Luis; Castro-Jaimes, Semiramis; Cevallos, Miguel A.; Volkow, Patricia

    2016-01-01

    Acinetobacter baumannii has emerged as an important nosocomial pathogen worldwide. Here, we present the draft genome of the first multidrug-resistant A. baumannii isolate, sampled from a tertiary hospital in Mexico City. This genome will provide a starting point for studying the genomic diversity of this species in Mexico. PMID:27013043

  8. Antibiotic exposure can induce various bacterial virulence phenotypes in multidrug-resistant Salmonella enterica serovar Typhimurium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Salmonella is one of the most prevalent bacterial foodborne diseases in the United States and causes an estimated 1 million human cases every year. Multidrug-resistant (MDR) Salmonella has emerged as a public health issue as it has been associated with increased morbidity in humans and mortality in...

  9. Geraniol Restores Antibiotic Activities against Multidrug-Resistant Isolates from Gram-Negative Species▿ †

    PubMed Central

    Lorenzi, Vannina; Muselli, Alain; Bernardini, Antoine François; Berti, Liliane; Pagès, Jean-Marie; Amaral, Leonard; Bolla, Jean-Michel

    2009-01-01

    The essential oil of Helichrysum italicum significantly reduces the multidrug resistance of Enterobacter aerogenes, Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii. Combinations of the two most active fractions of the essential oil with each other or with phenylalanine arginine β-naphthylamide yield synergistic activity. Geraniol, a component of one fraction, significantly increased the efficacy of β-lactams, quinolones, and chloramphenicol. PMID:19258278

  10. Multidrug-resistant viridans streptococcus (MDRVS) osteomyelitis of the mandible successfully treated with moxifloxacin.

    PubMed

    Ang, Jocelyn Y; Asmar, Basim I

    2008-05-01

    Multidrug-resistant viridans group streptococcus (MDRVS) strains have emerged as important pathogens. Treatment of MDRVS infections is problematic. The use of fluoroquinolones for treatment of MDRVS osteomyelitis has not been established. We present the first case of MDRVS osteomyelitis of the mandible successfully treated with sequential intravenous then oral moxifloxacin, and review the literature on the subject. PMID:18414152

  11. Increased risk for multidrug-resistant tuberculosis in migratory workers, Armenia.

    PubMed

    Truzyan, Nune; Crape, Byron; Grigoryan, Ruzanna; Martirosyan, Hripsime; Petrosyan, Varduhi

    2015-03-01

    To understand use of tuberculosis (TB) services for migrant workers, we conducted a cross-sectional census of 95 migrant workers with TB from Armenia by using medical record reviews and face-to-face interviews. Prolonged time between diagnosis and treatment, treatment interruption, and treatment defaults caused by migrant work might increase the risk for multidrug-resistant TB. PMID:25695488

  12. Fecal Microbiota Transplantation and Successful Resolution of Multidrug-Resistant-Organism Colonization

    PubMed Central

    Sullivan, Eva; Ballon-Landa, Gonzalo

    2015-01-01

    We report a case in which fecal microbiota transplantation (FMT) utilized for relapsing Clostridium difficile colitis successfully eradicated colonization with several multidrug-resistant organisms (MDROs). FMT may have an additive benefit of reducing MDRO carriage and should be further investigated as a potential measure to eradicate additional potentially virulent organisms beyond C. difficile. PMID:25878340

  13. Increased Risk for Multidrug-Resistant Tuberculosis in Migratory Workers, Armenia

    PubMed Central

    Crape, Byron; Grigoryan, Ruzanna; Martirosyan, Hripsime; Petrosyan, Varduhi

    2015-01-01

    To understand use of tuberculosis (TB) services for migrant workers, we conducted a cross-sectional census of 95 migrant workers with TB from Armenia by using medical record reviews and face-to-face interviews. Prolonged time between diagnosis and treatment, treatment interruption, and treatment defaults caused by migrant work might increase the risk for multidrug-resistant TB. PMID:25695488

  14. Recycling antibiotics into GUMBOS: A new combination strategy to combat multi-drug resistant bacteria

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The emergence of multi-drug resistant bacteria, coupled with the lack of new antibiotics in development, is fast evolving into a global crisis. New strategies utilizing existing antibacterial agents are urgently needed. We propose one such strategy in which four outmoded ß-lactam antibiotics (amp...

  15. Fecal Microbiota Transplantation Inhibits Multidrug-Resistant Gut Pathogens: Preliminary Report Performed in an Immunocompromised Host.

    PubMed

    Biliński, Jarosław; Grzesiowski, Paweł; Muszyński, Jacek; Wróblewska, Marta; Mądry, Krzysztof; Robak, Katarzyna; Dzieciątkowski, Tomasz; Wiktor-Jedrzejczak, Wiesław; Basak, Grzegorz W

    2016-06-01

    Colonization of the gastrointestinal tract with multidrug-resistant (MDR) bacteria is a consequence of gut dysbiosis. We describe the successful utilization of fecal microbiota transplantation to inhibit Klebsiella pneumoniae MBL(+) and Escherichia coli ESBL(+) gut colonization in the immunocompromised host as a novel tool in the battle against MDR microorganisms. ClinicalTrials.gov identifier NCT02461199. PMID:26960790

  16. [Coxitis due to multidrug resistant Mycobacterium tuberculosis in a HIV negative patient].

    PubMed

    Palmero, D J; Simboli, N; Alberti, F A; Francos, J L; Güemes Gurtubay, J L; Ochoa, E J; Cardozo, L; Waisman, J L

    2000-01-01

    A case of an HIV negative female patient with coxofemoral arthritis of tuberculous etiology, multidrug-resistant strain, and connective tissue disease associated to glucocorticoid therapy is reported. The patient was treated with cycloserine, ethambutol, p-aminosalicylic acid and ofloxacin, with improvement of the joint lesions. Previous publications on this subject are reviewed. PMID:11050817

  17. Structural contributions to multidrug recognition in the multidrug resistance (MDR) gene regulator, BmrR

    PubMed Central

    Bachas, Sharrol; Eginton, Christopher; Gunio, Drew; Wade, Herschel

    2011-01-01

    Current views of multidrug (MD) recognition focus on large drug-binding cavities with flexible elements. However, MD recognition in BmrR is supported by a small, rigid drug-binding pocket. Here, a detailed description of MD binding by the noncanonical BmrR protein is offered through the combined use of X-ray and solution studies. Low shape complementarity, suboptimal packing, and efficient burial of a diverse set of ligands is facilitated by an aromatic docking platform formed by a set of conformationally fixed aromatic residues, hydrophobic pincer pair that locks the different drug structures on the adaptable platform surface, and a trio of acidic residues that enables cation selectivity without much regard to ligand structure. Within the binding pocket is a set of BmrR-derived H-bonding donor and acceptors that solvate a wide range of ligand polar substituent arrangements in a manner analogous to aqueous solvent. Energetic analyses of MD binding by BmrR are consistent with structural data. A common binding orientation for the different BmrR ligands is in line with promiscuous allosteric regulation. PMID:21690368

  18. ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal

    PubMed Central

    Choi, Cheol-Hee

    2005-01-01

    One of the major problems related with anticancer chemotherapy is resistance against anticancer drugs. The ATP-binding cassette (ABC) transporters are a family of transporter proteins that are responsible for drug resistance and a low bioavailability of drugs by pumping a variety of drugs out cells at the expense of ATP hydrolysis. One strategy for reversal of the resistance of tumor cells expressing ABC transporters is combined use of anticancer drugs with chemosensitizers. In this review, the physiological functions and structures of ABC transporters, and the development of chemosensitizers are described focusing on well-known proteins including P-glycoprotein, multidrug resistance associated protein, and breast cancer resistance protein. PMID:16202168

  19. Evaluation of Multidrug Resistant Staphylococcus aureus and their Association with Biofilm Production in a Tertiary Care Hospital, Tripura, Northeast India

    PubMed Central

    Bir, Raunak; Majumdar, Tapan

    2015-01-01

    Background High morbidity and mortality rates are associated with Methicillin-resistant Staphylococcus aureus (MRSA) because of development of multidrug resistance. Staphylococcus aureus (S. aureus) has the ability to colonize and form biofilms on biomaterials which is causing resistance towards antimicrobials and thus making them difficult to eradicate from the infected hosts. Materials and Methods Culture isolation, identification was done following standard protocol and antibiogram of the isolates were done. The detection of MRSA, Macrolide-Lincosamide-Streptogramin B resistance (MLSB), vancomycin resistance phenotypes were done by using cefoxitin disc diffusion test, D zone test and vancomycin E test. Biofilm was detected by Congo red agar method. Results A total of 100 (31.7%) S. aureus strains were isolated from 315 clinical specimens. The prevalence of MRSA was 47% (47/100) with 85.1% were homogeneous MRSA and 14.9% were heterogeneous. Out of 47 MRSA strains, 63.8% were Hospital acquired-MRSA (HA-MRSA) infections whereas rests 36.2% were caused by Community acquired-MRSA (CA-MRSA) strains. Maximum number of MRSA isolates belonged to group A biotype (34%). A 14.9% isolates were of nontypeable group. Out of 100 S. aureus isolates, the prevalence of Vancomycin resistant S. aureus (VRSA) was found to be 3%. The MLSB phenotypes showed that the rates of inducible MLSB (iMLSB), constitutive MLSB (cMLSB) and Macrolide-Streptogramin B (MSB) in case of MRSA to be 19.1%, 31.9% and 12.8%. Prevalence of low-level (MUPL) and high-level mupirocin resistance (MUPH) among MRSA was 19.1% and 6.4%. Biofilm production was found in 55% strains of S. aureus. Out of 47 MRSA strains 76.6%were producing biofilm in comparison to 38.8% in methicillin-sensitive S. aureus (MSSA). Higher degree of antibiotic resistance in biofilm producers was seen especially in case of ciprofloxacin, co-trimoxazole, rifampicin, kanamycin, erythromycin and clindamycin whereas gentamycin, tetracycline and

  20. Antimicrobial Organometallic Dendrimers with Tunable Activity against Multidrug-Resistant Bacteria.

    PubMed

    Abd-El-Aziz, Alaa S; Agatemor, Christian; Etkin, Nola; Overy, David P; Lanteigne, Martin; McQuillan, Katherine; Kerr, Russell G

    2015-11-01

    Multidrug-resistant pathogens are an increasing threat to public health. In an effort to curb the virulence of these pathogens, new antimicrobial agents are sought. Here we report a new class of antimicrobial organometallic dendrimers with tunable activity against multidrug-resistant Gram-positive bacteria that included methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. Mechanistically, these redox-active, cationic organometallic dendrimers induced oxidative stress on bacteria and also disrupted the microbial cell membrane. The minimum inhibitory concentrations, which provide a quantitative measure of the antimicrobial activity of these dendrimers, were in the low micromolar range. AlamarBlue cell viability assay also confirms the antimicrobial activity of these dendrimers. Interestingly, these dendrimers were noncytotoxic to epidermal cell lines and to mammalian red blood cells, making them potential antimicrobial platforms for topical applications. PMID:26452022

  1. Novel type of Streptococcus pneumoniae causing multidrug-resistant acute otitis media in children.

    PubMed

    Xu, Qingfu; Pichichero, Michael E; Casey, Janet R; Zeng, Mingtao

    2009-04-01

    After our recent discovery of a Streptococcus pneumoniae 19A "superbug" (Legacy strain) that is resistant to all Food and Drug Administration-approved antimicrobial drugs for treatment of acute otitis media (AOM) in children, other S. pneumoniae isolates from children with AOM were characterized by multilocus sequence typing (MLST). Among 40 isolates studied, 16 (40%) were serotype 19A, and 9 (23%) were resistant to multiple antimicrobial drugs. Two others had unreported sequence types (STs) that expressed the 19A capsule, and 8 (88%) of the 9 multidrug-resistant strains were serotype 19A, including the Legacy strain with the new ST-2722. In genetic relatedness, ST-2722 belonged to a cluster of reported strains of S. pneumoniae in which all strains had 6 of the same alleles as ST-156. The multidrug-resistant strains related to ST-156 expressed different capsular serotypes: 9V, 14, 11A, 15C, and 19F. PMID:19331730

  2. Thermotolerance and multidrug resistance in bacteria isolated from equids and their environment.

    PubMed

    Singh, B R

    2009-06-13

    Sixty-nine vaginal swabs and 138 rectal swabs collected from 195 equids were analysed for the presence of thermotolerant bacteria, that is, bacteria surviving at 60+/-0.1 degrees C for one hour. Thermotolerant Escherichia coli, Enterobacter species, Klebsiella pneumoniae, Proteus species and Pseudomonas species were isolated from 41, 16, nine, three and three of the 138 rectal swabs, respectively; seven of the E coli and two of the Enterobacter species isolates survived pasteurisation at 63.8+/-0.1 degrees C for 30 minutes. All except three E coli, two Enterobacter species and one Proteus species isolate were resistant to three or more antimicrobial drugs, that is, they were multidrug resistant. Thermotolerant E coli, Enterobacter species and Proteus species were isolated from 11, two and two of the 69 vaginal swabs, respectively, but only one isolate of E coli survived pasteurisation at 63.8+/-0.1 degrees C for 30 minutes. All except two of the E coli isolates were multidrug resistant. None of the four thermotolerant isolates from nine soil samples collected on four of the farms where the equids were kept was pasteurisation resistant, but they were all multidrug resistant. Of the 10 pasteurisation-resistant isolates, nine were multidrug resistant but none was resistant to chloramphenicol, ciprofloxacin, cotrimazine, cotrimoxazole or streptomycin. All the isolates grew at 42+/-0.1 degrees C but none grew at 46+/-0.1 degrees C or above. The Enterobacter isolates were more tolerant to pasteurisation than the E coli isolates, particularly during the first few minutes of exposure. PMID:19525523

  3. Lab-on-Chip-Based Platform for Fast Molecular Diagnosis of Multidrug-Resistant Tuberculosis

    PubMed Central

    Cabibbe, Andrea M.; Miotto, Paolo; Moure, Raquel; Alcaide, Fernando; Feuerriegel, Silke; Pozzi, Gianni; Nikolayevskyy, Vladislav; Drobniewski, Francis; Niemann, Stefan; Reither, Klaus

    2015-01-01

    We evaluated the performance of the molecular lab-on-chip-based VerePLEX Biosystem for detection of multidrug-resistant tuberculosis (MDR-TB), obtaining a diagnostic accuracy of more than 97.8% compared to sequencing and MTBDRplus assay for Mycobacterium tuberculosis complex and rifampin and isoniazid resistance detection on clinical isolates and smear-positive specimens. The speed, user-friendly interface, and versatility make it suitable for routine laboratory use. PMID:26246486

  4. Inhibition of bacterial multidrug resistance by celecoxib, a cyclooxygenase-2 inhibitor.

    PubMed

    Kalle, Arunasree M; Rizvi, Arshad

    2011-01-01

    Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs inside the cell, thus reversing MDR in bacteria. PMID:20937780

  5. Epidemiology of Carbapenem Resistance among Multi-drug Resistant Enterobacteriaceae in Uganda

    PubMed Central

    Ampaire, Lucas M.; Katawera, Victoria; Nyehangane, Dan; Boum, Yap; Bazira, Joel

    2015-01-01

    Background Multi-drug resistant (MDR) Enterobacteriaceae are on the increase worldwide and their spread has become a global challenge. Escalating the challenge is the possibility that many of these are Carbapenemase-producing Enterobacteriaceae (CPE). This further complicates patient management. The magnitude of MDR-CPE in many developed settings has been reported, however, there is paucity of data from resource limited settings. We evaluated the epidemiology of MDR-CPE of clinical origin in South Western Uganda. Methods From September 2013 to June 2014, all Enterobacteriaceae isolated from diverse specimens obtained from patients attending Mbarara Regional Referral Hospital, South-western Uganda, were screened for MDR in a laboratory-based cross sectional study. Isolates found to be MDR were screened for carbapenem susceptibility/resistance phenotypically by Kirby Bauer disc diffusion method following CLSI guidelines and genetically using the multiplex real-time Polymerase Chain Reaction (RT-PCR). Results Of the 658 strains isolated, 183 (27.8%) were MDR and 68 (37.15%) of those MDR exhibited at least one form of carbapenem resistance with 23 (12.57%) and 56 (30.60%) isolates expressing phenotypic and genetic resistance, respectively. Eleven MDR-CPE (6.01%) isolates exhibited both phenotypic and genotypic resistance to carbapenems. Only blaVIM and blaOXA-48 genes were detected among the genetically resistant isolates. Conclusion The high prevalence of MDR-CPE calls for aggressive infection control and prevention strategies, including reinforcement of hand hygiene, using contact precautions and early detection of CPE through use of targeted surveillance and molecular techniques in resource limited settings. PMID:26605152

  6. Individualizing Risk of Multidrug-Resistant Pathogens in Community-Onset Pneumonia

    PubMed Central

    Falcone, Marco; Russo, Alessandro; Giannella, Maddalena; Cangemi, Roberto; Scarpellini, Maria Gabriella; Bertazzoni, Giuliano; Alarcón, José Martínez; Taliani, Gloria; Palange, Paolo; Farcomeni, Alessio; Vestri, Annarita; Bouza, Emilio; Violi, Francesco; Venditti, Mario

    2015-01-01

    Introduction The diffusion of multidrug-resistant (MDR) bacteria has created the need to identify risk factors for acquiring resistant pathogens in patients living in the community. Objective To analyze clinical features of patients with community-onset pneumonia due to MDR pathogens, to evaluate performance of existing scoring tools and to develop a bedside risk score for an early identification of these patients in the Emergency Department. Patients and Methods This was an open, observational, prospective study of consecutive patients with pneumonia, coming from the community, from January 2011 to January 2013. The new score was validated on an external cohort of 929 patients with pneumonia admitted in internal medicine departments participating at a multicenter prospective study in Spain. Results A total of 900 patients were included in the study. The final logistic regression model consisted of four variables: 1) one risk factor for HCAP, 2) bilateral pulmonary infiltration, 3) the presence of pleural effusion, and 4) the severity of respiratory impairment calculated by use of PaO2/FiO2 ratio. A new risk score, the ARUC score, was developed; compared to Aliberti, Shorr, and Shindo scores, this point score system has a good discrimination performance (AUC 0.76, 95% CI 0.71-0.82) and calibration (Hosmer-Lemeshow, χ2 = 7.64; p = 0.469). The new score outperformed HCAP definition in predicting etiology due to MDR organism. The performance of this bedside score was confirmed in the validation cohort (AUC 0.68, 95% CI 0.60-0.77). Conclusion Physicians working in ED should adopt simple risk scores, like ARUC score, to select the most appropriate antibiotic regimens. This individualized approach may help clinicians to identify those patients who need an empirical broad-spectrum antibiotic therapy. PMID:25860142

  7. Additional Drug Resistance of Multidrug-Resistant Tuberculosis in Patients in 9 Countries

    PubMed Central

    Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; Van Der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Contreras, Carmen; Leimane, Vaira; Via, Laura E.; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y.; Volchenkov, Grigory V.; Jou, Ruwen; Kliiman, Kai; Demikhova, Olga V.; Cegielski, J. Peter

    2015-01-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5–6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2–4) drugs; 26% retained susceptibility to <2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens. PMID:25988299

  8. Additional drug resistance of multidrug-resistant tuberculosis in patients in 9 countries.

    PubMed

    Kurbatova, Ekaterina V; Dalton, Tracy; Ershova, Julia; Tupasi, Thelma; Caoili, Janice Campos; Van Der Walt, Martie; Kvasnovsky, Charlotte; Yagui, Martin; Bayona, Jaime; Contreras, Carmen; Leimane, Vaira; Via, Laura E; Kim, HeeJin; Akksilp, Somsak; Kazennyy, Boris Y; Volchenkov, Grigory V; Jou, Ruwen; Kliiman, Kai; Demikhova, Olga V; Cegielski, J Peter

    2015-06-01

    Data from a large multicenter observational study of patients with multidrug-resistant tuberculosis (MDR TB) were analyzed to simulate the possible use of 2 new approaches to treatment of MDR TB: a short (9-month) regimen and a bedaquiline-containing regimen. Of 1,254 patients, 952 (75.9%) had no resistance to fluoroquinolones and second-line injectable drugs and thus would qualify as candidates for the 9-month regimen; 302 (24.1%) patients with resistance to a fluoroquinolone or second-line injectable drug would qualify as candidates for a bedaquiline-containing regimen in accordance with published guidelines. Among candidates for the 9-month regimen, standardized drug-susceptibility tests demonstrated susceptibility to a median of 5 (interquartile range 5-6) drugs. Among candidates for bedaquiline, drug-susceptibility tests demonstrated susceptibility to a median of 3 (interquartile range 2-4) drugs; 26% retained susceptibility to <2 drugs. These data may assist national TB programs in planning to implement new drugs and drug regimens. PMID:25988299

  9. High isolation rates of multidrug-resistant bacteria from water and carpets of mosques

    PubMed Central

    Mohamed Ali, Mostafa Mohamed; Alemary, Fuoad; Alrtail, Amna; Rzeg, Moftah M.; Albakush, Abdulla M.; Ghenghesh, Khalifa Sifaw

    2014-01-01

    Objective There is little information regarding the isolation of antimicrobial-resistant potentially pathogenic bacteria from water and carpets of mosques worldwide. The objective of the present investigation is to determine the bacteriological quality of water and carpets of mosques in Elkhomes city in Libya. Methods Potentially pathogenic bacteria were isolated from water samples (n=44) and dust samples from carpets (n=50) of 50 mosques in Elkhomes city, Libya, using standard bacteriological procedures. Susceptibility of isolated bacteria to antimicrobial agents was determined by the disc-diffusion method. Results Of the water samples examined, 12 (27.3%) were positive for Escherichia coli, 10 (22.7%) for Klebsiella spp., and 15 (34.1%) for other enteric bacteria. Of the dust samples of carpets examined, 6 (12%) were positive for E. coli, 33 (66%) for Klebsiella spp., and 30 (60%) for Staphylococcus spp. Multidrug resistance (MDR, resistance to three or more antimicrobial groups) was found among 48.7% (19/37) and 46.9% (30/64) of the examined enterobacteria from water and carpets, respectively, and among 66.7% (20/30) of Staphylococcus spp. from carpets. In addition, methicillin-resistant Staphylococcus aureus (MRSA) was isolated from a carpet of one mosque. Conclusion Presence of multidrug-resistant potentially pathogenic bacteria in examined water and carpets indicate that mosques as communal environments may play a role in the spread of multidrug-resistant bacteria in the community and pose a serious health risk to worshipers. PMID:25128691

  10. Directly observed treatment, short-course strategy and multidrug-resistant tuberculosis: are any modifications required?

    PubMed Central

    Bastian, I.; Rigouts, L.; Van Deun, A.; Portaels, F.

    2000-01-01

    Multidrug-resistant tuberculosis (MDRTB) should be defined as tuberculosis with resistance to at least isoniazid and rifampicin because these drugs are the cornerstone of short-course chemotherapy, and combined isoniazid and rifampicin resistance requires prolonged treatment with second-line agents. Short-course chemotherapy is a key ingredient in the tuberculosis control strategy known as directly observed treatment, short-course (DOTS). For populations in which multidrug-resistant tuberculosis is endemic, the outcome of the standard short-course chemotherapy regimen remains uncertain. Unacceptable failure rates have been reported and resistance to additional agents may be induced. As a consequence there have been calls for well-functioning DOTS programmes to provide additional services in areas with high rates of multidrug-resistant tuberculosis. These "DOTS-plus for MDRTB programmes" may need to modify all five elements of the DOTS strategy: the treatment may need to be individualized rather than standardized; laboratory services may need to provide facilities for on-site culture and antibiotic susceptibility testing; reliable supplies of a wide range of expensive second-line agents would have to be supplied; operational studies would be required to determine the indications for and format of the expanded programmes; financial and technical support from international organizations and Western governments would be needed in addition to that obtained from local governments. PMID:10743297

  11. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia

    PubMed Central

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry. PMID:26483759

  12. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia.

    PubMed

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry. PMID:26483759

  13. Photoaffinity labeling of the multidrug-resistance-related P-glycoprotein with photoactive analogs of verapamil

    SciTech Connect

    Safa, A.R. )

    1988-10-01

    Verapamil, a phenylalkylamine calcium channel blocker, has been shown to reverse multidrug resistance in tumor cells, possibly by increasing drug retention through interaction with an outward drug transporter of the resistant cells. In this study two photoactive radioactive analogs of verapamil, N-(p-azido(3,5-{sup 3}H)benzoyl)aminomethyl verapamil and N-(p-azido(3-{sup 125}I)salicyl)aminomethyl verapamil, were synthesized and used to identify the possible biochemical target(s) for verapamil in multidrug-resistance DC-3F/VCRd-5L Chinese hamster lung cells selected for resistance to vincristine. The results show that a specifically labeled 150- to 180-kDa membrane protein in resistant cells was immunoprecipitated with a monoclonal antibody specific for P-glycoprotein. Phenylalkylamine binding specificity was established by competitive blocking of specific photolabeling with the nonradioactive photoactive analogs as well as with verapamil. Photoaffinity labeling was also inhibited by 50 {mu}M concentrations of the calcium channel blockers nimodipine, nifedipine, nicardipine, azidopine, bepridil, and diltiazem and partially by prenylamine. Moreover, P-glycoprotein labeling was inhibited in a dose-dependent manner by vinblastine with half-maximal inhibition at 0.2 {mu}M compared to that by verapamil at 8 {mu}M. These data provide direct evidence that P-glycoprotein has broad drug recognition capacity and that it serves as a molecular target for calcium channel blocker action in reversing multidrug resistance.

  14. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition.

    PubMed

    Rathert, Philipp; Roth, Mareike; Neumann, Tobias; Muerdter, Felix; Roe, Jae-Seok; Muhar, Matthias; Deswal, Sumit; Cerny-Reiterer, Sabine; Peter, Barbara; Jude, Julian; Hoffmann, Thomas; Boryń, Łukasz M; Axelsson, Elin; Schweifer, Norbert; Tontsch-Grunt, Ulrike; Dow, Lukas E; Gianni, Davide; Pearson, Mark; Valent, Peter; Stark, Alexander; Kraut, Norbert; Vakoc, Christopher R; Zuber, Johannes

    2015-09-24

    Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukaemia (AML), bromodomain and extra terminal protein (BET) inhibitors are being explored as a promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced haematological malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukaemia, here we perform a chromatin-focused RNAi screen in a sensitive MLL-AF9;Nras(G12D)-driven AML mouse model, and investigate dynamic transcriptional profiles in sensitive and resistant mouse and human leukaemias. Our screen shows that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodelling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukaemias regardless of their sensitivity, resistant leukaemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signalling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic chromatin immunoprecipitation sequencing and self-transcribing active regulatory region sequencing of enhancer profiles reveal that BET-resistant states are characterized by remodelled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signalling as a driver and candidate biomarker of primary and acquired BET resistance in leukaemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting

  15. Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

    PubMed Central

    Neumann, Tobias; Muerdter, Felix; Roe, Jae-Seok; Muhar, Matthias; Deswal, Sumit; Cerny-Reiterer, Sabine; Peter, Barbara; Jude, Julian; Hoffmann, Thomas; Boryń, Łukasz M.; Axelsson, Elin; Schweifer, Norbert; Tontsch-Grunt, Ulrike; Dow, Lukas E.; Gianni, Davide; Pearson, Mark; Valent, Peter; Stark, Alexander; Kraut, Norbert; Vakoc, Christopher R.; Zuber, Johannes

    2016-01-01

    Summary Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukemia (AML)1,2, BET inhibitors are being explored as promising therapeutic avenue in numerous cancers3–5. While clinical trials have reported single-agent activity in advanced hematologic malignancies6, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukemia, we performed a chromatin-focused RNAi screen in a sensitive MLL/AF9; NrasG12D -driven AML model, and investigated dynamic transcriptional profiles in sensitive and resistant murine and human leukemias. Our screen reveals that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET inhibitor resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodeling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukemias regardless of their sensitivity, resistant leukemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signaling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic ChIP- and STARR-seq enhancer profiles reveal that BET-resistant states are characterized by remodeled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signaling as a driver and candidate biomarker of primary and acquired BET resistance in leukemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies. PMID:26367798

  16. Inducible and Acquired Clarithromycin Resistance in the Mycobacterium abscessus Complex

    PubMed Central

    Rubio, Marc; March, Francesca; Garrigó, Montserrat; Moreno, Carmen; Español, Montserrat; Coll, Pere

    2015-01-01

    Purpose Clarithromycin was considered the cornerstone for the treatment of Mycobacterium abscessus complex infections. Genetic resistance mechanisms have been described and many experts propose amikacin as an alternative. Nevertheless, clarithromycin has several advantages; therefore, it is necessary to identify the non-functional erm(41) allele to determine the most suitable treatment. The aims of this study were to characterize the molecular mechanisms of clarithromycin resistance in a collection of Mycobacterium abscessus complex isolates and to verify the relationship between these mechanisms and the antibiogram. Materials and Methods Clinical isolates of M. abscessus complex (n = 22) from 16 patients were identified using four housekeeping genes (rpoB, secA1, sodA and hsp65), and their genetic resistance was characterized by studying erm(41) and rrl genes. Nine strains were recovered from the clinical isolates and subjected to E-test and microdilution clarithromycin susceptibility tests, with readings at 3, 7 and 14 days. Results We classified 11/16 (68.8%) M. abscessus subsp. abscessus, 4/16 (25.0%) M. abscessus subsp. bolletii, and 1/16 (6.3%) M. abscessus subsp. massiliense. T28 erm(41) allele was observed in 8 Mycobacterium abscessus subps. abscessus and 3 Mycobacterium abscessus subsp. bolletii. One strain of M. abscessus subsp. bolletii had an erm(41) gene truncated and was susceptible to clarithromycin. No mutations were observed in rrl gene first isolates. In three patients, follow-up of initial rrl wild-type strains showed acquired resistance. Conclusions Most clinical isolates of M. abscessus complex had inducible resistance to clarithromycin and total absence of constitutive resistance. Our findings showed that the acquisition of resistance mutations in rrl gene was associated with functional and non-functional erm(41) gene. Caution is needed when using erm(41) sequencing alone to identify M. abscessus subspecies. This study reports an acquired

  17. First report of an OXA-48-producing multidrug-resistant Proteus mirabilis strain from Gaza, Palestine.

    PubMed

    Chen, Liang; Al Laham, Nahed; Chavda, Kalyan D; Mediavilla, Jose R; Jacobs, Michael R; Bonomo, Robert A; Kreiswirth, Barry N

    2015-07-01

    We report the first multidrug-resistant Proteus mirabilis strain producing the carbapenemase OXA-48 (Pm-OXA-48) isolated at Al-Shifa hospital in Gaza, Palestine. Draft genome sequencing of Pm-OXA-48 identified 16 antimicrobial resistance genes, encoding resistance to β-lactams, aminoglycosides, fluoroquinolones, phenicols, streptothricin, tetracycline, and trimethoprim-sulfamethoxazole. Complete sequencing of the bla(OXA-48)-harboring plasmid revealed that it is a 72 kb long IncL/M plasmid, harboring carbapenemase gene bla(OXA-48), extended spectrum β-lactamase gene bla(CTX-M-14), and aminoglycoside resistance genes strA, strB, and aph(3')-VIb. PMID:25896692

  18. Overcoming of multidrug resistance by introducing the apoptosis gene, bcl-Xs, into MRP-overexpressing drug resistant cells.

    PubMed

    Ohi, Y; Kim, R; Toge, T

    2000-05-01

    Multidrug resistance associated protein (MRP) is one of drug transport membranes that confer multidrug resistance in cancer cells. Multidrug resistance has been known to be associated with resistance to apoptosis. In this study, using MRP overexpressing multidrug resistant nasopharyngeal cancer cells, we examined the expression of apoptosis related genes including p53, p21WAF1, bax and bcl-Xs between drug sensitive KB and its resistant KB/7D cells. We also examined whether the introduction of apoptosis related gene could increase the sensitivity to anticancer drugs in association with apoptotic cell death. The relative resistances to anticancer drugs in KB/7D cells evaluated by IC50 values were 3.6, 61.3, 10.4 and 10.5 to adriamycin (ADM), etoposide (VP-16), vincristine (VCR) and vindesine (VDS), respectively. The resistance to anticancer drugs in KB/7D cells was associated with the attenuation of internucleosomal DNA ladder formation in apoptosis. Of important, the mRNA expression of bcl-Xs gene in KB/7D cells was decreased in one-fourth as compared to that of KB cells among the apoptosis genes. The mRNA expression of bcl-Xs gene in a bcl-Xs transfected clone (KB/7Dbcl-Xs) was increased about 2-fold compared to that of KB/7Dneo cells, while the mRNA expression of MRP gene was not significantly different in KB/7bcl-Xs and KB/7Dneo cells. The sensitivities to anticancer drugs including ADM, VCR and VDS except VP-16 were increased in KB/7Dbcl-Xs cells, in turn, the relative resistance in KB/7Dbcl-Xs cells was decreased to 1.4, 4.0, and 3.0 in ADM, VCR and VDS, respectively, as compared to those of KB/7Dneo cells. Of interest, the studies on the accumulation of [3H]VCR showed that the decrease of [3H]VCR accumulation in KB/7Dbcl-Xs was not significantly different from that of KB/7Dneo cells. Collectively, these results indicated that the mechanism(s) of drug resistance in KB/7D cells could be explained at least by two factors: a) reduced drug accumulation mediated by

  19. 20(S)-Protopanaxadiol (PPD) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs.

    PubMed

    Liu, Junhua; Wang, Xu; Liu, Peng; Deng, Rongxin; Lei, Min; Chen, Wantao; Hu, Lihong

    2013-07-15

    Novel 20(S)-protopanoxadiol (PPD) analogues were designed, synthesized, and evaluated for the chemosensitizing activity against a multidrug resistant (MDR) cell line (KBvcr) overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic substituted aliphatic amine at the 24-positions (groups V) effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as docetaxel (DOC), vincristine (VCR), and adriamycin (ADM). PPD derivatives 12 and 18 showed 1.3-2.6 times more effective reversal ability than verapamil (VER) for DOC and VCR. Importantly, no cytotoxicity was observed by the active PPD analogues (5μM) against both non-MDR and MDR cells, suggesting that PPD analogues serve as novel lead compounds toward a potent and safe resistance modulator. Moreover, a preliminary mechanism study demonstrated that the chemosensitizing activity of PPD analogues results from inhibition of P-glycoprotein (P-gp) overexpressed in MDR cancer cells. PMID:23683834

  20. A Case of Disseminated Multidrug-Resistant Tuberculosis involving the Brain

    PubMed Central

    Chang, Ji Young; Lee, Yoon Pyo; Chung, Min Kyung; Seo, Eui Kyo; Koo, Hea Soo

    2016-01-01

    We report a case of a 23-year-old female immigrant from China who was diagnosed with multidrug-resistant tuberculosis affecting her lung and brain, resistant to the standard first-line therapeutics and streptomycin. She was treated with prothionamide, moxifloxacin, cycloserine, and kanamycin. However, her headache and brain lesion worsened. After the brain biopsy, the patient was confirmed with intracranial tuberculoma. Linezolid was added to intensify the treatment regimen, and steroid was added for the possibility of paradoxical response. Kanamycin was discontinued 6 months after initiation of the treatment; she was treated for 18 months with susceptible drugs and completely recovered. To our knowledge, this case is the first multidrug-resistant tuberculosis that disseminated to the brain in Korea. PMID:27104015

  1. Moxifloxacin Improves Treatment Outcomes in Patients with Ofloxacin-Resistant Multidrug-Resistant Tuberculosis.

    PubMed

    Chien, Jung-Yien; Chien, Shun-Tien; Chiu, Wei-Yih; Yu, Chong-Jen; Hsueh, Po-Ren

    2016-08-01

    It is unclear whether the use of moxifloxacin (MFX), a newer synthetic fluoroquinolone, results in better outcomes in patients with ofloxacin (OFX)-resistant multidrug-resistant tuberculosis (MDR-TB). During the period from April 2006 to December 2013, a total of 2,511 patients with culture-confirmed tuberculosis (TB) were treated at a TB referral hospital in southern Taiwan. Of the 2,511 patients, 325 (12.9%) had MDR-TB, and of those 325 patients, 81 (24.9%) had OFX-resistant MDR-TB and were included in the study. Among the 81 patients with OFX-resistant MDR-TB, 50 (61.7%) were successfully treated and 31 (38.3%) had unfavorable outcomes, including treatment failure (n = 25; 30.9%), loss to follow-up (n = 2; 2.5%), and death (n = 4; 4.9%). Patients treated with MFX had a significantly higher rate of treatment success (77.3% versus 43.2%; odds ratio [OR] = 4.46, 95% confidence interval [CI] = 1.710 to 11.646, P = 0.002) than patients not treated with MFX, especially among those infected with MFX-susceptible isolates (40.7%) or isolates with low-level resistance to MFX (28.4%). Multivariate logistic regression analysis showed that treatment with MFX (adjusted odds ratio = 6.54, 95% CI = 1.44 to 29.59, P = 0.015) was the only independent factor associated with treatment success. Mutation at codon 94 in the gyrA gene was the most frequent mutation (68.0%) associated with high-level MFX resistance. Multivariate Cox proportional hazards regression analysis showed that treatment with MFX was also an independent factor associated with early culture conversion (hazard ratio = 3.12, 95% CI = 1.48 to 6.54, P = 0.003). Our results show that a significant proportion of OFX-resistant MDR-TB isolates were susceptible or had low-level resistance to MFX, indicating that patients with OFX-resistant MDR-TB benefit from treatment with MFX. PMID:27216062

  2. Assessment of multidrug resistance on cell coculture patterns using scanning electrochemical microscopy.

    PubMed

    Kuss, Sabine; Polcari, David; Geissler, Matthias; Brassard, Daniel; Mauzeroll, Janine

    2013-06-01

    The emergence of resistance to multiple unrelated chemotherapeutic drugs impedes the treatment of several cancers. Although the involvement of ATP-binding cassette transporters has long been known, there is no in situ method capable of tracking this transporter-related resistance at the single-cell level without interfering with the cell's environment or metabolism. Here, we demonstrate that scanning electrochemical microscopy (SECM) can quantitatively and noninvasively track multidrug resistance-related protein 1-dependent multidrug resistance in patterned adenocarcinoma cervical cancer cells. Nonresistant human cancer cells and their multidrug resistant variants are arranged in a side-by-side format using a stencil-based patterning scheme, allowing for precise positioning of target cells underneath the SECM sensor. SECM measurements of the patterned cells, performed with ferrocenemethanol and [Ru(NH3)6](3+) serving as electrochemical indicators, are used to establish a kinetic "map" of constant-height SECM scans, free of topography contributions. The concept underlying the work described herein may help evaluate the effectiveness of treatment administration strategies targeting reduced drug efflux. PMID:23686580

  3. Heat Shock-Independent Induction of Multidrug Resistance by Heat Shock Factor 1†

    PubMed Central

    Tchénio, Thierry; Havard, Marilyne; Martinez, Luis A.; Dautry, François

    2006-01-01

    The screening of two different retroviral cDNA expression libraries to select genes that confer constitutive doxorubicin resistance has in both cases resulted in the isolation of the heat shock factor 1 (HSF1) transcription factor. We show that HSF1 induces a multidrug resistance phenotype that occurs in the absence of heat shock or cellular stress and is mediated at least in part through the constitutive activation of the multidrug resistance gene 1 (MDR-1). This drug resistance phenotype does not correlate with an increased expression of heat shock-responsive genes (heat shock protein genes, or HSPs). In addition, HSF1 mutants lacking HSP gene activation are also capable of conferring multidrug resistance, and only hypophosphorylated HSF1 complexes accumulate in transduced cells. Our results indicate that HSF1 can activate MDR-1 expression in a stress-independent manner that differs from the canonical heat shock-activated mechanism involved in HSP induction. We further provide evidence that the induction of MDR-1 expression occurs at a posttranscriptional level, revealing a novel undocumented role for hypophosphorylated HSF1 in posttranscriptional gene regulation. PMID:16382149

  4. Assessment of multidrug resistance on cell coculture patterns using scanning electrochemical microscopy

    PubMed Central

    Kuss, Sabine; Polcari, David; Geissler, Matthias; Brassard, Daniel; Mauzeroll, Janine

    2013-01-01

    The emergence of resistance to multiple unrelated chemotherapeutic drugs impedes the treatment of several cancers. Although the involvement of ATP-binding cassette transporters has long been known, there is no in situ method capable of tracking this transporter-related resistance at the single-cell level without interfering with the cell’s environment or metabolism. Here, we demonstrate that scanning electrochemical microscopy (SECM) can quantitatively and noninvasively track multidrug resistance-related protein 1–dependent multidrug resistance in patterned adenocarcinoma cervical cancer cells. Nonresistant human cancer cells and their multidrug resistant variants are arranged in a side-by-side format using a stencil-based patterning scheme, allowing for precise positioning of target cells underneath the SECM sensor. SECM measurements of the patterned cells, performed with ferrocenemethanol and [Ru(NH3)6]3+ serving as electrochemical indicators, are used to establish a kinetic “map” of constant-height SECM scans, free of topography contributions. The concept underlying the work described herein may help evaluate the effectiveness of treatment administration strategies targeting reduced drug efflux. PMID:23686580

  5. Multidrug resistance in parasites: ABC transporters, P-glycoproteins and molecular modelling.

    PubMed

    Jones, P M; George, A M

    2005-04-30

    Parasitic diseases, caused by protozoa, helminths and arthropods, rank among the most important problems in human and veterinary medicine, and in agriculture, leading to debilitating sicknesses and loss of life. In the absence of vaccines and with the general failure of vector eradication programs, drugs are the main line of defence, but the newest drugs are being tracked by the emergence of resistance in parasites, sharing ominous parallels with multidrug resistance in bacterial pathogens. Any of a number of mechanisms will elicit a drug resistance phenotype in parasites, including: active efflux, reduced uptake, target modification, drug modification, drug sequestration, by-pass shunting, or substrate competition. The role of ABC transporters in parasitic multidrug resistance mechanisms is being subjected to more scrutiny, due in part to the established roles of certain ABC transporters in human diseases, and also to an increasing portfolio of ABC transporters from parasite genome sequencing projects. For example, over 100 ABC transporters have been identified in the Escherichia coli genome, but to date only about 65 in all parasitic genomes. Long established laboratory investigations are now being assisted by molecular biology, bioinformatics, and computational modelling, and it is in these areas that the role of ABC transporters in parasitic multidrug resistance mechanisms may be defined and put in perspective with that of other proteins. We discuss ABC transporters in parasites, and conclude with an example of molecular modelling that identifies a new interaction between the structural domains of a parasite P-glycoprotein. PMID:15826647

  6. Resistance patterns of multidrug resistant Acinetobacter baumannii in an ICU of a tertiary care hospital, Malaysia

    PubMed Central

    Janahiraman, Sivakami; Aziz, Muhammad Nazri; Hoo, Fan Kee; P’ng, Hon Shen; Boo, Yang Liang; Ramachandran, Vasudevan; Shamsuddin, Ahmad Fuad

    2015-01-01

    Backgrounds & Objective: Antimicrobial resistance is a major health problem worldwide in hospitals. The main contributing factors are exposures to broad-spectrum antimicrobials and cross-infections. Understanding the extent and type of antimicrobial use in tertiary care hospitals will aid in developing national antimicrobial stewardship priorities. Methods: In this study, we have analyzed the antimicrobial agents’ usage for acquisition of multidrug resistant using retrospective, cross-sectional, single-centre study in a multidisciplinary ICU at tertiary care hospital. Results: Acinetobacter baumannii (ACB) was isolated in various specimens from 662 patients. From these, 136 patients who were diagnosed with Ventilator-associated pneumonia (VAP) caused by ACB were included into the study. In our study, MDR strain accounts for 51% of all VAP cases caused by ACB. The development of ACB VAP were 10.5 + 6.4 days for MDR strains compared to susceptible organism (7.8 + 4.5 days) and had significantly longer ICU stay. Conclusion: The study concludes that prudent use of antimicrobial agents is important to reduce acquisition of MDR ACB. PMID:26870101

  7. Presence of multidrug-resistant enteric bacteria in dairy farm topsoil.

    PubMed

    Burgos, J M; Ellington, B A; Varela, M F

    2005-04-01

    In addition to human and veterinary medicine, antibiotics are extensively used in agricultural settings, such as for treatment of infections, growth enhancement, and prophylaxis in food animals, leading to selection of drug and multidrug-resistant bacteria. To help circumvent the problem of bacterial antibiotic resistance, it is first necessary to understand the scope of the problem. However, it is not fully understood how widespread antibiotic-resistant bacteria are in agricultural settings. The lack of such surveillance data is especially evident in dairy farm environments, such as soil. It is also unknown to what extent various physiological modulators, such as salicylate, a component of aspirin and known model modulator of multiple antibiotic resistance (mar) genes, influence bacterial multi-drug resistance. We isolated and identified enteric soil bacteria from local dairy farms within Roosevelt County, NM, determined the resistance profiles to antibiotics associated with mar, such as chloramphenicol, nalidixic acid, penicillin G, and tetracycline. We then purified and characterized plasmid DNA and detected mar phenotypic activity. The minimal inhibitory concentrations (MIC) of antibiotics for the isolates ranged from 6 to >50 microg/mL for chloramphenicol, 2 to 8 microg/mL for nalidixic acid, 25 to >300 microg/mL for penicillin G, and 1 to >80 microg/mL for tetracycline. On the other hand, many of the isolates had significantly enhanced MIC for the same antibiotics in the presence of 5 mM salicylate. Plasmid DNA extracted from 12 randomly chosen isolates ranged in size from 6 to 12.5 kb and, in several cases, conferred resistance to chloramphenicol and penicillin G. It is concluded that enteric bacteria from dairy farm topsoil are multidrug resistant and harbor antibiotic-resistance plasmids. A role for dairy topsoil in zoonoses is suggested, implicating this environment as a reservoir for development of bacterial resistance against clinically relevant

  8. Abrupt Emergence of a Single Dominant Multidrug-Resistant Strain of Escherichia coli

    PubMed Central

    Johnson, James R.; Tchesnokova, Veronika; Johnston, Brian; Clabots, Connie; Roberts, Pacita L.; Billig, Mariya; Riddell, Kim; Rogers, Peggy; Qin, Xuan; Butler-Wu, Susan; Price, Lance B.; Aziz, Maliha; Nicolas-Chanoine, Marie-Hélène; DebRoy, Chitrita; Robicsek, Ari; Hansen, Glen; Urban, Carl; Platell, Joanne; Trott, Darren J.; Zhanel, George; Weissman, Scott J.; Cookson, Brad T.; Fang, Ferric C.; Limaye, Ajit P.; Scholes, Delia; Chattopadhyay, Sujay; Hooper, David C.; Sokurenko, Evgeni V.

    2013-01-01

    Background. Fluoroquinolone-resistant Escherichia coli are increasingly prevalent. Their clonal origins—potentially critical for control efforts—remain undefined. Methods. Antimicrobial resistance profiles and fine clonal structure were determined for 236 diverse-source historical (1967–2009) E. coli isolates representing sequence type ST131 and 853 recent (2010–2011) consecutive E. coli isolates from 5 clinical laboratories in Seattle, Washington, and Minneapolis, Minnesota. Clonal structure was resolved based on fimH sequence (fimbrial adhesin gene: H subclone assignments), multilocus sequence typing, gyrA and parC sequence (fluoroquinolone resistance-determining loci), and pulsed-field gel electrophoresis. Results. Of the recent fluoroquinolone-resistant clinical isolates, 52% represented a single ST131 subclonal lineage, H30, which expanded abruptly after 2000. This subclone had a unique and conserved gyrA/parC allele combination, supporting its tight clonality. Unlike other ST131 subclones, H30 was significantly associated with fluoroquinolone resistance and was the most prevalent subclone among current E. coli clinical isolates, overall (10.4%) and within every resistance category (11%–52%). Conclusions. Most current fluoroquinolone-resistant E. coli clinical isolates, and the largest share of multidrug-resistant isolates, represent a highly clonal subgroup that likely originated from a single rapidly expanded and disseminated ST131 strain. Focused attention to this strain will be required to control the fluoroquinolone and multidrug-resistant E. coli epidemic. PMID:23288927

  9. In vitro Antibacterial Activity of Aqueous and Ethanol Extracts of Aristolochia indica and Toddalia asiatica Against Multidrug-Resistant Bacteria.

    PubMed

    Venkatadri, B; Arunagirinathan, N; Rameshkumar, M R; Ramesh, Latha; Dhanasezhian, A; Agastian, P

    2015-01-01

    Bacteria have developed multidrug resistance against available antimicrobial agents. Infectious diseases caused by these multidrug-resistant bacteria are major causes of morbidity and mortality in human beings. Synthetic drugs are expensive and inadequate for the treatment of diseases, causing side effects and ineffective against multidrug-resistant bacteria. The medicinal plants are promising to have effective antimicrobial property due to presence of phytochemical compounds like alkaloids, flavanoids, tannins and phenolic compounds. The present study aimed to find the antimicrobial activity of medicinal plants against multidrug-resistant bacteria. Multidrug-resistant bacteria were identified by Kirby-Bauer disc diffusion method. Production of β-lactamases (extended spectrum β-lactamases, metallo β-lactamase and AmpC β-lactamase) were identified by combination disc method. Antibacterial activity of aqueous and ethanol extract of Aristolochia indica and Toddalia asiatica were detected by agar well diffusion assay and minimum inhibitory concentration. All bacteria used in this study showed antibiotic resistance to ≥3 antibiotics. Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Proteus mirabilis and Vibrio cholerae were found to be positive for β-lactamase production. Ethanol extract of Aristolochia indica showed more significant antibacterial activity against multidrug-resistant bacteria than Toddalia asiatica. Ethanol extracts of Aristolochia indica and Toddalia asiatica showed minimum inhibitory concentration values of 50-100 μg/ml and 100-200 μg/ml, respectively against multidrug-resistant bacteria. From this study, it was concluded that Aristolochia indica has more potential to treat multidrug-resistant bacteria than Toddalia asiatica. PMID:26997710

  10. Does Alcohol Consumption during Multidrug-resistant Tuberculosis Treatment Affect Outcome?

    PubMed Central

    Duraisamy, Karthickeyan; Mrithyunjayan, Sunilkumar; Ghosh, Smita; Nair, Sreenivas Achuthan; Balakrishnan, Shibu; Subramoniapillai, Jayasankar; Oeltmann, John E.; Moonan, Patrick K.; Kumar, Ajay M. V.

    2015-01-01

    Rationale India reports the largest number of multidrug-resistant tuberculosis cases in the world; yet, no longitudinal study has assessed factors related to treatment outcomes under programmatic conditions in the public sector. Objectives To describe demographic, clinical, and risk characteristics associated with treatment outcomes for all patients with multidrug-resistant tuberculosis registered in the Revised National Tuberculosis Control Programme, Kerala State, India from January 1, 2009 to June 30, 2010. Methods Cox regression methods were used to calculate adjusted hazard ratios with 95% confidence intervals (CIs) to assess factors associated with an unsuccessful treatment outcome. Measurements and Main Results Of 179 patients with multidrug-resistant tuberculosis registered, 112 (63%) had successful treatment outcomes (77 bacteriologically cured, 35 treatment completed) and 67 (37%) had unsuccessful treatment outcomes (30 died, 26 defaulted, 9 failed treatment, 1 stopped treatment because of drug-related adverse events, and 1 developed extensively drug-resistant tuberculosis). The hazard for unsuccessful outcome was significantly higher among patients who consumed alcohol during treatment (adjusted hazard ratio, 4.3; 95% CI, 1.1–17.6) than those who did not. Persons who consumed alcohol during treatment, on average, missed 18 more intensive-phase doses (95% CI, 13–22) than those who did not. Although many patients had diabetes (33%), were ever smokers (39%), or had low body mass index (47%), these factors were not associated with outcome. Conclusion Overall treatment success was greater than global and national averages; however, outcomes among patients consuming alcohol remained poor. Integration of care for multidrug-resistant tuberculosis and alcoholism should be considered to improve treatment adherence and outcomes. PMID:24735096

  11. Ascites Increases Expression/Function of Multidrug Resistance Proteins in Ovarian Cancer Cells.

    PubMed

    Mo, Lihong; Pospichalova, Vendula; Huang, Zhiqing; Murphy, Susan K; Payne, Sturgis; Wang, Fang; Kennedy, Margaret; Cianciolo, George J; Bryja, Vitezslav; Pizzo, Salvatore V; Bachelder, Robin E

    2015-01-01

    Chemotherapy resistance is the major reason for the failure of ovarian cancer treatment. One mechanism behind chemo-resistance involves the upregulation of multidrug resistance (MDR) genes (ABC transporters) that effectively transport (efflux) drugs out of the tumor cells. As a common symptom in stage III/IV ovarian cancer patients, ascites is associated with cancer progression. However, whether ascites drives multidrug resistance in ovarian cancer cells awaits elucidation. Here, we demonstrate that when cultured with ascites derived from ovarian cancer-bearing mice, a murine ovarian cancer cell line became less sensitive to paclitaxel, a first line chemotherapeutic agent for ovarian cancer patients. Moreover, incubation of murine ovarian cancer cells in vitro with ascites drives efflux function in these cells. Functional studies show ascites-driven efflux is suppressible by specific inhibitors of either of two ABC transporters [Multidrug Related Protein (MRP1); Breast Cancer Related Protein (BCRP)]. To demonstrate relevance of our findings to ovarian cancer patients, we studied relative efflux in human ovarian cancer cells obtained from either patient ascites or from primary tumor. Immortalized cell lines developed from human ascites show increased susceptibility to efflux inhibitors (MRP1, BCRP) compared to a cell line derived from a primary ovarian cancer, suggesting an association between ascites and efflux function in human ovarian cancer. Efflux in ascites-derived human ovarian cancer cells is associated with increased expression of ABC transporters compared to that in primary tumor-derived human ovarian cancer cells. Collectively, our findings identify a novel activity for ascites in promoting ovarian cancer multidrug resistance. PMID:26148191

  12. Multidrug-resistant Gram-negative bacterial infections: the emerging threat and potential novel treatment options.

    PubMed

    Vergidis, Paschalis I; Falagas, Matthew E

    2008-02-01

    Gram-negative bacterial infections constitute an emerging threat because of the development of multidrug-resistant organisms. There is a relative shortage of new drugs in the antimicrobial development pipeline that have been tested in vitro and evaluated in clinical studies. Antibiotics that are in the pipeline for the treatment of serious Gram-negative bacterial infections include the cephalosporins, ceftobiprole, ceftarolin and FR-264205. Tigecycline is the first drug approved from a new class of antibiotics called glycylcyclines, and there has been renewed interest in this drug for the treatment of some multidrug-resistant Gram-negative organisms. Carbapenems in the pipeline include tomopenem, with the approved drugs doripenem and faropenem, an oral agent, under evaluation for activity against multidrug-resistant Gram-negative bacterial infections. Polymyxins are old antibiotics traditionally considered to be toxic, but which are being used because of their activity against resistant Gram-negative organisms. New pharmacokinetic and pharmacodynamic data are available regarding the use of these agents. Finally, antimicrobial peptides and efflux pump inhibitors are two new classes of agents under development. This review of investigational antibiotics shows that several new agents will become available in the coming years, even though the pace of antimicrobial research is far from ideal. PMID:18246520

  13. Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness.

    PubMed

    Cohen, Ted; Murray, Megan

    2004-10-01

    Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease. PMID:15378056

  14. Photosensitized labeling of a functional multidrug transporter in living drug-resistant tumor cells

    SciTech Connect

    Raviv, Y.; Pollard, H.B.; Bruggemann, E.P.; Pastan, I.; Gottesman, M.M. )

    1990-03-05

    A 170,000-Da glycoprotein (P170 multidrug transporter) becomes specifically labeled in multidrug-resistant human KB carcinoma cells by the photolabile lipophilic membrane probe 5-(125I)iodonaphthalene-1-azide ((125I)INA) when photoactivation of the probe is triggered by energy transfer from intracellular doxorubicin or rhodamine 123. In contrast, in drug-sensitive cells, drug-induced specific labeling of membrane proteins with (125I)INA was not observed. Instead, multiple membrane proteins became labeled in a nonspecific manner. This phenomenon of drug-induced specific labeling of P170 by (125I)INA is observed only in living cells, but not in purified membrane vesicles or lysed cells. It is generated by doxorubicin and rhodamine 123, drugs that are chromophores and to which the cells exhibit resistance; but it is not observed with other drugs or dyes. Verapamil, a calcium channel blocker which reverses resistance to doxorubicin, also abolishes doxorubicin-induced specific (125I)INA labeling of P170. These results reveal that a specific interaction between P170 and doxorubicin takes place in living cells and demonstrate that P170 is directly involved in the mechanism of drug resistance in vivo. They also provide a possible means to label functional domains in the multidrug transporter. The results demonstrate that photosensitized (125I)INA labeling is a technique which provides sufficient spatial and time resolution to detect specific intracellular interactions between chromophores and proteins in vivo.

  15. Most drugs that reverse multidrug resistance also inhibit photoaffinity labeling of P-glycoprotein by a vinblastine analog

    SciTech Connect

    Akiyama, S.; Cornwell, M.M.; Kuwano, M.; Pastan, I.; Gottesman, M.M.

    1988-02-01

    Multidrug-resistant human KB carcinoma cells express a 170,000-dalton membrane glycoprotein (P-glycoprotein) that can be photoaffinity labeled with the vinblastine analog N-(p-azido-(3-/sup 125/I)salicyl)-N'-(beta-aminoethyl)vindesine. Several agents that suppress the multidrug-resistant phenotype, including N-solanesyl-N,N'-bis(3,4-dimethylbenzyl)ethylenediamine, cepharanthine, quinidine, and reserpine, were found to inhibit photolabeling of P-glycoprotein at doses comparable to those that reverse multidrug resistance. However, the phenothiazines chlorpromazine and trifluoperazine, which also effectively reverse multidrug resistance, were poor inhibitors of the photoaffinity labeling of P-glycoprotein. Chloroquine, propranolol, or atropine, which only partially reversed the drug resistance, also did not inhibit photolabeling. Naphthalene sulfonamide calmodulin inhibitors, W7 and W5, as well as many other drugs that did not circumvent multidrug resistance, did not inhibit photolabeling. These studies suggest that most, but not all, agents that phenotypically suppress multidrug resistance also inhibit drug binding to a site on P-glycoprotein with which a photoaffinity analog of vinblastine interacts.

  16. [Molecular genetic and bacteriological methods for the diagnosis of multidrug resistant M. tuberculosis].

    PubMed

    Agaev, F F; Aliev, K A; Salimova, N A; Abuzarov, R M; Gasymov, I A; Griadunov, D A

    2009-01-01

    For the early diagnosis of multidrug resistant tuberculosis, 67 sputum samples obtained from primary patients with different clinical forms of pulmonary tuberculosis were examined by the molecular genetic test using the TB-Biochip test system. Having a high sensitivity and specificity, the molecular genetic test for determining the drug sensitivity of Mycobacterium tuberculosis substantially accelerates its diagnosis (2-3 days) before the real-time mode of a patient's admission to the clinic. The method allows identification of mutations in the rpoB (resistance to R), katG, inhG, and ahpC (resistance to H) genes, which permits timely correction of performed specific treatment. PMID:19886013

  17. Characterization of an IncA/C Multidrug Resistance Plasmid in Vibrio alginolyticus.

    PubMed

    Ye, Lianwei; Li, Ruichao; Lin, Dachuan; Zhou, Yuanjie; Fu, Aisi; Ding, Qiong; Chan, Edward Wai Chi; Yao, Wen; Chen, Sheng

    2016-05-01

    Cephalosporin-resistant Vibrio alginolyticus was first isolated from food products, with β-lactamases encoded by blaPER-1, blaVEB-1, and blaCMY-2 being the major mechanisms mediating their cephalosporin resistance. The complete sequence of a multidrug resistance plasmid, pVAS3-1, harboring the blaCMY-2 and qnrVC4 genes was decoded in this study. Its backbone exhibited genetic homology to known IncA/C plasmids recoverable from members of the family Enterobacteriaceae, suggesting its possible origin in Enterobacteriaceae. PMID:26976864

  18. Clinically Relevant Chromosomally Encoded Multidrug Resistance Efflux Pumps in Bacteria

    PubMed Central

    Piddock, Laura J. V.

    2006-01-01

    Efflux pump genes and proteins are present in both antibiotic-susceptible and antibiotic-resistant bacteria. Pumps may be specific for one substrate or may transport a range of structurally dissimilar compounds (including antibiotics of multiple classes); such pumps can be associated with multiple drug (antibiotic) resistance (MDR). However, the clinical relevance of efflux-mediated resistance is species, drug, and infection dependent. This review focuses on chromosomally encoded pumps in bacteria that cause infections in humans. Recent structural data provide valuable insights into the mechanisms of drug transport. MDR efflux pumps contribute to antibiotic resistance in bacteria in several ways: (i) inherent resistance to an entire class of agents, (ii) inherent resistance to specific agents, and (iii) resistance conferred by overexpression of an efflux pump. Enhanced efflux can be mediated by mutations in (i) the local repressor gene, (ii) a global regulatory gene, (iii) the promoter region of the transporter gene, or (iv) insertion elements upstream of the transporter gene. Some data suggest that resistance nodulation division systems are important in pathogenicity and/or survival in a particular ecological niche. Inhibitors of various efflux pump systems have been described; typically these are plant alkaloids, but as yet no product has been marketed. PMID:16614254

  19. An oligonucleotide microarray to characterize multidrug resistant plasmids

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacteria plasmids are fragments of extra-chromosomal double stranded deoxyribonucleic acid (DNA) that can contain a variety of genes beneficial to the host organism like antibiotic drug resistance. Many of the Enterobacteriaceae carry multiple drug resistance (MDR) genes on large plasmids of replic...

  20. Multidrug-Resistant Salmonella Isolates from Swine in the Eastern Cape Province, South Africa.

    PubMed

    Iwu, Chinwe Juliana; Iweriebor, Benson Chuks; Obi, Larry Chikwelu; Basson, Albertus Kotze; Okoh, Anthony Ifeanyi

    2016-07-01

    The exposure of farm animals to antimicrobials for treatment, prophylaxis, or growth promotion can select for resistant bacteria that can be transmitted to humans, and Salmonella as an important zoonotic pathogen can act as a potential reservoir of antimicrobial resistance determinants. We assessed the antibiogram profiles of Salmonella species isolated from pig herds in two commercial farms in South Africa. Two hundred fifty-eight presumptive Salmonella isolates were recovered from the fecal samples of 500 adult pigs. Specific primers targeting Salmonella serogroups A, B, C1, C2, and D were used to determine the prevalence of different serogroups. Only serogroup A (n = 48) was detected, while others were not. Antimicrobial susceptibility of the confirmed Salmonella serogroup A isolates was performed by using the disk diffusion method against a panel of 18 antibiotics. All the 48 isolates were resistant to tetracycline and oxytetracycline, while 75% were resistant to ampicillin, sulphamethoxazole-trimethoprim, nalidixic acid, and streptomycin. All the isolates exhibited multidrug resistance, with the predominant phenotype being against 11 antibiotics, and multiple antibiotic resistance index ranged between 0.3 and 0.6. The incidence of genes encoding resistance against ampicillin (ampC), tetracycline (tetA), and streptomycin (strA) were 54, 61, and 44%, respectively. We conclude that healthy pigs are potential reservoirs of multidrug-resistant Salmonella that could be transmitted to humans through the food chain and, hence, a significant public health threat. PMID:27357044

  1. Cooperative Antibiotic Resistance in a Multi-Drug Environment

    NASA Astrophysics Data System (ADS)

    Yurtsev, Eugene; Dai, Lei; Gore, Jeff

    2013-03-01

    The emergence of antibiotic resistance in bacteria is a significant health concern. A frequent mechanism of antibiotic resistance involves the production of an enzyme which inactivates the antibiotic. By inactivating the antibiotic, resistant cells can ``share'' their resistance with other cells in the bacterial population, suggesting that it may be possible to observe cooperation between strains that inactivate different antibiotics. Here, we experimentally track the population dynamics of two E. coli strains in the presence of two different antibiotics. We find that together the strains are able to grow in antibiotic concentrations that inhibit growth of either of the strains individually. We observe that even when there is stable coexistence between the two strains, the population size of each strain can undergo large oscillations. We expect that our results will provide insight into the evolution of antibiotic resistance and the evolutionary origin of phenotypic diversity and cooperative behaviors.

  2. Community-acquired pneumonia caused by carbapenem-resistant Streptococcus pneumoniae: re-examining its prevention and treatment

    PubMed Central

    Doi, Asako; Iwata, Kentaro; Takegawa, Hiroshi; Miki, Kanji; Sono, Yumi; Nishioka, Hiroaki; Takeshita, Jumpei; Tomii, Keisuke; Haruta, Tsunekazu

    2014-01-01

    A 73-year-old man with no significant past medical history or any history of health care visits was hospitalized for pneumonia. Sputum culture revealed multidrug-resistant Streptococcus pneumoniae, even to carbapenems. The patient was later treated successfully with levofloxacin. Throat cultures from his two grandchildren revealed S. pneumoniae with the same susceptibility pattern. Analysis for resistant genes revealed gPRSP (pbp1a + pbp2x + pbp2b gene variants) in both the patient and his grandchildren, none of whom had received pneumococcal vaccines of any kind. This case illustrates the importance of the emergence of carbapenem-resistant S. pneumoniae. Non-rational use of carbapenems for community-acquired infections may be counterproductive. This case also highlights the importance of pneumococcal vaccinations in children and the elderly. PMID:24899822

  3. Molecular modeling of the human multidrug resistance protein 1 (MRP1/ABCC1)

    SciTech Connect

    DeGorter, Marianne K.; Conseil, Gwenaelle; Deeley, Roger G.; Campbell, Robert L.; Cole, Susan P.C.

    2008-01-04

    Multidrug resistance protein 1 (MRP1/ABCC1) is a 190 kDa member of the ATP-binding cassette (ABC) superfamily of transmembrane transporters that is clinically relevant for its ability to confer multidrug resistance by actively effluxing anticancer drugs. Knowledge of the atomic structure of MRP1 is needed to elucidate its transport mechanism, but only low resolution structural data are currently available. Consequently, comparative modeling has been used to generate models of human MRP1 based on the crystal structure of the ABC transporter Sav1866 from Staphylococcus aureus. In these Sav1866-based models, the arrangement of transmembrane helices differs strikingly from earlier models of MRP1 based on the structure of the bacterial lipid transporter MsbA, both with respect to packing of the twelve helices and their interactions with the nucleotide binding domains. The functional importance of Tyr{sup 324} in transmembrane helix 6 predicted to project into the substrate translocation pathway was investigated.

  4. Role of tipranavir in treatment of patients with multidrug-resistant HIV

    PubMed Central

    Courter, Joshua D; Teevan, Colleen J; Li, Michael H; Girotto, Jennifer E; Salazar, Juan C

    2010-01-01

    The worldwide emergence of multidrug-resistant human immunodeficiency virus (HIV)-1 strains has the driven the development of new antiretroviral (ARV) agents. Over the past 5 years, HIV-entry and integrase inhibitor ARVs, as well as improved non-nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs), have become available for treatment. It is important to assess how these new ARVs might be most judiciously used, paying close attention to viral susceptibility patterns, pharmacodynamic parameters, and the likelihood that patients will adhere to their therapy. Herein we review published material in Medline, EMBASE, and ISI for each antiretroviral agent/classes currently approved and summarize the available data on their efficacy, safety, and pharmacologic parameters. We focus on the role of tipranavir, a recently approved nonpeptidic PI, for treating HIV-infected children, adolescents, and adults with a history of multidrug-resistant HIV. PMID:20957134

  5. Meayamycin Inhibits pre-mRNA Splicing and Exhibits Picomolar Activity Against Multidrug Resistant Cells

    PubMed Central

    Albert, Brian J.; McPherson, Peter A.; O'Brien, Kristine; Czaicki, Nancy L.; DeStefino, Vincent; Osman, Sami; Li, Miaosheng; Day, Billy W.; Grabowski, Paula J.; Moore, Melissa J.; Vogt, Andreas; Koide, Kazunori

    2009-01-01

    FR901464 is a potent antitumor natural product that binds to the SF3b complex and inhibits pre-mRNA splicing. Its analogue, meayamycin, is two orders of magnitude more potent as an antiproliferative agent against human breast cancer MCF-7 cells. Here, we report the picomolar antiproliferative activity of meayamycin against various cancer cell lines and multidrug resistant cells. Time-dependence studies implied that meayamycin may form a covalent bond with its target protein(s). Meayamycin inhibited pre-mRNA splicing in HEK-293 cells but not alternative splicing in a neuronal system. Meayamycin exhibited specificity toward human lung cancer cells compared to non-tumorigenic human lung fibroblasts and retained picomolar growth inhibitory activity against multi-drug resistant cells. These data suggest that meayamycin is a useful chemical probe to study pre-mRNA splicing in live cells and is a promising lead as an anticancer agent. PMID:19671752

  6. Jatrophane diterpenoid esters from Euphorbia sororia serving as multidrug resistance reversal agents.

    PubMed

    Lu, Dongli; Liu, Yongqiang; Aisa, Haji Akber

    2014-01-01

    Six (1-6) new jatrophane diterpenoid esters together with four known compounds (7-10) were isolated from the acetone extract of fructus Euphorbia sororia. Their structures were elucidated by the spectral technology, including the 2D NMR experiments (HMQC, HMBC and NOESY). The absolute configuration of compound 1 and compound 7 were first confirmed by X-ray crystallographic analysis. Compounds 1-7 were assayed for their antiproliferative activity in human cancer cell lines: human mammary adenocarcinoma (MCF-7) and human lung adenocarcinoma (A549). All the compounds were inactive for the cell lines. The multidrug-resistance reversal activity was also tested on KBv200 cells and compound 2 displayed strong multidrug resistance reversal activity, outperforming verapamil at 10 μM. PMID:24291755

  7. AIDS and multidrug-resistant tuberculosis: an epidemic transforms an old disease.

    PubMed

    Farley, T A

    1992-08-01

    Since 1985, tuberculosis case counts in the United States have increased, primarily because of the influence of the HIV epidemic. In addition, during this time outbreaks of multidrug-resistant tuberculosis among patients with AIDS or HIV infection have been reported in New York City and Florida. These outbreaks have occurred in hospitals and prisons and have been characterized by high case fatality rates, disease transmission within the institutions, and high infection rates in health care workers. The increase in tuberculosis rates and the outbreaks have raised concern that multidrug-resistant tuberculosis could become a widespread problem in the United States. Dealing with tuberculosis in the 1990s will require reconsideration of our current methods of tuberculosis prevention, diagnosis, treatment, and control. PMID:1453093

  8. Outbreak of mastitis in sheep caused by multi-drug resistant Enterococcus faecalis in Sardinia, Italy.

    PubMed

    Sanciu, G; Marogna, G; Paglietti, B; Cappuccinelli, P; Leori, G; Rappelli, P

    2013-03-01

    An outbreak of infective mastitis due to Enterococcus faecalis occurred in an intensive sheep farm in north Sardinia (Italy). E. faecalis, which is only rarely isolated from sheep milk, was unexpectedly found in 22·3% of positive samples at microbiological examination. Forty-five out of the 48 E. faecalis isolates showed the same multi-drug resistance pattern (cloxacillin, streptomycin, kanamycin, clindamycin, oxytetracycline). E. faecalis isolates were analysed by pulsed-field gel electrophoresis, and all 45 multi-drug resistant strains showed an indistinguishable macrorestiction profile, indicating their clonal origin. To our knowledge, this is the first report of an outbreak of mastitis in sheep caused by E. faecalis. PMID:22595402

  9. Complexation study and anticellular activity enhancement by doxorubicin-cyclodextrin complexes on a multidrug-resistant adenocarcinoma cell line.

    PubMed

    Al-Omar, A; Abdou, S; De Robertis, L; Marsura, A; Finance, C

    1999-04-19

    Ability of molecular complexes of [Doxorubicin (DX)-cyclodextrin (Cd)] to enhance the anticellular activity of antineoplastic drug Doxorubicin and to reverse its multidrug resistance has been investigated. A spectroscopic study of the alpha, beta, and gamma-[DX-Cds] complexes has been investigated in relation to their biological effects on a multidrug resistant (MDR) human rectal adenocarcinoma cell line (HRT-18). A ten fold enhancement of DX anticellular activity in presence of beta-cyclodextrin alone was detected. PMID:10328296

  10. Combination of essential oils and antibiotics reduce antibiotic resistance in plasmid-conferred multidrug resistant bacteria.

    PubMed

    Yap, Polly Soo Xi; Lim, Swee Hua Erin; Hu, Cai Ping; Yiap, Beow Chin

    2013-06-15

    In this study we investigated the relationship between several selected commercially available essential oils and beta-lactam antibiotics on their antibacterial effect against multidrug resistant bacteria. The antibacterial activity of essential oils and antibiotics was assessed using broth microdilution. The combined effects between essential oils of cinnamon bark, lavender, marjoram, tea tree, peppermint and ampicillin, piperacillin, cefazolin, cefuroxime, carbenicillin, ceftazidime, meropenem, were evaluated by means of the checkerboard method against beta-lactamase-producing Escherichia coli. In the latter assays, fractional inhibitory concentration (FIC) values were calculated to characterize interaction between the combinations. Substantial susceptibility of the bacteria toward natural antibiotics and a considerable reduction in the minimum inhibitory concentrations (MIC) of the antibiotics were noted in some paired combinations of antibiotics and essential oils. Out of 35 antibiotic-essential oil pairs tested, four of them showed synergistic effect (FIC≤0.5) and 31 pairs showed no interaction (FIC>0.5-4.0). The preliminary results obtained highlighted the occurrence of a pronounced synergistic relationship between piperacillin/cinnamon bark oil, piperacillin/lavender oil, piperacillin/peppermint oil as well as meropenem/peppermint oil against two of the three bacteria under study with a FIC index in the range 0.26-0.5. The finding highlighted the potential of peppermint, cinnamon bark and lavender essential oils being as antibiotic resistance modifying agent. Reduced usage of antibiotics could be employed as a treatment strategy to decrease the adverse effects and possibly to reverse the beta-lactam antibiotic resistance. PMID:23537749

  11. Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

    PubMed

    Avner, Benjamin S; Fialho, Arsenio M; Chakrabarty, Ananda M

    2012-01-01

    Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their

  12. Effect of honey on multidrug resistant organisms and its synergistic action with three common antibiotics.

    PubMed

    Karayil, S; Deshpande, S D; Koppikar, G V

    1998-01-01

    A total of 15 bacterial strains (7 Pseudomonas & 8 Klebsiella species) isolated from various samples which showed multi-drug resistance were studied to verify in vitro antibacterial action of honey on the principle of Minimum Inhibitory Concentration (MIC) & its synergism with 3 common antibiotics--Gentamicin, Amikacin & Ceftazidime. The MIC of honey with saline for both organisms was found to be 1:2. The synergistic action was seen in the case of Pseudomonas spp. and not with Klebsiella spp. PMID:10703581

  13. Attitudes and perceptions of health care workers in Northeastern Germany about multidrug-resistant organisms.

    PubMed

    Marschall, P; Hübner, N-O; Maletzki, S; Wilke, F; Dittmann, K; Kramer, A

    2016-06-01

    There were 256 health care workers in 39 facilities who were interviewed about their perceptions of the quality of care of patients with and without multidrug-resistant organisms based on a standardized questionnaire. There are remarkable differences in the responses between facility types (acute care hospitals, long-term care hospitals, rehabilitation hospitals, and home care services). Hygiene management must be specifically tailored to the requirements of each facility. PMID:26897700

  14. IMPACT OF SEPSIS CLASSIFICATION AND MULTIDRUG RESISTANCE STATUS ON OUTCOME AMONG PATIENTS TREATED WITH APPROPRIATE THERAPY

    PubMed Central

    Burnham, Jason P.; Lane, Michael A.; Kollef, Marin H.

    2015-01-01

    Objective To assess the impact of sepsis classification and multidrug resistance status on outcome in patients receiving appropriate initial antibiotic therapy. Design A retrospective cohort study. Setting Barnes-Jewish Hospital, a 1250-bed teaching hospital. Patients Individuals with Enterobacteriaceae sepsis, severe sepsis, and septic shock that received appropriate initial antimicrobial therapy between June 2009 and December 2013. Interventions Clinical outcomes were compared according to multidrug resistance status, sepsis classification, demographics, severity of illness, comorbidities, and antimicrobial treatment. Measurements and Main Results We identified 510 patients with Enterobacteriaceae bacteremia and sepsis, severe sepsis, or septic shock. Sixty-seven patients (13.1%) were non-survivors. Mortality increased significantly with increasing severity of sepsis (3.5%, 9.9%, and 28.6%, for sepsis, severe sepsis, and septic shock, respectively, p<0.05). Time to antimicrobial therapy was not significantly associated with outcome. APACHE II was more predictive of mortality than age-adjusted Charlson comorbidity index. Multidrug resistance status did not result in excess mortality. Length of intensive care unit and hospital stay increased with more severe sepsis. In multivariate logistic regression analysis, African-American race, sepsis severity, APACHE II score, solid organ cancer, cirrhosis, and transfer from an outside hospital were all predictors of mortality. Conclusions Our results support sepsis severity, but not multidrug resistance status as being an important predictor of death when all patients receive appropriate initial antibiotic therapy. Future sepsis trials should attempt to provide appropriate antimicrobial therapy and take sepsis severity into careful account when determining outcomes. PMID:25855900

  15. Multidrug-resistant Salmonella enterica serotype Typhi, Gulf of Guinea Region, Africa.

    PubMed

    Baltazar, Murielle; Ngandjio, Antoinette; Holt, Kathryn Elizabeth; Lepillet, Elodie; Pardos de la Gandara, Maria; Collard, Jean-Marc; Bercion, Raymond; Nzouankeu, Ariane; Le Hello, Simon; Dougan, Gordon; Fonkoua, Marie-Christine; Weill, François-Xavier

    2015-04-01

    We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid. PMID:25811307

  16. A case of acute postoperative keratitis after deep anterior lamellar keratoplasty by multidrug resistant Klebsiella

    PubMed Central

    Bajracharya, Leena; Sharma, Binita; Gurung, Reeta

    2015-01-01

    A healthy lady of 42 years underwent deep anterior lamellar keratoplasty for granular dystrophy. The very next day, it was complicated by development of infectious keratitis. The organism was identified as multidrug resistant Klebsiella pneumoniae. Donor corneal button may be implicated in the transmission of infection in an otherwise uneventful surgery and follow-up. Nosocomial infections are usually severe, rapidly progressive and difficult to treat. Finally, the lady had to undergo therapeutic penetrating keratoplasty for complete resolution of infection. PMID:26044477

  17. Multidrug-Resistant Salmonella enterica Serotype Typhi, Gulf of Guinea Region, Africa

    PubMed Central

    Baltazar, Murielle; Ngandjio, Antoinette; Holt, Kathryn Elizabeth; Lepillet, Elodie; Pardos de la Gandara, Maria; Collard, Jean-Marc; Bercion, Raymond; Nzouankeu, Ariane; Le Hello, Simon; Dougan, Gordon; Fonkoua, Marie-Christine

    2015-01-01

    We identified 3 lineages among multidrug-resistant (MDR) Salmonella enterica serotype Typhi isolates in the Gulf of Guinea region in Africa during the 2000s. However, the MDR H58 haplotype, which predominates in southern Asia and Kenya, was not identified. MDR quinolone-susceptible isolates contained a 190-kb incHI1 pST2 plasmid or a 50-kb incN pST3 plasmid. PMID:25811307

  18. Poly(ethylene glycol)-conjugated multi-walled carbon nanotubes as an efficient drug carrier for overcoming multidrug resistance

    SciTech Connect

    Cheng Jinping; Meziani, Mohammed J.; Sun Yaping; Cheng, Shuk Han

    2011-01-15

    The acquisition of multidrug resistance poses a serious problem in chemotherapy, and new types of transporters have been actively sought to overcome it. In the present study, poly(ethylene glycol)-conjugated (PEGylated) multi-walled carbon nanotubes (MWCNTs) were prepared and explored as drug carrier to overcome multidrug resistance. The prepared PEGylated MWCNTs penetrated into mammalian cells without damage plasma membrane, and its accumulation did not affect cell proliferation and cell cycle distribution. More importantly, PEGylated MWCNTs accumulated in the multidrug-resistant cancer cells as efficient as in the sensitive cancer cells. Intracellular translocation of PEGylated MWCNTs was visualized in both multidrug-resistant HepG2-DR cells and sensitive HepG2 cells, as judged by both fluorescent and transmission electron microscopy. PEGylated MWCNTs targeted cancer cells efficiently and multidrug-resistant cells failed to remove the intracellular MWCNTs. However, if used in combination with drugs without conjugation, PEGylated MWCNTs prompted drug efflux in MDR cells by stimulating the ATPase activity of P-glycoprotein. This study suggests that PEGylated MWCNTs can be developed as an efficient drug carrier to conjugate drugs for overcoming multidrug resistance in cancer chemotherapy.

  19. High heterogeneity of plasma membrane microfluidity in multidrug-resistant cancer cells

    NASA Astrophysics Data System (ADS)

    Boutin, Céline; Roche, Yann; Millot, Christine; Deturche, Régis; Royer, Pascal; Manfait, Michel; Plain, Jérôme; Jeannesson, Pierre; Millot, Jean-Marc; Jaffiol, Rodolphe

    2009-05-01

    Diffusion-time distribution analysis (DDA) has been used to explore the plasma membrane fluidity of multidrug-resistant cancer cells (LR73 carcinoma cells) and also to characterize the influence of various membrane agents present in the extracellular medium. DDA is a recent single-molecule technique, based on fluorescence correlation spectroscopy (FCS), well suited to retrieve local organization of cell membrane. The method was conducted on a large number of living cells, which enabled us to get a detailed overview of plasma membrane microviscosity, and plasma membrane micro-organization, between the cells of the same line. Thus, we clearly reveal the higher heterogeneity of plasma membrane in multidrug-resistant cancer cells in comparison with the nonresistant ones (denoted sensitive cells). We also display distinct modifications related to a membrane fluidity modulator, benzyl alcohol, and two revertants of multidrug resistance, verapamil and cyclosporin-A. A relation between the distribution of the diffusion-time values and the modification of membrane lateral heterogeneities is proposed.

  20. Green Tea Catechin-Based Complex Micelles Combined with Doxorubicin to Overcome Cardiotoxicity and Multidrug Resistance

    PubMed Central

    Cheng, Tangjian; Liu, Jinjian; Ren, Jie; Huang, Fan; Ou, Hanlin; Ding, Yuxun; Zhang, Yumin; Ma, Rujiang; An, Yingli; Liu, Jianfeng; Shi, Linqi

    2016-01-01

    Chemotherapy for cancer treatment has been demonstrated to cause some side effects on healthy tissues and multidrug resistance of the tumor cells, which greatly limits therapeutic efficacy. To address these limitations and achieve better therapeutic efficacy, combination therapy based on nanoparticle platforms provides a promising approach through delivering different agents simultaneously to the same destination with synergistic effect. In this study, a novel green tea catechin-based polyion complex (PIC) micelle loaded with doxorubicin (DOX) and (-)-Epigallocatechin-3-O-gallate (EGCG) was constructed through electrostatic interaction and phenylboronic acid-catechol interaction between poly(ethylene glycol)-block-poly(lysine-co-lysine-phenylboronic acid) (PEG-PLys/PBA) and EGCG. DOX was co-loaded in the PIC micelles through π-π stacking interaction with EGCG. The phenylboronic acid-catechol interaction endowed the PIC micelles with high stability under physiological condition. Moreover, acid cleavability of phenylboronic acid-catechol interaction in the micelle core has significant benefits for delivering EGCG and DOX to same destination with synergistic effects. In addition, benefiting from the oxygen free radicals scavenging activity of EGCG, combination therapy with EGCG and DOX in the micelle core could protect the cardiomyocytes from DOX-mediated cardiotoxicity according to the histopathologic analysis of hearts. Attributed to modulation of EGCG on P-glycoprotein (P-gp) activity, this kind of PIC micelles could effectively reverse multidrug resistance of cancer cells. These results suggested that EGCG based PIC micelles could effectively overcome DOX induced cardiotoxicity and multidrug resistance. PMID:27375779

  1. Multidrug-resistance P-glycoprotein (MDR1) secretes platelet-activating factor.

    PubMed Central

    Raggers, R J; Vogels, I; van Meer, G

    2001-01-01

    The human multidrug-resistance (MDR1) P-glycoprotein (Pgp) is an ATP-binding-cassette transporter (ABCB1) that is ubiquitously expressed. Often its concentration is high in the plasma membrane of cancer cells, where it causes multidrug resistance by pumping lipophilic drugs out of the cell. In addition, MDR1 Pgp can transport analogues of membrane lipids with shortened acyl chains across the plasma membrane. We studied a role for MDR1 Pgp in transport to the cell surface of the signal-transduction molecule platelet-activating factor (PAF). PAF is the natural short-chain phospholipid 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine. [(14)C]PAF synthesized intracellularly from exogenous alkylacetylglycerol and [(14)C]choline became accessible to albumin in the extracellular medium of pig kidney epithelial LLC-PK1 cells in the absence of vesicular transport. Its translocation across the apical membrane was greatly stimulated by the expression of MDR1 Pgp, and inhibited by the MDR1 inhibitors PSC833 and cyclosporin A. Basolateral translocation was not stimulated by expression of the basolateral drug transporter MRP1 (ABCC1). It was insensitive to the MRP1 inhibitor indomethacin and to depletion of GSH which is required for MRP1 activity. While efficient transport of PAF across the apical plasma membrane may be physiologically relevant in MDR1-expressing epithelia, PAF secretion in multidrug-resistant tumours may stimulate angiogenesis and thereby tumour growth. PMID:11463358

  2. Pluronic mixed micelles overcoming methotrexate multidrug resistance: in vitro and in vivo evaluation

    PubMed Central

    Chen, Yanzuo; Sha, Xianyi; Zhang, Wei; Zhong, Weitong; Fan, Zhuoyang; Ren, Qiuyue; Chen, Liangcen; Fang, Xiaoling

    2013-01-01

    A Pluronic polymeric mixed micelle delivery system was developed in this study by using Pluronic P105 and F127 block copolymers to encapsulate the antitumor compound, methotrexate (MTX). The MTX-loaded Pluronic P105/F127 mixed micelle exhibited the spherical shape with about 22 nm in diameter, high encapsulation efficiency (about 85%) and pH-dependent in vitro drug release. In this study, A-549 and KBv cell lines were selected as multidrug resistance tumor cell models, while H-460 and KB cell lines were chosen as sensitive tumor cells. The MTX-loaded Pluronic P105/F127 mixed micelle exhibited significant higher in vitro cytotoxicity in multidrug resistant tumor cells than that of control (MTX injection) mainly because of higher cellular uptake of MTX. The pharmacokinetic studies indicated that the Pluronic micelles significantly prolonged systemic circulation time of MTX compared to MTX injection. Moreover, a much stronger antitumor efficacy in KBv tumor xenografts nude mice was observed in the MTX-loaded Pluronic P105/F127 mixed micelle group, than MTX. Collectively, Pluronic P105/F127 mixed micelles could significantly enhance the antitumor activity of MTX and might be a promising drug delivery platform for multidrug resistance modulation. PMID:23620663

  3. Resin glycosides from Ipomoea wolcottiana as modulators of the multidrug resistance phenotype in vitro.

    PubMed

    Corona-Castañeda, Berenice; Rosas-Ramírez, Daniel; Castañeda-Gómez, Jhon; Aparicio-Cuevas, Manuel Alejandro; Fragoso-Serrano, Mabel; Figueroa-González, Gabriela; Pereda-Miranda, Rogelio

    2016-03-01

    Recycling liquid chromatography was used for the isolation and purification of resin glycosides from the CHCl3-soluble extracts prepared using flowers of Ipomoea wolcottiana Rose var. wolcottiana. Bioassay-guided fractionation, using modulation of both antibiotic activity against multidrug-resistant strains of Gram-negative bacteria and vinblastine susceptibility in breast carcinoma cells, was used to isolate the active glycolipids as modulators of the multidrug resistance phenotype. An ester-type dimer, wolcottine I, one tetra- and three pentasaccharides, wolcottinosides I-IV, in addition to the known intrapilosin VII, were characterized by NMR spectroscopy and mass spectrometry. In vitro assays established that none of these metabolites displayed antibacterial activity (MIC>512 μg/mL) against multidrug-resistant strains of Escherichia coli, and two nosocomial pathogens: Salmonella enterica serovar Typhi and Shigella flexneri; however, when tested (25 μg/mL) in combination with tetracycline, kanamycin or chloramphenicol, they exerted a potentiation effect of the antibiotic susceptibility up to eightfold (64 μg/mL from 512 μg/mL). It was also determined that these non-cytotoxic (CI50>8.68 μM) agents modulated vinblastine susceptibility at 25 μg/mL in MFC-7/Vin(+) cells with a reversal factor (RFMCF-7/Vin(+)) of 2-130 fold. PMID:26774597

  4. Inhibition of multidrug resistant Listeria monocytogenes by peptides isolated from combinatorial phage display libraries.

    PubMed

    Flachbartova, Z; Pulzova, L; Bencurova, E; Potocnakova, L; Comor, L; Bednarikova, Z; Bhide, M

    2016-01-01

    The aim of the study was to isolate and characterize novel antimicrobial peptides from peptide phage library with antimicrobial activity against multidrug resistant Listeria monocytogenes. Combinatorial phage-display library was used to affinity select peptides binding to the cell surface of multidrug resistant L. monocytogenes. After several rounds of affinity selection followed by sequencing, three peptides were revealed as the most promising candidates. Peptide L2 exhibited features common to antimicrobial peptides (AMPs), and was rich in Asp, His and Lys residues. Peptide L3 (NSWIQAPDTKSI), like peptide L2, inhibited bacterial growth in vitro, without any hemolytic or cytotoxic effects on eukaryotic cells. L1 peptide showed no inhibitory effect on Listeria. Structurally, peptides L2 and L3 formed random coils composed of α-helix and β-sheet units. Peptides L2 and L3 exhibited antimicrobial activity against multidrug resistant isolates of L. monocytogenes with no haemolytic or toxic effects. Both peptides identified in this study have the potential to be beneficial in human and veterinary medicine. PMID:27296960

  5. Genomic structure, gene expression, and promoter analysis of human multidrug resistance-associated protein 7

    SciTech Connect

    Kao, Hsin-Hsin; Chang, Ming-Shi; Cheng, Jan-Fang; Huang, Jin-Ding

    2002-03-15

    The multidrug resistance-associated protein (MRP) subfamily transporters associated with anticancer drug efflux are attributed to the multidrug-resistance of cancer cells. The genomic organization of human multidrug resistance-associated protein 7 (MRP7) was identified. The human MRP7 gene, consisting of 22 exons and 21 introns, greatly differs from other members of the human MRP subfamily. A splicing variant of human MRP7, MRP7A, expressed in most human tissues, was also characterized. The 1.93-kb promoter region of MRP7 was isolated and shown to support luciferase activity at a level 4- to 5-fold greater than that of the SV40 promoter. Basal MRP7 gene expression was regulated by 2 regions in the 5-flanking region at 1,780 1,287 bp, and at 611 to 208 bp. In Madin-Darby canine kidney (MDCK) cells, MRP7 promoter activity was increased by 226 percent by genotoxic 2-acetylaminofluorene and 347 percent by the histone deacetylase inhibitor, trichostatin A. The protein was expressed in the membrane fraction of transfected MDCK cells.

  6. Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel-7402/5-fluorouracil cells

    PubMed Central

    LING, SUNBIN; TIAN, YU; ZHANG, HAIQUAN; JIA, KAIQI; FENG, TINGTING; SUN, DEGUANG; GAO, ZHENMING; XU, FEI; HOU, ZHAOYUAN; LI, YAN; WANG, LIMING

    2014-01-01

    Metformin exhibits anti-proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel-7402/5-fluorouracil (5-Fu; Bel/Fu) cells. The synergistic anti-proliferative effect of metformin combined with 5-Fu was evaluated using a Cell Counting kit-8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription-polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti-proliferative effect with 5-Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia-inducible factor-1α (HIF-1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P-glycoprotein (P-gp) and multidrug resistance-associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF-1α/P-gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma. PMID:25310259

  7. Early multidrug resistance, defined by changes in intracellular doxorubicin distribution, independent of P-glycoprotein.

    PubMed Central

    Schuurhuis, G. J.; Broxterman, H. J.; de Lange, J. H.; Pinedo, H. M.; van Heijningen, T. H.; Kuiper, C. M.; Scheffer, G. L.; Scheper, R. J.; van Kalken, C. K.; Baak, J. P.

    1991-01-01

    Resistance to multiple antitumour drugs, mostly antibiotics or alkaloids, has been associated with a cellular plasma membrane P-glycoprotein (Pgp), causing energy-dependent transport of drugs out of cells. However, in many common chemotherapy resistant human cancers there is no overexpression of Pgp, which could explain drug resistance. In order to characterise early steps in multidrug resistance we have derived a series of P-glycoprotein-positive (Pgp/+) and P-glycoprotein-negative (Pgp/-) multidrug resistant cell lines, from a human non-small cell lung cancer cell line, SW-1573, by stepwise selection with increasing concentrations of doxorubicin. These cells were exposed to doxorubicin and its fluorescence in nucleus (N) and cytoplasm (C) was quantified with laserscan microscopy and image analysis. The fluorescence N/C ratio in parent cells was 3.8 and decreased both in Pgp/+ and Pgp/- cells with increasing selection pressure to 1.2-2.6 for cells with a resistance factor of 7-17. N/C ratios could be restored partly with verapamil only in Pgp/+ cells. N/C ratio measurements may define a general Pgp-independent type of defense of mammalian cells against certain anticancer agents which may precede Pgp expression in early doxorubicin resistance. Images Figure 1 PMID:1681887

  8. Transgenic Mice that Express the Human Multidrug-Resistance Gene in Bone Marrow Enable a Rapid Identification of Agents that Reverse Drug Resistance

    NASA Astrophysics Data System (ADS)

    Mickisch, Gerald H.; Merlino, Glenn T.; Galski, Hanan; Gottesman, Michael M.; Pastan, Ira

    1991-01-01

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M_r 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. We have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lymphocytes are protected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. Verapamil and quinine, both at levels suitable for human trials that produced only partial sensitization of the MDR1-transgenic mice, were fully sensitizing when used in combination. We conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.

  9. Transgenic mice that express the human multidrug-resistance gene in bone marrow enable a rapid identification of agents that reverse drug resistance

    SciTech Connect

    Mickisch, G.H.; Merlino, G.T.; Galski, H.; Gottesman, M.M.; Pastan, I. )

    1991-01-15

    The development of preclinical models for the rapid testing of agents that circumvent multidrug resistance in cancer is a high priority of research on drug resistance. A common form of multidrug resistance in human cancer results from expression of the MDR1 gene, which encodes a M{sub r} 170,000 glycoprotein that functions as a plasma membrane energy-dependent multidrug efflux pump. The authors have engineered transgenic mice that express this multidrug transporter in their bone marrow and demonstrated that these animals are resistant to leukopenia by a panel of anticancer drugs including anthracyclines, vinca alkaloids, etoposide, taxol, and actinomycin D. Differential leukocyte counts indicate that both neutrophils and lympohcytes are pretected. Drugs such as cisplatin, methotrexate, and 5-fluorouracil, which are not handled by the multidrug transporter, produce bone marrow suppression in both normal and transgenic mice. The resistance conferred by the MDR1 gene can be circumvented in a dose-dependent manner by simultaneous administration of agents previously shown to be inhibitors of the multidrug transporter in vitro, including verapamil isomers, quinidine, and quinine. They conclude that MDR1-transgenic mice provide a rapid and reliable system to determine the bioactivity of agents that reverse multidrug resistance in animals.

  10. Tetrandrine and fangchinoline, bisbenzylisoquinoline alkaloids from Stephania tetrandra can reverse multidrug resistance by inhibiting P-glycoprotein activity in multidrug resistant human cancer cells.

    PubMed

    Sun, Yan Fang; Wink, Michael

    2014-01-01

    The overexpression of ABC transporters is a common reason for multidrug resistance (MDR) in cancer cells. In this study, we found that the isoquinoline alkaloids tetrandrine and fangchinoline from Stephania tetrandra showed a significant synergistic cytotoxic effect in MDR Caco-2 and CEM/ADR5000 cancer cells in combination with doxorubicin, a common cancer chemotherapeutic agent. Furthermore, tetrandrine and fangchinoline increased the intracellular accumulation of the fluorescent P-glycoprotein (P-gp) substrate rhodamine 123 (Rho123) and inhibited its efflux in Caco-2 and CEM/ADR5000 cells. In addition, tetrandrine and fangchinoline significantly reduced P-gp expression in a concentration-dependent manner. These results suggest that tetrandrine and fangchinoline can reverse MDR by increasing the intracellular concentration of anticancer drugs, and thus they could serve as a lead for developing new drugs to overcome P-gp mediated drug resistance in clinic cancer therapy. PMID:24856768

  11. Molecular Characterization of Multidrug-Resistant Isolates of Mycobacterium tuberculosis from Patients in North India

    PubMed Central

    Siddiqi, Noman; Shamim, Mohammed; Hussain, Seema; Choudhary, Rakesh Kumar; Ahmed, Niyaz; Prachee; Banerjee, Sharmistha; Savithri, G. R.; Alam, Mahfooz; Pathak, Niteen; Amin, Amol; Hanief, Mohammed; Katoch, V. M.; Sharma, S. K.; Hasnain, Seyed E.

    2002-01-01

    The World Health Organization has identified India as a major hot-spot region for Mycobacterium tuberculosis infection. We have characterized the sequences of the loci associated with multidrug resistance in 126 clinical isolates of M. tuberculosis from India to identify the respective mutations. The loci selected were rpoB (rifampin), katG and the ribosomal binding site of inhA (isoniazid), gyrA and gyrB (ofloxacin), and rpsL and rrs (streptomycin). We found known as well as novel mutations at these loci. Few of the mutations at the rpoB locus could be correlated with the drug resistance levels exhibited by the M. tuberculosis isolates and occurred with frequencies different from those reported earlier. Missense mutations at codons 526 to 531 seemed to be crucial in conferring a high degree of resistance to rifampin. We identified a common Arg463Leu substitution in the katG locus and certain novel insertions and deletions. Mutations were also mapped in the ribosomal binding site of the inhA gene. A Ser95Thr substitution in the gyrA locus was the most common mutation observed in ofloxacin-resistant isolates. A few isolates showed other mutations in this locus. Seven streptomycin-resistant isolates had a silent mutation at the lysine residue at position 121. While certain mutations are widely present, pointing to the magnitude of the polymorphisms at these loci, others are not common, suggesting diversity in the multidrug-resistant M. tuberculosis strains prevalent in this region. Our results additionally have implications for the development of methods for multidrug resistance detection and are also relevant in the shaping of future clinical treatment regimens and drug design strategies. PMID:11796356

  12. Intermediate risk of multidrug-resistant organisms in patients who admitted intensive care unit with healthcare-associated pneumonia

    PubMed Central

    Lee, Hongyeul; Park, Ji Young; Lee, Taehoon; Lee, Yeon Joo; Lim, Hyo-Jeong; Park, Jong Sun; Yoon, Ho Il; Lee, Jae-Ho; Lee, Choon-Taek; Cho, Young-Jae

    2016-01-01

    Background/Aims: Healthcare-associated pneumonia (HCAP) was proposed asa new pneumonia category in 2005, and treatment recommendations includebroad-spectrum antibiotics directed at multidrug-resistant (MDR) pathogens.However, this concept continues to be controversial, and microbiological data arelacking for HCAP patients in the intensive care unit (ICU). This study was conductedto determine the rate and type of antibiotic-resistant organisms and theclinical outcomes in patients with HCAP in the ICU, compared to patients withcommunity-acquired pneumonia (CAP) or hospital-acquired pneumonia (HAP). Methods: We conducted a retrospective cohort analysis of patients with pneumonia(n = 195) who admitted to medical ICU in tertiary teaching hospital fromMarch 2011 to February 2013. Clinical characteristics, microbiological distributions,treatment outcomes, and prognosis of HCAP (n = 74) were compared tothose of CAP (n = 75) and HAP (n = 46). Results: MDR pathogens were significantly higher in HCAP patients (39.1%) thanin CAP (13.5%) and lower than in HAP (79.3%, p < 0.001). The initial use of inappropriateantibiotic treatment occurred more frequently in the HCAP (32.6%) andHAP (51.7%) groups than in the CAP group (11.8%, p = 0.006). There were no differencesin clinical outcomes. The significant prognostic factors were pneumoniaseverity and treatment response. Conclusions: MDR pathogens were isolated in HCAP patients requiring ICU admissionat intermediate rates between those of CAP and HAP. PMID:26968189

  13. Establishment and characterization of gemcitabine-resistant human cholangiocarcinoma cell lines with multidrug resistance and enhanced invasiveness.

    PubMed

    Wattanawongdon, Wareeporn; Hahnvajanawong, Chariya; Namwat, Nisana; Kanchanawat, Sirimas; Boonmars, Thidarut; Jearanaikoon, Patcharee; Leelayuwat, Chanwit; Techasen, Anchalee; Seubwai, Wunchana

    2015-07-01

    To establish and characterize the gemcitabine-resistant cholangiocarcinoma (CCA) cell lines, CCA KKU‑M139 and KKU‑M214 cell lines were exposed stepwisely to increasing gemcitabine (GEM). The resultant drug-resistant cell lines, KKU‑M139/GEM and KKU‑M214/GEM, retained the resistant phenotype in drug-free medium at least for 2 months. Sulforhodamine B assay demonstrated that KKU‑M139/GEM and KKU‑M214/GEM were 25.88- and 62.31-fold more resistant to gemcitabine than their parental cells. Both gemcitabine-resistant cell lines were cross-resistant to 5-fluorouracil (5-FU), doxorubicin and paclitaxel indicating their multidrug-resistant nature. Using reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR and western blot analyses, gemcitabine-resistant cells showed upregulation of RRM1 and downregulation of hENT1 and dCK. In relation to multidrug resistance, these cell lines showed upregulation of multidrug resistance protein 1 (MRP1) leading to an increase of drug efflux. Using cell adhesion and Boyden chamber transwell assays, these cell lines also showed higher cell adhesion, migration and invasion capabilities via the activations of protein kinase C (PKC), focal adhesion kinase (FAK), extracellular signal-regulated kinase-1/2 (ERK1/2) and nuclear factor-κB (NF-κB). Higher activity of matrix metalloproteinase-9 (MMP-9) and urokinase plasminogen activator (uPA) was also observed by a gelatin zymography assay and a casein-plasminogen zymography assay. Flow cytometry analysis indicated the G2/M arrest regulated by downregulation of cyclin B1 and cyclin-dependent kinase 1 (Cdk1) resulted in an extended population doubling time. Using Annexin V/propidium iodide staining, evasion of apoptosis via an intrinsic pathway was observed in both cell lines in association with upregulation of Bcl-2 and downregulation of Bax. Interestingly, Fas was additionally downregulated in KKU‑M214/GEM supporting the view of its higher GEM resistant

  14. The Relationship between Extensively Drug-Resistant Tuberculosis and Multidrug-Resistant Gram-Negative Bacilli

    PubMed Central

    Zhao, Jiang-nan; Zhang, Xian-xin; He, Xiao-chun; Yang, Guo-ru; Zhang, Xiao-qi; Li, Huai-chen

    2015-01-01

    Objective The relationship between extensively drug-resistant tuberculosis (XDR-TB) and multidrug-resistant Gram-negative bacilli (MDR-GNB) is unclear. Identification of the relationship between XDR-TB and MDR-GNB would have important implications for patient care. Methods We conducted a retrospective study reviewing the records of patients admitted with a confirmed pulmonary TB from 2011 to 2014. To identify the relationship between XDR-TB and MDR-GNB, univariable comparison and multivariable logistic regression were performed. Results Among 2962 pulmonary TB patients, 45(1.5%) patients had a diagnosis of XDR-TB. A total of 165 MDR-GNB strains were detected in 143 (4.8%) pulmonary TB patients. XDR-TB patients had a significantly higher occurrence of MDR-GNB than non-XDR-TB patients (24.4% vs. 4.5%; P<0.001). Age (OR 1.02, 95% CI 1.01–1.03), hypoalbuminemia (OR 1.48, 95% CI 1.18–1.85), chronic renal failure (OR 6.67, 95% CI 1.42–31.47), chronic hepatic insufficiency (OR 1.99, 95% CI 1.15–3.43), presence of XDR-TB (OR 6.56, 95% CI 1.61–26.69), and duration of TB diagnostic delay (OR 1.01, 95% CI 1.00–1.02) were the independent risk factors for MDR-GNB infection. Conclusions Patients with XDR-TB have a significantly higher risk of being affected by MDR-GNB pathogen. The underlying mechanism association warrant further studies. PMID:26230499

  15. Antibiotic strategies in the era of multidrug resistance.

    PubMed

    Karam, George; Chastre, Jean; Wilcox, Mark H; Vincent, Jean-Louis

    2016-01-01

    The rapid emergence and dissemination of antibiotic-resistant microorganisms in ICUs worldwide threaten adequate antibiotic coverage of infected patients in this environment. The causes of this problem are multifactorial, but the core issues are clear: the emergence of antibiotic resistance is highly correlated with selective pressure resulting from inappropriate use of these drugs. Because a significant increase in mortality is observed when antibiotic therapy is delayed in infected ICU patients, initial therapy should be broad enough to cover all likely pathogens. Receipt of unnecessary prolonged broad-spectrum antibiotics, however, should be avoided. Local microbiologic data are extremely important to predict the type of resistance that may be present for specific causative bacteria, as is prior antibiotic exposure, and antibiotic choices should thus be made at an individual patient level. PMID:27329228

  16. Nanobiotechnological Approaches Against Multidrug Resistant Bacterial Pathogens: An Update.

    PubMed

    Shaikh, Sibhghatulla; Shakil, Shazi; Abuzenadah, Adel M; Rizvi, Syed Mohd Danish; Roberts, Philip Michael; Mushtaq, Gohar; Kamal, Mohammad Amjad

    2015-01-01

    Multiple drug resistant bacteria remain the greatest challenge in public health care. Globally, infections produced by such resistant strains are on the rise. Recent advent of genetic tolerance to antibiotics in many pathogens such as multiple drug resistant Staphylococcus aureus is a matter of concern, prompting researchers and pharmaceutical companies to search for new molecules and unconventional antibacterial agents. Recent advances in nanotechnology offer new opportunities to develop formulations based on metallic nanoparticles with different shapes and sizes and variable antimicrobial properties. This article is an extensive literature review that covers the latest approaches in the development of new and unconventional antibacterial agents using nanobiotechnological approaches which will better equip scientists and clinicians to face the challenges in view of dwindling stocks of effective and potent antimicrobial agents and formulations. PMID:26419545

  17. Isolation and molecular characterization of multidrug-resistant halophilic bacteria from shrimp farm effluents of Parangipettai coastal waters.

    PubMed

    Sundaramanickam, Arumugam; Kumar, Poominathan Suresh; Kumaresan, Saravanan; Balasubramanian, Thangavel

    2015-08-01

    Multidrug resistance of heterotrophic bacteria isolated from an aquaculture farm effluent in Parangipettai, at the southeastern coast of India, was investigated. In the initial screening, 27 antibiotic-resistant strains were isolated. All the strains were tested for antibiotic susceptibility against chloramphenicol with varying concentrations. From these, two highly resistant strains, i.e. S1 and S5, were isolated. The selected strains were identified by 16S ribosomal RNA (rRNA) sequencing techniques and confirmed as Bacillus pumilus and Bacillus flexus. Both the antibiotic-resistant strains were further utilized for multidrug susceptibility test by using various antibiotics. These two strains showed antibiotic resistance to 14 of 17 antibiotics tested. Both microdilution assay and well assay methods were used to determine the minimal inhibitory concentration (MIC) for the sensitive strains. Both the tests were shown to be almost similar. Our study highlights the occurrence of multidrug-resistant bacteria in the shrimp farm effluents. PMID:25850744

  18. Whole-genome sequencing of multidrug-resistant Mycobacterium tuberculosis isolates from Myanmar.

    PubMed

    Aung, Htin Lin; Tun, Thanda; Moradigaravand, Danesh; Köser, Claudio U; Nyunt, Wint Wint; Aung, Si Thu; Lwin, Thandar; Thinn, Kyi Kyi; Crump, John A; Parkhill, Julian; Peacock, Sharon J; Cook, Gregory M; Hill, Philip C

    2016-09-01

    Drug-resistant tuberculosis (TB) is a major health threat in Myanmar. An initial study was conducted to explore the potential utility of whole-genome sequencing (WGS) for the diagnosis and management of drug-resistant TB in Myanmar. Fourteen multidrug-resistant Mycobacterium tuberculosis isolates were sequenced. Known resistance genes for a total of nine antibiotics commonly used in the treatment of drug-susceptible and multidrug-resistant TB (MDR-TB) in Myanmar were interrogated through WGS. All 14 isolates were MDR-TB, consistent with the results of phenotypic drug susceptibility testing (DST), and the Beijing lineage predominated. Based on the results of WGS, 9 of the 14 isolates were potentially resistant to at least one of the drugs used in the standard MDR-TB regimen but for which phenotypic DST is not conducted in Myanmar. This study highlights a need for the introduction of second-line DST as part of routine TB diagnosis in Myanmar as well as new classes of TB drugs to construct effective regimens. PMID:27530852

  19. Induction of multidrug resistance downregulates the expression of CFTR in colon epithelial cells.

    PubMed

    Breuer, W; Slotki, I N; Ausiello, D A; Cabantchik, I Z

    1993-12-01

    The epithelial cell line HT-29, which constitutively expresses the cystic fibrosis transmembrane conductance regulator (CFTR), was induced to become drug resistant by cultivation in the presence of colchicine. The gradual acquisition of drug resistance was associated with a corresponding increase in the expression of the multidrug resistance P-glycoprotein (P-gp) and a marked (> 80%) decrease in the constitutive levels of CFTR protein, as determined by immunoblotting. The reduction in CFTR content occurred at the onset of acquisition of drug resistance when P-gp expression was still relatively low. Reversal of drug resistance by removal of colchicine from the culture medium led to a 70% decrease in P-gp levels and a concomitant 40% increase in CFTR. The levels of other membrane proteins such as Na(+)-K(+)-ATPase and alkaline phosphatase remained relatively constant (< 26% variation). We propose that a selective downregulation of CFTR is elicited by acquisition of the multidrug resistance (MDR) phenotype and that induction of P-gp expression leads to a reversible repression of CFTR biosynthesis. These findings provide an experimental foundation for the complementary patterns of expression of the CFTR and MDR1 genes observed in vivo. PMID:7506492

  20. Overcoming ABC transporter-mediated multidrug resistance: Molecular mechanisms and novel therapeutic drug strategies.

    PubMed

    Li, Wen; Zhang, Han; Assaraf, Yehuda G; Zhao, Kun; Xu, Xiaojun; Xie, Jinbing; Yang, Dong-Hua; Chen, Zhe-Sheng

    2016-07-01

    Multidrug resistance is a key determinant of cancer chemotherapy failure. One of the major causes of multidrug resistance is the enhanced efflux of drugs by membrane ABC transporters. Targeting ABC transporters projects a promising approach to eliminating or suppressing drug resistance in cancer treatment. To reveal the functional mechanisms of ABC transporters in drug resistance, extensive studies have been conducted from identifying drug binding sites to elucidating structural dynamics. In this review article, we examined the recent crystal structures of ABC proteins to depict the functionally important structural elements, such as domains, conserved motifs, and critical amino acids that are involved in ATP-binding and drug efflux. We inspected the drug-binding sites on ABC proteins and the molecular mechanisms of various substrate interactions with the drug binding pocket. While our continuous battle against drug resistance is far from over, new approaches and technologies have emerged to push forward our frontier. Most recent developments in anti-MDR strategies include P-gp inhibitors, RNA-interference, nano-medicines, and delivering combination strategies. With the advent of the 'Omics' era - genomics, epigenomics, transcriptomics, proteomics, and metabolomics - these disciplines play an important role in fighting the battle against chemoresistance by further unraveling the molecular mechanisms of drug resistance and shed light on medical therapies that specifically target MDR. PMID:27449595

  1. Extensive multidrug resistance of coagulase-negative staphylococci in medical students.

    PubMed

    Higuchi, Wataru; Isobe, Hirokazu; Iwao, Yasuhisa; Dohmae, Soshi; Saito, Kohei; Takano, Tomomi; Otsuka, Taketo; Baranovich, Tatiana; Endo, Chiho; Suzuki, Nobuaki; Tomiyama, Yasuyuki; Yamamoto, Tatsuo

    2007-02-01

    Staphylococcus aureus and coagulase-negative staphylococci (CNS) isolated from the nasal mucosa of medical students were examined for susceptibility to 16 antimicrobial agents. No methicillin-resistant S. aureus (MRSA) was isolated, while MRCNS was present in 23.5% of the medical students. CNS exhibited significantly more resistance to antimicrobial agents such as gentamicin, in addition to oxacillin, compared to S. aureus, and 13.1% of the CNS strains (mostly MRCNS) were multidrug-resistant (to five or more drugs). In contrast, ampicillin resistance was higher in S. aureus. The rate of hospitalization or of taking an antimicrobial agent within the past 1 year was lower in CNS+ students than in S. aureus+ students. The data suggest that CNS could serve as a reservoir of drug resistance by persistent colonization in the nasal mucosa. In this study, MRCNS with multidrug resistance was found in medical students. More attention should be given to nasal MRCNS in medical students as a possible spreader in hospitals. PMID:17334733

  2. Potential multidrug resistance gene POHL: an ecologically relevant indicator in marine sponges.

    PubMed

    Krasko, A; Kurelec, B; Batel, R; Müller, I M; Müller, W E

    2001-01-01

    Sponges are sessile filter feeders found in all aquatic habitats from the tropics to the arctic. Against potential environmental hazards, they are provided with efficient defense systems, e.g., protecting chaperones and/or the P-170/multidrug resistance pump system. Here we report on a further multidrug resistance pathway that is related to the pad one homologue (POH1) mechanism recently identified in humans. It is suggested that proteolysis is involved in the inactivation of xenobiotics by the POH1 system. Two cDNAs were cloned, one from the demosponge Geodia cydonium and a second from the hexactinellid sponge Aphrocallistes vastus. The cDNA from G. cydonium, termed GCPOHL, encodes a deduced polypeptide with a size of 34,591 Da and that from A. vastus, AVPOHL, a protein of a calculated M(r) of 34,282. The two sponge cDNAs are highly similar to each other as well as to the known sequences from fungi (Schizosaccharomyces pombe and Saccharomyces cerevisiae) and other Metazoa (from Schistosoma mansoni to humans). Under controlled laboratory conditions, the expression of the potential multidrug resistance gene POHL is, in G. cydonium, strongly upregulated in response to the toxins staurosporin (20 microM) or taxol (50 microM); the first detectable transcripts appear after 1 d and reach a maximum after 3 to 5 d of incubation. The relevance of the expression pattern of the G. cydonium gene POHL for the assessment of pollution in the field was determined at differently polluted sites in the area around Rovinj (Croatia; Mediterranean Sea, Adriatic Sea). The load of the selected sites was assessed by measuring the potency of XAD-7 concentrates of water samples taken from those places to induce the level of benzo[a]pyrene monooxygenase (BaPMO) in fish and to impair the multidrug resistance (MDR)/P-170 extrusion pump in clams. These field experiments revealed that the levels of inducible BaPMO activity in fish and of the MDR potential by the water concentrates are highly

  3. Inhibiting fungal multidrug resistance by disrupting an activator-Mediator interaction.

    PubMed

    Nishikawa, Joy L; Boeszoermenyi, Andras; Vale-Silva, Luis A; Torelli, Riccardo; Posteraro, Brunella; Sohn, Yoo-Jin; Ji, Fei; Gelev, Vladimir; Sanglard, Dominique; Sanguinetti, Maurizio; Sadreyev, Ruslan I; Mukherjee, Goutam; Bhyravabhotla, Jayaram; Buhrlage, Sara J; Gray, Nathanael S; Wagner, Gerhard; Näär, Anders M; Arthanari, Haribabu

    2016-02-25

    Eukaryotic transcription activators stimulate the expression of specific sets of target genes through recruitment of co-activators such as the RNA polymerase II-interacting Mediator complex. Aberrant function of transcription activators has been implicated in several diseases. However, therapeutic targeting efforts have been hampered by a lack of detailed molecular knowledge of the mechanisms of gene activation by disease-associated transcription activators. We previously identified an activator-targeted three-helix bundle KIX domain in the human MED15 Mediator subunit that is structurally conserved in Gal11/Med15 Mediator subunits in fungi. The Gal11/Med15 KIX domain engages pleiotropic drug resistance transcription factor (Pdr1) orthologues, which are key regulators of the multidrug resistance pathway in Saccharomyces cerevisiae and in the clinically important human pathogen Candida glabrata. The prevalence of C. glabrata is rising, partly owing to its low intrinsic susceptibility to azoles, the most widely used antifungal agent. Drug-resistant clinical isolates of C. glabrata most commonly contain point mutations in Pdr1 that render it constitutively active, suggesting that this transcriptional activation pathway represents a linchpin in C. glabrata multidrug resistance. Here we perform sequential biochemical and in vivo high-throughput screens to identify small-molecule inhibitors of the interaction of the C. glabrata Pdr1 activation domain with the C. glabrata Gal11A KIX domain. The lead compound (iKIX1) inhibits Pdr1-dependent gene activation and re-sensitizes drug-resistant C. glabrata to azole antifungals in vitro and in animal models for disseminated and urinary tract C. glabrata infection. Determining the NMR structure of the C. glabrata Gal11A KIX domain provides a detailed understanding of the molecular mechanism of Pdr1 gene activation and multidrug resistance inhibition by iKIX1. We have demonstrated the feasibility of small-molecule targeting of a

  4. Genome Evolution and Plasticity of Serratia marcescens, an Important Multidrug-Resistant Nosocomial Pathogen

    PubMed Central

    Iguchi, Atsushi; Nagaya, Yutaka; Pradel, Elizabeth; Ooka, Tadasuke; Ogura, Yoshitoshi; Katsura, Keisuke; Kurokawa, Ken; Oshima, Kenshiro; Hattori, Masahira; Parkhill, Julian; Sebaihia, Mohamed; Coulthurst, Sarah J.; Gotoh, Naomasa; Thomson, Nicholas R.; Ewbank, Jonathan J.; Hayashi, Tetsuya

    2014-01-01

    Serratia marcescens is an important nosocomial pathogen that can cause an array of infections, most notably of the urinary tract and bloodstream. Naturally, it is found in many environmental niches, and is capable of infecting plants and animals. The emergence and spread of multidrug-resistant strains producing extended-spectrum or metallo beta-lactamases now pose a threat to public health worldwide. Here we report the complete genome sequences of two carefully selected S. marcescens strains, a multidrug-resistant clinical isolate (strain SM39) and an insect isolate (strain Db11). Our comparative analyses reveal the core genome of S. marcescens and define the potential metabolic capacity, virulence, and multidrug resistance of this species. We show a remarkable intraspecies genetic diversity, both at the sequence level and with regards genome flexibility, which may reflect the diversity of niches inhabited by members of this species. A broader analysis with other Serratia species identifies a set of approximately 3,000 genes that characterize the genus. Within this apparent genetic diversity, we identified many genes implicated in the high virulence potential and antibiotic resistance of SM39, including the metallo beta-lactamase and multiple other drug resistance determinants carried on plasmid pSMC1. We further show that pSMC1 is most closely related to plasmids circulating in Pseudomonas species. Our data will provide a valuable basis for future studies on S. marcescens and new insights into the genetic mechanisms that underlie the emergence of pathogens highly resistant to multiple antimicrobial agents. PMID:25070509

  5. Nuclear EGFR Contributes to Acquired Resistance to Cetuximab

    PubMed Central

    Li, Chunrong; Iida, Mari; Dunn, Emily F.; Ghia, Amol J.; Wheeler, Deric L.

    2010-01-01

    Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR blocking-antibody that has been approved for the treatment of patients with cancers of the head and neck (HNSCC) and metastatic colorectal cancer (mCRC). Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin (AR), heparin-binding EGF (HB-EGF) and β-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and re-sensitization to cetuximab. In addition, expression of a nuclear localization sequence tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab. PMID:19684613

  6. Nuclear EGFR contributes to acquired resistance to cetuximab.

    PubMed

    Li, C; Iida, M; Dunn, E F; Ghia, A J; Wheeler, D L

    2009-10-29

    Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparin-binding EGF and beta-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab. PMID:19684613

  7. Multidrug-Resistant Escherichia coli in Bovine Animals, Europe.

    PubMed

    Brennan, Evan; Martins, Marta; McCusker, Matthew P; Wang, Juan; Alves, Bruno Martins; Hurley, Daniel; El Garch, Farid; Woehrlé, Frédérique; Miossec, Christine; McGrath, Leisha; Srikumar, Shabarinath; Wall, Patrick; Fanning, Séamus

    2016-09-01

    Of 150 Escherichia coli strains we cultured from specimens taken from cattle in Europe, 3 had elevated MICs against colistin. We assessed all 3 strains for the presence of the plasmid-mediated mcr-1 gene and identified 1 isolate as mcr-1-positive and co-resistant to β-lactam, florfenicol, and fluoroquinolone antimicrobial compounds. PMID:27533105

  8. Multidrug-Resistant Salmonella enterica Serovar Infantis, Israel

    PubMed Central

    Valinsky, Lea; Weinberger, Miriam; Guy, Sara; Jaffe, Joseph; Schorr, Yosef Ilan; Raisfeld, Abraham; Agmon, Vered; Nissan, Israel

    2010-01-01

    To determine whether rapid emergence of Salmonella enterica serovar Infantis in Israel resulted from an increase in different biotypes or spread of 1 clone, we characterized 87 serovar Infantis isolates on the genotypic and phenotypic levels. The emerging strain comprised 1 genetic clone with a distinct pulsed-field gel electrophoresis profile and a common antimicrobial drug resistance pattern. PMID:21029536

  9. Multidrug-Resistant Escherichia coli in Bovine Animals, Europe

    PubMed Central

    Brennan, Evan; Martins, Marta; McCusker, Matthew P.; Wang, Juan; Alves, Bruno Martins; Hurley, Daniel; El Garch, Farid; Woehrlé, Frédérique; Miossec, Christine; McGrath, Leisha; Srikumar, Shabarinath; Wall, Patrick

    2016-01-01

    Of 150 Escherichia coli strains we cultured from specimens taken from cattle in Europe, 3 had elevated MICs against colistin. We assessed all 3 strains for the presence of the plasmid-mediated mcr-1 gene and identified 1 isolate as mcr-1–positive and co-resistant to β-lactam, florfenicol, and fluoroquinolone antimicrobial compounds. PMID:27533105

  10. Breast cancer resistance protein (BCRP/ABCG2): its role in multidrug resistance and regulation of its gene expression

    PubMed Central

    Nakanishi, Takeo; Ross, Douglas D.

    2012-01-01

    Breast cancer resistance protein (BCRP)/ATP-binding cassette subfamily G member 2 (ABCG2) is an ATP-binding cassette (ABC) transporter identified as a molecular cause of multidrug resistance (MDR) in diverse cancer cells. BCRP physiologically functions as a part of a self-defense mechanism for the organism; it enhances elimination of toxic xenobiotic substances and harmful agents in the gut and biliary tract, as well as through the blood-brain, placental, and possibly blood-testis barriers. BCRP recognizes and transports numerous anticancer drugs including conventional chemotherapeutic and targeted small therapeutic molecules relatively new in clinical use. Thus, BCRP expression in cancer cells directly causes MDR by active efflux of anticancer drugs. Because BCRP is also known to be a stem cell marker, its expression in cancer cells could be a manifestation of metabolic and signaling pathways that confer multiple mechanisms of drug resistance, self-renewal (sternness), and invasiveness (aggressiveness), and thereby impart a poor prognosis. Therefore, blocking BCRP-mediated active efflux may provide a therapeutic benefit for cancers. Delineating the precise molecular mechanisms for BCRP gene expression may lead to identification of a novel molecular target to modulate BCRP-mediated MDR. Current evidence suggests that BCRP gene transcription is regulated by a number of trans-acting elements including hypoxia inducible factor 1α, estrogen receptor, and peroxisome proliferator-activated receptor. Furthermore, alternative promoter usage, demethylation of the BCRP promoter, and histone modification are likely associated with drug-induced BCRP overexpression in cancer cells. Finally, PI3K/AKT signaling may play a critical role in modulating BCRP function under a variety of conditions. These biological events seem involved in a complicated manner. Untangling the events would be an essential first step to developing a method to modulate BCRP function to aid patients with

  11. Identification of multidrug-resistant Salmonella enterica serovar typhimurium isolates that have an antibiotic-induced invasion phenotype

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multidrug-resistant (MDR) Salmonella is an important food safety issue in humans and animals. The National Antimicrobial Resistance Monitoring System (NARMS) has reported that 27.3% of Salmonella enterica serotype Typhimurium isolates in humans were resistant to three or more classes of antibiotics...

  12. Comparison of effects of antimicrobial interventions on multidrug-resistant Salmonella, susceptible Salmonella, and Escherichia coli O157:H7

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Several strains of Salmonella have been identified as being resistant to multiple antibiotics. What is not known is if strains possessing multi-drug resistance (MDR) properties also have the ability to resist the killing effects of the antimicrobial interventions used in beef processing. The resea...

  13. Biofilm and multidrug resistance in uropathogenic Escherichia coli

    PubMed Central

    Mittal, Seema; Sharma, Madhu; Chaudhary, Uma

    2015-01-01

    Context: Escherichia coli is known as causative agent of urinary tract infections (UTIs) tends to form microcolonies in mucosa lining of urinary bladder known as biofilm. These biofilms make the organism to resist the host immune response, more virulent and lead to the evolution of antibacterial drug resistance by enclosing them in an extracellular biochemical matrix. Aims: This study was done to know the association of various virulence factors and biofilm production in uropathogenic E. coli (UPEC) and antibiotic susceptibility pattern. Settings and design: This study was conducted in Pt. B.D. Sharma PGIMS, Rohtak, Haryana during a period of 1 year from January 2011 to December 2011. Methods and material: Biofilm was detected by microtiter plate (MTP) method, and various virulence factors like hemolysin, hemagglutination, gelatinase, siderophore production, serum resistance, and hydrophobicity were detected. The antibiotic susceptibility testing was done by modified Kirby-Bauer disk diffusion and the disk diffusion method was used to confirm the ESBL, AmpC, MBL production by the UPEC statistical analysis used: The data were analyzed by using SPSS version 17.0. A two-sided P-value of less than or equal to 0.05 was considered to be significant. Results: Biofilm production was found in 18 (13.5%) isolates, more commonly in females (two times). These isolates were found to be resistant to antibiotics common in use and were 100% MDR. Conclusions: Biofilm production makes the organism to be more resistant to antibiotics and virulent as compared to non-biofilm producers. PMID:25605466

  14. Multidrug resistance in Salmonella enterica serotype Typhimurium from humans in France (1993 to 2003).

    PubMed

    Weill, François-Xavier; Guesnier, Françoise; Guibert, Véronique; Timinouni, Mohammed; Demartin, Marie; Polomack, Lucette; Grimont, Patrick A D

    2006-03-01

    The aim of this study was to determine the distribution of the antimicrobial resistance phenotypes (R types), the phage types and XbaI-pulsed-field gel electrophoresis (PFGE) types, the genes coding for resistance to beta-lactams and to quinolones, and the class 1 integrons among a representative sample of Salmonella enterica serotype Typhimurium isolates collected from humans in 2002 through the French National Reference Center for Salmonella (NRC-Salm) network. The trends in the evolution of antimicrobial resistance of serotype Typhimurium were reviewed by using NRC-Salm data from 1993, 1997, 2000, and 2003. In 2002, 3,998 isolates of serotype Typhimurium were registered at the NRC-Salm among 11,775 serotyped S. enterica isolates (34%). The most common multiple antibiotic resistance pattern was resistance to amoxicillin, chloramphenicol, streptomycin and spectinomycin, sulfonamides, and tetracycline (ACSSpSuTe R type), with 156 isolates (48.8%). One isolate resistant to extended-spectrum cephalosporins due to the production of TEM-52 extended-spectrum beta-lactamase was detected (0.3%), and one multidrug-resistant isolate was highly resistant to ciprofloxacin (MIC > 32 mg/liter). We found that 57.2% of the isolates tested belonged to the DT104 clone. The main resistance pattern of DT104 isolates was R type ACSSpSuTe (83.2%). However, evolutionary changes have occurred within DT104, involving both loss (variants of Salmonella genomic island 1) and acquisition of genes for drug resistance to trimethoprim or to quinolones. PFGE profile X1 was the most prevalent (74.5%) among DT104 isolates, indicating the need to use a more discriminatory subtyping method for such isolates. Global data from the NRC-Salm suggested that DT104 was the main cause of multidrug resistance in serotype Typhimurium from humans from at least 1997 to 2003, with a roughly stable prevalence during this period. PMID:16517842

  15. Identification and deconvolution of cross-resistance signals from antimalarial compounds using multidrug-resistant Plasmodium falciparum strains.

    PubMed

    Chugh, Monika; Scheurer, Christian; Sax, Sibylle; Bilsland, Elizabeth; van Schalkwyk, Donelly A; Wicht, Kathryn J; Hofmann, Natalie; Sharma, Anil; Bashyam, Sridevi; Singh, Shivendra; Oliver, Stephen G; Egan, Timothy J; Malhotra, Pawan; Sutherland, Colin J; Beck, Hans-Peter; Wittlin, Sergio; Spangenberg, Thomas; Ding, Xavier C

    2015-02-01

    Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs. PMID:25487796

  16. Identification and Deconvolution of Cross-Resistance Signals from Antimalarial Compounds Using Multidrug-Resistant Plasmodium falciparum Strains

    PubMed Central

    Chugh, Monika; Scheurer, Christian; Sax, Sibylle; Bilsland, Elizabeth; van Schalkwyk, Donelly A.; Wicht, Kathryn J.; Hofmann, Natalie; Sharma, Anil; Bashyam, Sridevi; Singh, Shivendra; Oliver, Stephen G.; Egan, Timothy J.; Malhotra, Pawan; Sutherland, Colin J.; Beck, Hans-Peter; Wittlin, Sergio; Spangenberg, Thomas

    2014-01-01

    Plasmodium falciparum, the most deadly agent of malaria, displays a wide variety of resistance mechanisms in the field. The ability of antimalarial compounds in development to overcome these must therefore be carefully evaluated to ensure uncompromised activity against real-life parasites. We report here on the selection and phenotypic as well as genotypic characterization of a panel of sensitive and multidrug-resistant P. falciparum strains that can be used to optimally identify and deconvolute the cross-resistance signals from an extended panel of investigational antimalarials. As a case study, the effectiveness of the selected panel of strains was demonstrated using the 1,2,4-oxadiazole series, a newly identified antimalarial series of compounds with in vitro activity against P. falciparum at nanomolar concentrations. This series of compounds was to be found inactive against several multidrug-resistant strains, and the deconvolution of this signal implicated pfcrt, the genetic determinant of chloroquine resistance. Targeted mode-of-action studies further suggested that this new chemical series might act as falcipain 2 inhibitors, substantiating the suggestion that these compounds have a site of action similar to that of chloroquine but a distinct mode of action. New antimalarials must overcome existing resistance and, ideally, prevent its de novo appearance. The panel of strains reported here, which includes recently collected as well as standard laboratory-adapted field isolates, is able to efficiently detect and precisely characterize cross-resistance and, as such, can contribute to the faster development of new, effective antimalarial drugs. PMID:25487796

  17. Vancomycin for multi-drug resistant Enterococcus faecium cholangiohepatitis in a cat.

    PubMed

    Pressel, Michelle A; Fox, Leslie E; Apley, Michael D; Simutis, Frank J

    2005-10-01

    A 12-year-old, neutered male domestic shorthair cat was evaluated with a life-long history of intermittent, predominantly small bowel diarrhea and a 3 day history of hematochezia. At presentation, the cat had increased liver enzyme activities and an inflammatory leukogram. Histopathology demonstrated inflammatory bowel disease (IBD), cholangiohepatitis and pancreatitis. The cholangiohepatitis was associated with a multi-drug resistant Enterococcus faecium. Gallbladder agenesis was also documented. Treatment with vancomycin was safely instituted for 10 days. Clinical signs resolved, however, cure of the bacterial cholangiohepatitis was not achieved. The risk of vancomycin resistant enterococci (VRE) in human and veterinary medicine is discussed. PMID:16182186

  18. Metformin reverses multidrug resistance in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil cells.

    PubMed

    Ling, Sunbin; Tian, Yu; Zhang, Haiquan; Jia, Kaiqi; Feng, Tingting; Sun, Deguang; Gao, Zhenming; Xu, Fei; Hou, Zhaoyuan; Li, Yan; Wang, Liming

    2014-12-01

    Metformin exhibits anti‑proliferative effects in tumor cells in vitro and in vivo. The present study investigated the ability of metformin to reverse multidrug resistance (MDR) in human hepatocellular carcinoma Bel‑7402/5‑fluorouracil (5‑Fu; Bel/Fu) cells. The synergistic anti‑proliferative effect of metformin combined with 5‑Fu was evaluated using a Cell Counting kit‑8 assay. The variation in apoptotic rates and cell cycle distribution were evaluated using a flow cytometric assay and variations in target gene and protein expression were monitored using reverse transcription‑polymerase chain reaction and western blot analysis. The results demonstrated that metformin had a synergistic anti‑proliferative effect with 5‑Fu in the Bel/Fu cells. The variations in the number of apoptotic cells and distribution of the cell cycle were consistent with the variability in cell viability. Metformin targeted the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, suppressed the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and transcriptionally downregulated the expression of multidrug resistance protein 1/P‑glycoprotein (P‑gp) and multidrug resistance‑associated protein 1 (MRP1). Collectively, these findings suggested that metformin may target the AMPK/mTOR/HIF‑1α/P‑gp and MRP1 pathways to reverse MDR in hepatocellular carcinoma. PMID:25310259

  19. Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives

    PubMed Central

    Ła̧cka, Izabela; Konieczny, Marek T.; Bułakowska, Anita; Kodedová, Marie; Gašková, Dana; Maurya, Indresh K.; Prasad, Rajendra; Milewski, Sławomir

    2015-01-01

    Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux pumps. The observed effect of sensitization of resistant strains of Candida albicans to fluconazole activity in the presence of active compounds most likely resulted from inhibition of the pump-mediated efflux, as was revealed by the results of studies involving the fluorescent probes, Nile Red, Rhodamine 6G and diS-C3(3). PMID:26300857

  20. Impact of HIV co-infection on the evolution and transmission of multidrug-resistant tuberculosis.

    PubMed

    Eldholm, Vegard; Rieux, Adrien; Monteserin, Johana; Lopez, Julia Montana; Palmero, Domingo; Lopez, Beatriz; Ritacco, Viviana; Didelot, Xavier; Balloux, Francois

    2016-01-01

    The tuberculosis (TB) epidemic is fueled by a parallel Human Immunodeficiency Virus (HIV) epidemic, but it remains unclear to what extent the HIV epidemic has been a driver for drug resistance in Mycobacterium tuberculosis (Mtb). Here we assess the impact of HIV co-infection on the emergence of resistance and transmission of Mtb in the largest outbreak of multidrug-resistant TB in South America to date. By combining Bayesian evolutionary analyses and the reconstruction of transmission networks utilizing a new model optimized for TB, we find that HIV co-infection does not significantly affect the transmissibility or the mutation rate of Mtb within patients and was not associated with increased emergence of resistance within patients. Our results indicate that the HIV epidemic serves as an amplifier of TB outbreaks by providing a reservoir of susceptible hosts, but that HIV co-infection is not a direct driver for the emergence and transmission of resistant strains. PMID:27502557

  1. Multidrug-resistant Gram-negative bacteria: a product of globalization.

    PubMed

    Hawkey, P M

    2015-04-01

    Global trade and mobility of people has increased rapidly over the last 20 years. This has had profound consequences for the evolution and the movement of antibiotic resistance genes. There is increasing exposure of populations all around the world to resistant bacteria arising in the emerging economies. Arguably the most important development of the last two decades in the field of antibiotic resistance is the emergence and spread of extended-spectrum β-lactamases (ESBLs) of the CTX-M group. A consequence of the very high rates of ESBL production among Enterobacteriaceae in Asian countries is that there is a substantial use of carbapenem antibiotics, resulting in the emergence of plasmid-mediated resistance to carbapenems. This article reviews the emergence and spread of multidrug-resistant Gram-negative bacteria, focuses on three particular carbapenemases--imipenem carbapenemases, Klebsiella pneumoniae carbapenemase, and New Delhi metallo-β-lactamase--and highlights the importance of control of antibiotic use. PMID:25737092

  2. The prevention and management of infections due to multidrug resistant organisms in haematology patients.

    PubMed

    Trubiano, Jason A; Worth, Leon J; Thursky, Karin A; Slavin, Monica A

    2015-02-01

    Infections due to resistant and multidrug resistant (MDR) organisms in haematology patients and haematopoietic stem cell transplant recipients are an increasingly complex problem of global concern. We outline the burden of illness and epidemiology of resistant organisms such as gram-negative pathogens, vancomycin-resistant Enterococcus faecium (VRE), and Clostridium difficile in haematology cohorts. Intervention strategies aimed at reducing the impact of these organisms are reviewed: infection prevention programmes, screening and fluoroquinolone prophylaxis. The role of newer therapies (e.g. linezolid, daptomycin and tigecycline) for treatment of resistant and MDR organisms in haematology populations is evaluated, in addition to the mobilization of older agents (e.g. colistin, pristinamycin and fosfomycin) and the potential benefit of combination regimens. PMID:24341410

  3. [Mycobacterium tuberculosis mutants with multidrug resistance: history of origin, genetic and molecular mechanisms of resistance, and emerging challenges].

    PubMed

    Prozorov, A A; Zaĭchikova, M V; Danilenko, V N

    2012-01-01

    The review summarizes the data on the Mycobacterium tuberculosis mutations that lead to multidrug resistance (MDR) to various antibiotics. MDR strains arose over the past 30 years as a variety of antituberculosis drugs were introduced in medicine, and they largely discount the results of chemotherapy for tuberculosis. The most dangerous of them are strains with extensive drug resistance (XDR), which are resistant to four or five different drugs on average. The molecular mechanisms that make a strain resistant are considered. XDR and MDR strains result from successive and usually independent resistance mutations, which arise in various regions of the mycobacterial genome. In addition, the formation of resistant strains is affected by the phenomenon of tolerance and mycobacterial latency in infected tissues. PMID:22567849

  4. Multidrug resistance genes in staphylococci from animals that confer resistance to critically and highly important antimicrobial agents in human medicine.

    PubMed

    Wendlandt, Sarah; Shen, Jianzhong; Kadlec, Kristina; Wang, Yang; Li, Beibei; Zhang, Wan-Jiang; Feßler, Andrea T; Wu, Congming; Schwarz, Stefan

    2015-01-01

    Most antimicrobial resistance genes known so far to occur in staphylococci of animal origin confer resistance to a specific class of antimicrobial agents or to selected members within such a class. However, there are also a few examples of multidrug resistance (MDR) genes that confer resistance to antimicrobial agents of different classes by either target site methylation or active efflux via ATP-binding cassette (ABC) transporters. The present review provides an overview of these MDR genes with particular reference to those genes involved in resistance to critically or highly important antimicrobial agents used in human and veterinary medicine. Moreover, their location on mobile genetic elements and colocated resistance genes, which may play a role in coselection and persistence of the MDR genes, are addressed. PMID:25455417

  5. Management of multidrug-resistant TB: novel treatments and their expansion to low resource settings

    PubMed Central

    Sloan, Derek J.; Lewis, Joseph M.

    2016-01-01

    Despite overall progress in global TB control, the rising burden of multidrug-resistant TB (MDR-TB) threatens to undermine efforts to end the worldwide epidemic. Of the 27 countries classified as high burden for MDR-TB, 17 are in ‘low’ or ‘low–middle’ income countries. Shorter, all oral and less toxic multidrug combinations are required to improve treatment outcomes in these settings. Suitability for safe co-administration with HIV drugs is also desirable. A range of strategies and several new drugs (including bedaquiline, delamanid and linezolid) are currently undergoing advanced clinical evaluations to define their roles in achieving these aims. However, several clinical questions and logistical challenges need to be overcome before these new MDR-TB treatments fulfil their potential. PMID:26884496

  6. Management of multidrug-resistant TB: novel treatments and their expansion to low resource settings.

    PubMed

    Sloan, Derek J; Lewis, Joseph M

    2016-03-01

    Despite overall progress in global TB control, the rising burden of multidrug-resistant TB (MDR-TB) threatens to undermine efforts to end the worldwide epidemic. Of the 27 countries classified as high burden for MDR-TB, 17 are in 'low' or 'low-middle' income countries. Shorter, all oral and less toxic multidrug combinations are required to improve treatment outcomes in these settings. Suitability for safe co-administration with HIV drugs is also desirable. A range of strategies and several new drugs (including bedaquiline, delamanid and linezolid) are currently undergoing advanced clinical evaluations to define their roles in achieving these aims. However, several clinical questions and logistical challenges need to be overcome before these new MDR-TB treatments fulfil their potential. PMID:26884496

  7. Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression.

    PubMed

    Jia, Ming; Hu, Jing; Li, Weiwei; Su, Peng; Zhang, Hui; Zhang, Xiaofang; Zhou, Gengyin

    2014-03-01

    Multidrug resistance (MDR) is a significant clinical problem in the chemotherapy of osteosarcoma and has been linked to the cellular expression of several multidrug-efflux transporters such as MDR1/P-gp. Our inhibition of the transcription factor Trps1 led to repression of MDR1/P-gp while its overexpression resulted in upregulation of MDR1/P-gp. Flow cytometric analysis suggested Trps1 increased the release of several anti-cancer drugs, thus decreasing their accumulation. Immunohistochemical analysis of clinical samples indicated that the expression of Trps1 directly correlated with MDR1/P-gp. Trps1 inhibited TGFbeta-1 and directly bound to the MDR1 promoter. Our data demonstrate a role for Trps1 in the regulation of MDR1 expression in osteosarcoma. PMID:24491996

  8. Cytotoxicity of Salvia miltiorrhiza Against Multidrug-Resistant Cancer Cells.

    PubMed

    Wu, Ching-Fen; Bohnert, Stefan; Thines, Eckhard; Efferth, Thomas

    2016-01-01

    Salvia miltiorrhiza Bunge (Lamiaceae) is a well-known Chinese herb that possesses numerous therapeutic activities, including anticancer effects. In this study, the cytotoxicity and the biological mechanisms of S. miltiorrhiza (SM) root extract on diverse resistant and sensitive cancer cell lines were investigated. CEM/ADR5000 cells were 1.68-fold resistant to CCRF-CEM cells, while HCT116 (p53[Formula: see text] and U87.MG[Formula: see text]EGFR cells were hypersensitive (collateral sensitive) compared to their parental cells. SM root extract stimulated ROS generation, cell cycle S phase arrest and apoptosis. The induction of the intrinsic apoptotic pathway was validated by increased cleavage of caspase 3, 7, 9 and poly ADP-ribose polymerase (PARP). MAP kinases including JNK, ERK1/2 and p38 were obviously phosphorylated and nuclear P65 was downregulated upon SM treatment. Transcriptome-wide COMPARE analysis revealed that the expression of encoding genes with diverse functions were associated with the cellular response to cryptotanshinone, one of the main constituents of SM root extract. In conclusion, SM root extract exerted profound cytotoxicity towards various sensitive and resistant cancer cells and induced the intrinsic apoptotic pathway. PMID:27222067

  9. Bioengineering approaches to study multidrug resistance in tumor cells

    PubMed Central

    Fallica, Brian; Makin, Guy

    2015-01-01

    The ability of cancer cells to become resistant to chemotherapeutic agents is a major challenge for the treatment of malignant tumors. Several strategies have emerged to attempt to inhibit chemoresistance, but the fact remains that resistance is a problem for every effective anticancer drug. The first part of this review will focus on the mechanisms of chemoresistance. It is important to understand the environmental cues, transport limitations and the cellular signaling pathways associated with chemoresistance before we can hope to effectively combat it. The second part of this review focuses on the work that needs to be done moving forward. Specifically, this section focuses on the necessity of translational research and interdisciplinary directives. It is critical that the expertise of oncologists, biologists, and engineers be brought together to attempt to tackle the problem. This discussion is from an engineering perspective, as the dialogue between engineers and other cancer researchers is the most challenging due to non-overlapping background knowledge. Chemoresistance is a complex and devastating process, meaning that we urgently need sophisticated methods to study the process of how cells become resistant. PMID:21387035

  10. Intracellular targeted co-delivery of shMDR1 and gefitinib with chitosan nanoparticles for overcoming multidrug resistance

    PubMed Central

    Yu, Xiwei; Yang, Guang; Shi, Yijie; Su, Chang; Liu, Ming; Feng, Bo; Zhao, Liang

    2015-01-01

    Nowadays, multidrug resistance and side effects of drugs limit the effectiveness of chemotherapies in clinics. P-glycoprotein (P-gp) (MDR1), as a member of the ATP-binding cassette family, acts on transporting drugs into cell plasma across the membrane of cancer cells and leads to the occurrence of multidrug resistance, thus resulting in the failure of chemotherapy in cancer. The main aims of this research were to design a nanodelivery system for accomplishing the effective co-delivery of gene and antitumor drug and overcoming multidrug resistance effect. In this study, shMDR1 and gefitinib-encapsulating chitosan nanoparticles with sustained release, small particle size, and high encapsulation efficiency were prepared. The serum stability, protection from nuclease, and transfection efficiency of gene in vitro were investigated. The effects of co-delivery of shMDR1 and gefitinib in nanoparticles on reversing multidrug resistance were also evaluated by investigating the cytotoxicity, cellular uptake mechanism, and cell apoptosis on established gefitinib-resistant cells. The results demonstrated that chitosan nanoparticles entrapping gefitinib and shMDR1 had the potential to overcome the multidrug resistance and improve cancer treatment efficacy, especially toward resistant cells. PMID:26648717

  11. Selection of a Multidrug Resistance Plasmid by Sublethal Levels of Antibiotics and Heavy Metals

    PubMed Central

    Gullberg, Erik; Albrecht, Lisa M.; Karlsson, Christoffer; Sandegren, Linus

    2014-01-01

    ABSTRACT How sublethal levels of antibiotics and heavy metals select for clinically important multidrug resistance plasmids is largely unknown. Carriage of plasmids generally confers substantial fitness costs, implying that for the plasmid-carrying bacteria to be maintained in the population, the plasmid cost needs to be balanced by a selective pressure conferred by, for example, antibiotics or heavy metals. We studied the effects of low levels of antibiotics and heavy metals on the selective maintenance of a 220-kbp extended-spectrum β-lactamase (ESBL) plasmid identified in a hospital outbreak of Klebsiella pneumoniae and Escherichia coli. The concentrations of antibiotics and heavy metals required to maintain plasmid-carrying bacteria, the minimal selective concentrations (MSCs), were in all cases below (almost up to 140-fold) the MIC of the plasmid-free susceptible bacteria. This finding indicates that the very low antibiotic and heavy metal levels found in polluted environments and in treated humans and animals might be sufficiently high to maintain multiresistance plasmids. When resistance genes were moved from the plasmid to the chromosome, the MSC decreased, showing that MSC for a specific resistance conditionally depends on genetic context. This finding suggests that a cost-free resistance could be maintained in a population by an infinitesimally low concentration of antibiotic. By studying the effect of combinations of several compounds, it was observed that for certain combinations of drugs each new compound added lowered the minimal selective concentration of the others. This combination effect could be a significant factor in the selection of multidrug resistance plasmids/bacterial clones in complex multidrug environments. PMID:25293762

  12. Variable recombination dynamics during the emergence, transmission and ‘disarming’ of a multidrug-resistant pneumococcal clone

    PubMed Central

    2014-01-01

    Background Pneumococcal β-lactam resistance was first detected in Iceland in the late 1980s, and subsequently peaked at almost 25% of clinical isolates in the mid-1990s largely due to the spread of the internationally-disseminated multidrug-resistant PMEN2 (or Spain6B-2) clone of Streptococcus pneumoniae. Results Whole genome sequencing of an international collection of 189 isolates estimated that PMEN2 emerged around the late 1960s, developing resistance through multiple homologous recombinations and the acquisition of a Tn5253-type integrative and conjugative element (ICE). Two distinct clades entered Iceland in the 1980s, one of which had acquired a macrolide resistance cassette and was estimated to have risen sharply in its prevalence by coalescent analysis. Transmission within the island appeared to mainly emanate from Reykjavík and the Southern Peninsular, with evolution of the bacteria effectively clonal, mainly due to a prophage disrupting a gene necessary for genetic transformation in many isolates. A subsequent decline in PMEN2’s prevalence in Iceland coincided with a nationwide campaign that reduced dispensing of antibiotics to children in an attempt to limit its spread. Specific mutations causing inactivation or loss of ICE-borne resistance genes were identified from the genome sequences of isolates that reverted to drug susceptible phenotypes around this time. Phylogenetic analysis revealed some of these occurred on multiple occasions in parallel, suggesting they may have been at least temporarily advantageous. However, alteration of ‘core’ sequences associated with resistance was precluded by the absence of any substantial homologous recombination events. Conclusions PMEN2’s clonal evolution was successful over the short-term in a limited geographical region, but its inability to alter major antigens or ‘core’ gene sequences associated with resistance may have prevented persistence over longer timespans. PMID:24957517

  13. Urban riverine environment is a source of multidrug-resistant and ESBL-producing clinically important Acinetobacter spp.

    PubMed

    Maravić, Ana; Skočibušić, Mirjana; Fredotović, Željana; Šamanić, Ivica; Cvjetan, Svjetlana; Knezović, Mia; Puizina, Jasna

    2016-02-01

    Some Acinetobacter species have emerged as very important opportunistic pathogens in humans. We investigated Acinetobacter spp. from the polluted urban riverine environment in Croatia in regard to species affiliation, antibiotic resistance pattern, and resistance mechanisms. Considerable number of isolates produced acquired extended-spectrum β-lactamase(s) (ESBLs), CTX-M-15 solely or with TEM-116. By Southern blot hybridization, bla TEM-116 was identified on plasmids ca. 10, 3, and 1.2 kb in Acinetobacter junii, A. gandensis, and A. johnsonii. The bla TEM-116-carrying plasmid in A. gandensis was successfully transferred by conjugation to azide-resistant Escherichia coli J53. A. radioresistens isolate also carried an intrinsic carbapenemase gene bla OXA-133 with ISAba1 insertion sequence present upstream to promote its expression. Majority of ESBL-producing isolates harbored integrases intI1 and/or intI2 and the sulfamethoxazole resistance gene sul1. Almost all isolates had overexpressed resistance-nodulation-cell division (RND) efflux system, indicating that this mechanism may have contributed to multidrug resistance phenotypes. This is the first report of environmental CTX-M-15-producing Acinetobacter spp. and the first identification of CTX-M-15 in A. johnsonii, A. junii, A. calcoaceticus, A. gandensis, A. haemolyticus, and A. radioresistens worldwide. We identified, also for the first time, the environmental Acinetobacter-producing TEM ESBLs, highlighting the potential risk for human health, and the role of these bacteria in maintenance and dissemination of clinically important antibiotic resistance genes in community through riverine environments. PMID:26490931

  14. Whole Genome Sequencing Reveals Complex Evolution Patterns of Multidrug-Resistant Mycobacterium tuberculosis Beijing Strains in Patients

    PubMed Central

    Merker, Matthias; Kohl, Thomas A.; Roetzer, Andreas; Truebe, Leona; Richter, Elvira; Rüsch-Gerdes, Sabine; Fattorini, Lanfranco; Oggioni, Marco R.; Cox, Helen; Varaine, Francis; Niemann, Stefan

    2013-01-01

    Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains represent a major threat for tuberculosis (TB) control. Treatment of MDR-TB patients is long and less effective, resulting in a significant number of treatment failures. The development of further resistances leads to extensively drug-resistant (XDR) variants. However, data on the individual reasons for treatment failure, e.g. an induced mutational burst, and on the evolution of bacteria in the patient are only sparsely available. To address this question, we investigated the intra-patient evolution of serial MTBC isolates obtained from three MDR-TB patients undergoing longitudinal treatment, finally leading to XDR-TB. Sequential isolates displayed identical IS6110 fingerprint patterns, suggesting the absence of exogenous re-infection. We utilized whole genome sequencing (WGS) to screen for variations in three isolates from Patient A and four isolates from Patient B and C, respectively. Acquired polymorphisms were subsequently validated in up to 15 serial isolates by Sanger sequencing. We determined eight (Patient A) and nine (Patient B) polymorphisms, which occurred in a stepwise manner during the course of the therapy and were linked to resistance or a potential compensatory mechanism. For both patients, our analysis revealed the long-term co-existence of clonal subpopulations that displayed different drug resistance allele combinations. Out of these, the most resistant clone was fixed in the population. In contrast, baseline and follow-up isolates of Patient C were distinguished each by eleven unique polymorphisms, indicating an exogenous re-infection with an XDR strain not detected by IS6110 RFLP typing. Our study demonstrates that intra-patient microevolution of MDR-MTBC strains under longitudinal treatment is more complex than previously anticipated. However, a mutator phenotype was not detected. The presence of different subpopulations might confound phenotypic and molecular drug

  15. Genomic definition of hypervirulent and multidrug-resistant Klebsiella pneumoniae clonal groups.

    PubMed

    Bialek-Davenet, Suzanne; Criscuolo, Alexis; Ailloud, Florent; Passet, Virginie; Jones, Louis; Delannoy-Vieillard, Anne-Sophie; Garin, Benoit; Le Hello, Simon; Arlet, Guillaume; Nicolas-Chanoine, Marie-Hélène; Decré, Dominique; Brisse, Sylvain

    2014-11-01

    Multidrug-resistant and highly virulent Klebsiella pneumoniae isolates are emerging, but the clonal groups (CGs) corresponding to these high-risk strains have remained imprecisely defined. We aimed to identify K. pneumoniae CGs on the basis of genome-wide sequence variation and to provide a simple bioinformatics tool to extract virulence and resistance gene data from genomic data. We sequenced 48 K. pneumoniae isolates, mostly of serotypes K1 and K2, and compared the genomes with 119 publicly available genomes. A total of 694 highly conserved genes were included in a core-genome multilocus sequence typing scheme, and cluster analysis of the data enabled precise definition of globally distributed hypervirulent and multidrug-resistant CGs. In addition, we created a freely accessible database, BIGSdb-Kp, to enable rapid extraction of medically and epidemiologically relevant information from genomic sequences of K. pneumoniae. Although drug-resistant and virulent K. pneumoniae populations were largely nonoverlapping, isolates with combined virulence and resistance features were detected. PMID:25341126

  16. Use of Ceftolozane/Tazobactam in the Treatment of Multidrug-resistant Pseudomonas aeruginosa Bloodstream Infection in a Pediatric Leukemia Patient.

    PubMed

    Aitken, Samuel L; Kontoyiannis, Dimitrios P; DePombo, April M; Bhatti, Micah M; Tverdek, Frank P; Gettys, Suzanne C; Nicolau, David P; Nunez, Cesar A

    2016-09-01

    Multidrug-resistant Pseudomonas aeruginosa is of increasing concern in pediatric patients. Ceftolozane/tazobactam is a novel cephalosporin/β-lactamase inhibitor combination with activity against multidrug-resistant Pseudomonas; however, no data exist on its use in children. This report summarizes the treatment of a multidrug-resistant P. aeruginosa bloodstream infection in a pediatric leukemia patient with ceftolozane/tazobactam and provides the first description of its pharmacokinetics in pediatrics. PMID:27254038

  17. Cytotoxicity of rhein, the active metabolite of sennoside laxatives, is reduced by multidrug resistance-associated protein 1

    PubMed Central

    van Gorkom, B A P; Timmer-Bosscha, H; de Jong, S; van der Kolk, D M; Kleibeuker, J H; de Vries, E G E

    2002-01-01

    Anthranoid laxatives, belonging to the anthraquinones as do anthracyclines, possibly increase colorectal cancer risk. Anthracyclines interfere with topoisomerase II, intercalate DNA and are substrates for P-glycoprotein and multidrug resistance-associated protein 1. P-glycoprotein and multidrug resistance-associated protein 1 protect colonic epithelial cells against xenobiotics. The aim of this study was to analyse the interference of anthranoids with these natural defence mechanisms and the direct cytotoxicity of anthranoids in cancer cell lines expressing these mechanisms in varying combinations. A cytotoxicity profile of rhein, aloe emodin and danthron was established in related cell lines exhibiting different levels of topoisomerases, multidrug resistance-associated protein 1 and P-glycoprotein. Interaction of rhein with multidrug resistance-associated protein 1 was studied by carboxy fluorescein efflux and direct cytotoxicity by apoptosis induction. Rhein was less cytotoxic in the multidrug resistance-associated protein 1 overexpressing GLC4/ADR cell line compared to GLC4. Multidrug resistance-associated protein 1 inhibition with MK571 increased rhein cytotoxicity. Carboxy fluorescein efflux was blocked by rhein. No P-glycoprotein dependent rhein efflux was observed, nor was topoisomerase II responsible for reduced toxicity. Rhein induced apoptosis but did not intercalate DNA. Aloe emodin and danthron were no substrates for MDR mechanisms. Rhein is a substrate for multidrug resistance-associated protein 1 and induces apoptosis. It could therefore render the colonic epithelium sensitive to cytotoxic agents, apart from being toxic in itself. British Journal of Cancer (2002) 86, 1494–1500. DOI: 10.1038/sj/bjc/6600255 www.bjcancer.com © 2002 Cancer Research UK PMID:11986786

  18. Role of mitochondrial translocation of telomerase in hepatocellular carcinoma cells with multidrug resistance.

    PubMed

    Ling, Xianlong; Wen, Lei; Zhou, Yuan

    2012-01-01

    Multidrug resistance (MDR) is a major obstacle of cancer chemotherapy. This study aimed to investigate the role of mitochondrial translocation of telomerase (hTERT) in MDR of human hepatocellular carcinoma (HCC) cells. In this study, three HCC cell lines (SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells) with differential resistance index (RI) to cisplatin (CDDP) were induced by pulse treatment of SK-Hep1 (human hepatocellular cell line) with CDDP in vitro. The RI of SK-Hep1/CDDP1 cells, SK-Hep1/CDDP2 cells and SK-Hep1/CDDP3 cells was 5.14, 8.66, and 14.25, respectively, and all the cell lines showed cross-resistance to Doxorubicin (DOX) and 5-Fuorouracil (5-FU). The apoptosis rates in drug-resistant cells were significantly reduced. Cell cycle analysis revealed the ratio of drug-resistant cells in G2/M and S phases increased, while that in G1 phase decreased. Immunofluorescence staining and Western blot assay demonstrated, with the gradual elevation in RI, increasing hTERT translocated from the nuclei to the mitochondria, while real-time PCR indicated the shortening of telomere length in drug-resistant cells under the chemotherapeutic stress and the reduction of damaged mtDNA with the increase in RI. Furthermore, JC-1 staining also indicated the reduction of mitochondrial membrane potential in drug-resistant cells. The mitochondrial translocation of hTERT increases in multidrug-resistant cells and exerts protective effect on mitochondrial function. Drug-resistant tumor cells escape from apoptosis through hTERT-mediated mitochondrial protection. Mitochondrial translocation of hTERT may serve as an underlying mechanism of MDR. PMID:22991493

  19. Spread of community-acquired methicillin-resistant Staphylococcus aureus (MRSA) in hospitals in Taipei, Taiwan in 2005, and comparison of its drug resistance with previous hospital-acquired MRSA.

    PubMed

    Takano, Tomomi; Saito, Kohei; Teng, Lee-Jene; Yamamoto, Tatsuo

    2007-01-01

    Panton-Valentine leucocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (PVL+ MRSA) is an emerging pathogen in the community worldwide. The incidence of PVL+ MRSA in Taipei, Taiwan was 23.3% for hospital MRSA. PVL+ MRSA was isolated from both outpatients and inpatients. Some PVL+ (mecA+) strains (36.8%) showed low MIC values (resistance pattern was oxacillin and clindamycin resistance (81%). There was no multidrug resistance over three drugs, in contrast to patient PVL- MRSA with resistance to five drugs as a major resistance pattern. The majority of PVL+ MRSA belonged to multilocus sequence (ST) type 59, while PVL+ MRSA belonged to ST239, ST59 and ST5. The data suggests that although PVL+ CA-MRSA is isolated at a high incidence from hospitals in Taipei, the drug resistance is mostly selected in the community and less prominent compared with previous PVL- hospital-acquired MRSA. PMID:17579274

  20. Transcriptional and proteomic analyses of two-component response regulators in multidrug-resistant Mycobacterium tuberculosis.

    PubMed

    Zhou, Lei; Yang, Liu; Zeng, Xianfei; Danzheng, Jiacuo; Zheng, Qing; Liu, Jiayun; Liu, Feng; Xin, Yijuan; Cheng, Xiaodong; Su, Mingquan; Ma, Yueyun; Hao, Xiaoke

    2015-07-01

    Two-component systems (TCSs) have been reported to exhibit a sensing and responding role under drug stress that induces drug resistance in several bacterial species. However, the relationship between TCSs and multidrug resistance in Mycobacterium tuberculosis has not been comprehensively analysed to date. In this study, 90 M. tuberculosis clinical isolates were analysed using 15-loci mycobacterial interspersed repetitive unit (MIRU)-variable number tandem repeat (VNTR) typing and repetitive extragenic palindromic (rep)-PCR-based DNA fingerprinting. The results showed that all of the isolates were of the Beijing lineage, and strains with a drug-susceptible phenotype had not diverged into similar genotype clusters. Expression analysis of 13 response regulators of TCSs using real-time PCR and tandem mass spectrometry (MS/MS) proteomic analysis demonstrated that four response regulator genes (devR, mtrA, regX3 and Rv3143) were significantly upregulated in multidrug-resistant (MDR) strains compared with the laboratory strain H37Rv as well as drug-susceptible and isoniazid-monoresistant strains (P<0.05). DNA sequencing revealed that the promoter regions of devR, mtrA, regX3 and Rv3143 did not contain any mutations. Moreover, expression of the four genes could be induced by most of the four first-line antitubercular agents. In addition, either deletion or overexpression of devR in Mycobacterium bovis BCG did not alter its sensitivity to the four antitubercular drugs. This suggests that upregulation of devR, which is common in MDR-TB strains, might be induced by drug stress and hypoxic adaptation following the acquisition of multidrug resistance. PMID:25937537

  1. Community-Acquired Methicillin-Resistant Pyogenic Liver Abscess

    PubMed Central

    Cherian, Joel; Singh, Rahul; Varma, Muralidhar; Vidyasagar, Sudha; Mukhopadhyay, Chiranjay

    2016-01-01

    Pyogenic liver abscesses are rare with an incidence of 0.5% to 0.8% and are mostly due to hepatobiliary causes (40% to 60%). Most are polymicrobial with less than 10% being caused by Staphylococcus aureus. Of these, few are caused by methicillin-resistant Staphylococcus aureus (MRSA) and fewer still by a community-acquired strain. Here we present a case study of a patient with a community-acquired MRSA liver abscess. The patient presented with fever since 1 month and tender hepatomegaly. Blood tests revealed elevated levels of alkaline phosphatase, C-reactive protein, erythrocyte sedimentation rate, and neutrophilic leukocytosis. Blood cultures were sterile. Ultrasound of the abdomen showed multiple abscesses, from which pus was drained and MRSA isolated. Computed tomography of the abdomen did not show any source of infection, and an amebic serology was negative. The patient was started on vancomycin for 2 weeks, following which he became afebrile and was discharged on oral linezolid for 4 more weeks. Normally a liver abscess is treated empirically with ceftriaxone for pyogenic liver abscess and metronidazole for amebic liver abscess. However, if the patient has risk factors for a Staphylococcal infection, it is imperative that antibiotics covering gram-positive organisms be added while waiting for culture reports. PMID:27540556

  2. Molecular Characterization of the Multidrug Resistant Escherichia coli ST131 Clone

    PubMed Central

    Schembri, Mark A.; Ben Zakour, Nouri L.; Phan, Minh-Duy; Forde, Brian M.; Stanton-Cook, Mitchell; Beatson, Scott A.

    2015-01-01

    Escherichia coli ST131 is a recently emerged and globally disseminated multidrug resistant clone associated with urinary tract and bloodstream infections in both community and clinical settings. The most common group of ST131 strains are defined by resistance to fluoroquinolones and possession of the type 1 fimbriae fimH30 allele. Here we provide an update on our recent work describing the globally epidemiology of ST131. We review the phylogeny of ST131 based on whole genome sequence data and highlight the important role of recombination in the evolution of this clonal lineage. We also summarize our findings on the virulence of the ST131 reference strain EC958, and highlight the use of transposon directed insertion-site sequencing to define genes associated with serum resistance and essential features of its large antibiotic resistance plasmid pEC958. PMID:26131613

  3. First Report of an OXA-48-Producing Multidrug-Resistant Proteus mirabilis Strain from Gaza, Palestine

    PubMed Central

    Chen, Liang; Chavda, Kalyan D.; Mediavilla, Jose R.; Jacobs, Michael R.; Bonomo, Robert A.

    2015-01-01

    We report the first multidrug-resistant Proteus mirabilis strain producing the carbapenemase OXA-48 (Pm-OXA-48) isolated at Al-Shifa hospital in Gaza, Palestine. Draft genome sequencing of Pm-OXA-48 identified 16 antimicrobial resistance genes, encoding resistance to β-lactams, aminoglycosides, fluoroquinolones, phenicols, streptothricin, tetracycline, and trimethoprim-sulfamethoxazole. Complete sequencing of the blaOXA-48-harboring plasmid revealed that it is a 72 kb long IncL/M plasmid, harboring carbapenemase gene blaOXA-48, extended spectrum β-lactamase gene blaCTX-M-14, and aminoglycoside resistance genes strA, strB, and aph(3′)-VIb. PMID:25896692

  4. Multifunctional mesoporous silica nanoparticles mediated co-delivery of paclitaxel and tetrandrine for overcoming multidrug resistance.

    PubMed

    Jia, Lejiao; Li, Zhenyu; Shen, Jingyi; Zheng, Dandan; Tian, Xiaona; Guo, Hejian; Chang, Ping

    2015-07-15

    The objective of the study is to fabricate multifunctional mesoporous silica nanoparticles for achieving co-delivery of conventional antitumor drug paclitaxel (PTX) and the multidrug resistance reversal agent tetrandrine (TET) expecting to overcome multidrug resistance of MCF-7/ADR cells. The nanoparticles were facile to prepare by self-assemble in situ drug loading approach. Namely, PTX and TET were solubilized in the cetyltrimethylammonium bromide (CTAB) micelles and simultaneously silica resources hydrolyze and condense to form nanoparticles. The obtained nanoparticles, denoted as PTX/TET-CTAB@MSN, exhibited pH-responsive release property with more easily released in the weak acidic environment. Studies on cellular uptake of nanoparticles demonstrated TET could markedly increase intracellular accumulation of nanoparticles. Furthermore, the PTX/TET-CTAB@MSN suppressed tumor cells growth more efficiently than only delivery of PTX (PTX-CTAB@MSN) or the free PTX. Moreover, the nanoparticle loading drugs with a PTX/TET molar ratio of 4.4:1 completely reversed the resistance of MCF-7/ADR cells to PTX and the resistance reversion index was 72.3. Mechanism research showed that both TET and CTAB could arrest MCF-7/ADR cells at G1 phase; and besides PTX arrested cells at G2 phase. This nanocarrier might have important potential in clinical implications for co-delivery of multiple drugs to overcome MDR. PMID:25956050

  5. In vitro antimicrobial activity of five essential oils on multidrug resistant Gram-negative clinical isolates

    PubMed Central

    Sakkas, Hercules; Gousia, Panagiota; Economou, Vangelis; Sakkas, Vassilios; Petsios, Stefanos; Papadopoulou, Chrissanthy

    2016-01-01

    Aim/Background: The emergence of drug-resistant pathogens has drawn attention on medicinal plants for potential antimicrobial properties. The objective of the present study was the investigation of the antimicrobial activity of five plant essential oils on multidrug resistant Gram-negative bacteria. Materials and Methods: Basil, chamomile blue, origanum, thyme, and tea tree oil were tested against clinical isolates of Acinetobacter baumannii (n = 6), Escherichia coli (n = 4), Klebsiella pneumoniae (n = 7), and Pseudomonas aeruginosa (n = 5) using the broth macrodilution method. Results: The tested essential oils produced variable antibacterial effect, while Chamomile blue oil demonstrated no antibacterial activity. Origanum, Thyme, and Basil oils were ineffective on P. aeruginosa isolates. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration values ranged from 0.12% to 1.50% (v/v) for tea tree oil, 0.25-4% (v/v) for origanum and thyme oil, 0.50% to >4% for basil oil and >4% for chamomile blue oil. Compared to literature data on reference strains, the reported MIC values were different by 2SD, denoting less successful antimicrobial activity against multidrug resistant isolates. Conclusions: The antimicrobial activities of the essential oils are influenced by the strain origin (wild, reference, drug sensitive, or resistant) and it should be taken into consideration whenever investigating the plants’ potential for developing new antimicrobials. PMID:27366345

  6. Screening dietary flavonoids for the reversal of P-glycoprotein-mediated multidrug resistance in cancer.

    PubMed

    Mohana, S; Ganesan, M; Agilan, B; Karthikeyan, R; Srithar, G; Beaulah Mary, R; Ananthakrishnan, D; Velmurugan, D; Rajendra Prasad, N; Ambudkar, Suresh V

    2016-07-19

    P-Glycoprotein (P-gp) serves as a therapeutic target for the development of inhibitors to overcome multidrug resistance in cancer cells. Although various screening procedures have been practiced so far to develop first three generations of P-gp inhibitors, their toxicity and drug interaction profiles are still a matter of concern. To address the above important problem of developing safe and effective P-gp inhibitors, we have made systematic computational and experimental studies on the interaction of natural phytochemicals with human P-gp. Molecular docking and QSAR studies were carried out for 40 dietary phytochemicals in the drug-binding site of the transmembrane domains (TMDs) of P-gp. Dietary flavonoids exhibit better interactions with homology modeled human P-gp. Based on the computational analysis, selected flavonoids were tested for their inhibitory potential against P-gp transport function in drug resistant cell lines using calcein-AM and rhodamine 123 efflux assays. It has been found that quercetin and rutin were the highly desirable flavonoids for the inhibition of P-gp transport function and they significantly reduced resistance in cytotoxicity assays to paclitaxel in P-gp overexpressing MDR cell lines. Hence, quercetin and rutin may be considered as potential chemosensitizing agents to overcome multidrug resistance in cancer. PMID:27216424

  7. Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid- and Multidrug-resistant Escherichia coli.

    PubMed

    Dwivedi, Gaurav Raj; Maurya, Anupam; Yadav, Dharmendra Kumar; Khan, Feroz; Darokar, Mahendra P; Srivastava, Santosh Kumar

    2015-09-01

    As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections. PMID:25476148

  8. Control of multidrug resistant bacteria in a tertiary care hospital in India

    PubMed Central

    2012-01-01

    Background The objective of this study was to assess the impact of antimicrobial stewardship programs on the multidrug resistance patterns of bacterial isolates. The study comprised an initial retrospective analysis of multidrug resistance in bacterial isolates for one year (July 2007-June 2008) followed by prospective evaluation of the impact of Antimicrobial Stewardship programs on resistance for two years and nine months (July 2008-March 2011). Setting A 300-bed tertiary care private hospital in Gurgaon, Haryana (India) Findings Methods Study Design • July 2007 to June 2008: Resistance patterns of bacterial isolates were studied. • July 2008: Phase I intervention programme Implementation of an antibiotic policy in the hospital. • July 2008 to June 2010: Assessment of the impact of the Phase I intervention programme. • July 2010 to March 2011: Phase II intervention programme: Formation and effective functioning of the antimicrobial stewardship committee. Statistical correlation of the Defined daily dose (DDD) for prescribed drugs with the antimicrobial resistance of Gram negatives. Results Phase I intervention programme (July 2008) resulted in a decrease of 4.47% in ESBLs (E.coli and Klebsiella) and a significant decrease of 40.8% in carbapenem-resistant Pseudomonas. Phase II intervention (July 2010) brought a significant reduction (24.7%) in carbapenem-resistant Pseudomonas. However, the resistance in the other Gram negatives (E.coli, Klebsiella, and Acinetobacter) rose and then stabilized. A positive correlation was observed in Pseudomonas and Acinetobacter with carbapenems and cefoperazone-sulbactam. Piperacillin-tazobactam showed a positive correlation with Acinetobacter only. E.coli and Klebsiella showed positive correlation with cefoparazone-sulbactam and piperacillin-tazobactam. Conclusion An antimicrobial stewardship programme with sustained and multifaceted efforts is essential to promote the judicious use of antibiotics. PMID:22958481

  9. Let-7 modulates acquired resistance of ovarian cancer to Taxanes via IMP-1-mediated stabilization of MDR1

    PubMed Central

    Boyerinas, Benjamin; Park, Sun-Mi; Murmann, Andrea E.; Gwin, Katja; Montag, Anton G.; Zillardt, Marion R.; Hua, You-Jia; Lengyel, Ernst; Peter, Marcus E.

    2011-01-01

    Summary Ovarian cancer patients frequently develop resistance to chemotherapy regiments utilizing Taxol and carboplatin. One of the resistance factors that protects cancer cells from Taxol-based therapy is multi-drug resistance 1 (MDR1). micro(mi)RNAs are small noncoding RNAs that negatively regulate protein expression. Members of the let-7 family of miRNAs are downregulated in many human cancers, and low let-7 expression has been correlated with resistance to microtubule targeting drugs (Taxanes), although little is known that would explain this activity. We now provide evidence that, while let-7 is not a universal sensitizer of cancer cells to Taxanes, it affects acquired resistance of cells to this class of drugs by targeting IMP-1, resulting in de-stabilization of the mRNA of MDR1. Introducing let-7g into ADR-RES cells expressing both IMP-1 and MDR1 reduced expression of both proteins rendering the cells more sensitive to treatment with either Taxol or vinblastine without affecting the sensitivity of the cells to carboplatin, a non-MDR1 substrate. This effect could be reversed by reintroducing IMP-1 into let-7g high/MDR1 low cells causing MDR1 to again become stabilized. Consistently, many relapsed ovarian cancer patients tested before and after chemotherapy were found to downregulate let-7 and to co-upregulate IMP-1 and MDR1, and the increase in the expression levels of both proteins after chemotherapy negatively correlated with disease-free time before recurrence. Our data point at IMP-1 and MDR1 as indicators for response to therapy, and at IMP-1 as a novel therapeutic target for overcoming multidrug resistance of ovarian cancer. PMID:21618519

  10. Detection of multi-drug resistant Escherichia coli in the urban waterways of Milwaukee, WI

    PubMed Central

    Kappell, Anthony D.; DeNies, Maxwell S.; Ahuja, Neha H.; Ledeboer, Nathan A.; Newton, Ryan J.; Hristova, Krassimira R.

    2015-01-01

    Urban waterways represent a natural reservoir of antibiotic resistance which may provide a source of transferable genetic elements to human commensal bacteria and pathogens. The objective of this study was to evaluate antibiotic resistance of Escherichia coli isolated from the urban waterways of Milwaukee, WI compared to those from Milwaukee sewage and a clinical setting in Milwaukee. Antibiotics covering 10 different families were utilized to determine the phenotypic antibiotic resistance for all 259 E. coli isolates. All obtained isolates were determined to be multi-drug resistant. The E. coli isolates were also screened for the presence of the genetic determinants of resistance including ermB (macrolide resistance), tet(M) (tetracycline resistance), and β-lactamases (blaOXA, blaSHV, and blaPSE). E. coli from urban waterways showed a greater incidence of antibiotic resistance to 8 of 17 antibiotics tested compared to human derived sources. These E. coli isolates also demonstrated a greater incidence of resistance to higher numbers of antibiotics compared to the human derived isolates. The urban waterways demonstrated a greater abundance of isolates with co-occurrence of antibiotic resistance than human derived sources. When screened for five different antibiotic resistance genes conferring macrolide, tetracycline, and β-lactam resistance, clinical E. coli isolates were more likely to harbor ermB and blaOXA than isolates from urban waterway. These results indicate that Milwaukee’s urban waterways may select or allow for a greater incidence of multiple antibiotic resistance organisms and likely harbor a different antibiotic resistance gene pool than clinical sources. The implications of this study are significant to understanding the presence of resistance in urban freshwater environments by supporting the idea that sediment from urban waterways serves as a reservoir of antibiotic resistance. PMID:25972844

  11. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance.

    PubMed

    Pape, Veronika F S; Tóth, Szilárd; Füredi, András; Szebényi, Kornélia; Lovrics, Anna; Szabó, Pál; Wiese, Michael; Szakács, Gergely

    2016-07-19

    There is a constant need for new therapies against multidrug resistant (MDR) cancer. An attractive strategy is to develop chelators that display significant antitumor activity in multidrug resistant cancer cell lines overexpressing the drug efflux pump P-glycoprotein. In this study we used a panel of sensitive and MDR cancer cell lines to evaluate the toxicity of picolinylidene and salicylidene thiosemicarbazone, arylhydrazone, as well as picolinylidene and salicylidene hydrazino-benzothiazole derivatives. Our results confirm the collateral sensitivity of MDR cells to isatin-β-thiosemicarbazones, and identify several chelator scaffolds with a potential to overcome multidrug resistance. Analysis of structure-activity-relationships within the investigated compound library indicates that NNS and NNN donor chelators show superior toxicity as compared to ONS derivatives regardless of the resistance status of the cells. PMID:27161177

  12. Autophagy and Transporter-Based Multi-Drug Resistance

    PubMed Central

    Kumar, Priyank; Zhang, Dong-Mei; Degenhardt, Kurt; Chen, Zhe-Sheng

    2012-01-01

    All the therapeutic strategies for treating cancers aim at killing the cancer cells via apoptosis (programmed cell death type I). Defective apoptosis endow tumor cells with survival. The cell can respond to such defects with autophagy. Autophagy is a cellular process by which cytoplasmic material is either degraded to maintain homeostasis or recycled for energy and nutrients in starvation. A plethora of evidence has shown that the role of autophagy in tumors is complex. A lot of effort is needed to underline the functional status of autophagy in tumor progression and treatment, and elucidate how to tweak autophagy to treat cancer. Furthermore, during the treatment of cancer, the limitation for the cure rate and survival is the phenomenon of multi drug resistance (MDR). The development of MDR is an intricate process that could be regulated by drug transporters, enzymes, anti-apoptotic genes or DNA repair mechanisms. Reports have shown that autophagy has a dual role in MDR. Furthermore, it has been reported that activation of a death pathway may overcome MDR, thus pointing the importance of other death pathways to regulate tumor cell progression and growth. Therefore, in this review we will discuss the role of autophagy in MDR tumors and a possible link amongst these phenomena. PMID:24710490

  13. Multidrug-resistant bacteria in unaccompanied refugee minors arriving in Frankfurt am Main, Germany, October to November 2015.

    PubMed

    Heudorf, Ursel; Krackhardt, Bernhard; Karathana, Maria; Kleinkauf, Niels; Zinn, Christian

    2016-01-01

    Many refugees arriving in Germany originate or have travelled through countries with high prevalence of multidrug-resistant Gram-negative organisms. Therefore, all unaccompanied refugee minors (<18 years-old) arriving in Frankfurt am Main between 12 October and 6 November 2015, were screened for multidrug-resistant Enterobacteriaceae in stool samples. Enterobacteriaceae with extended spectrum beta-lactamases (ESBL) were detected in 42 of 119 (35%) individuals, including nine with additional resistance to fluoroquinolones (8% of total screened), thus exceeding the prevalences in the German population by far. PMID:26838714

  14. Transmission of multidrug-resistant tuberculosis in the USA: a cross-sectional study

    PubMed Central

    Moonan, Patrick K; Teeter, Larry D; Salcedo, Katya; Ghosh, Smita; Ahuja, Shama D; Flood, Jennifer; Graviss, Edward A

    2015-01-01

    Summary Background Multidrug-resistant (MDR) tuberculosis is a potential threat to tuberculosis elimination, but the extent of MDR tuberculosis disease in the USA that is attributable to transmission within the country is unknown. We assessed transmission of MDR tuberculosis and potential contributing factors in the USA. Methods In a cross-sectional study, clinical, demographic, epidemiological, and Mycobacterium tuberculosis genotype data were obtained during routine surveillance of all verified cases of MDR tuberculosis reported from eight states in the USA (California from Jan 1, 2007, to Dec 31, 2009; Texas from Jan 1, 2007, to March 31, 2009; and the states of Colorado, Maryland, Massachusetts, New York, Tennessee, and Washington from Jan 1, 2007 to Dec 31, 2008). In-depth interviews and health-record abstraction were done for all who consented to ascertain potential interpersonal connections. Findings 168 cases of MDR tuberculosis were reported in the eight states during our study period. 92 individuals (55%) consented to in-depth interview. 20 (22%) of these individuals developed MDR tuberculosis as a result of transmission in the USA; a source case was identified for eight of them (9%). 20 individuals (22%) had imported active tuberculosis (ie, culture-confirmed disease within 3 months of entry into the USA). 38 (41%) were deemed to have reactivation of disease, of whom 14 (15%) had a known previous episode of tuberculosis outside the USA. Five individuals (5%) had documented treatment of a previous episode in the USA, and so were deemed to have relapsed. For nine cases (10%), insufficient evidence was available to definitively classify reason for presentation. Interpretation About a fifth of cases of MDR tuberculosis in the USA can be linked to transmission within the country. Many individuals acquire MDR tuberculosis before entry into the USA. MDR tuberculosis needs to be diagnosed rapidly to reduce potential infectious periods, and clinicians should

  15. Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center.

    PubMed

    Hujer, Kristine M; Hujer, Andrea M; Hulten, Edward A; Bajaksouzian, Saralee; Adams, Jennifer M; Donskey, Curtis J; Ecker, David J; Massire, Christian; Eshoo, Mark W; Sampath, Rangarajan; Thomson, Jodi M; Rather, Philip N; Craft, David W; Fishbain, Joel T; Ewell, Allesa J; Jacobs, Michael R; Paterson, David L; Bonomo, Robert A

    2006-12-01

    Military medical facilities treating patients injured in Iraq and Afghanistan have identified a large number of multidrug-resistant (MDR) Acinetobacter baumannii isolates. In order to anticipate the impact of these pathogens on patient care, we analyzed the antibiotic resistance genes responsible for the MDR phenotype in Acinetobacter sp. isolates collected from patients at the Walter Reed Army Medical Center (WRAMC). Susceptibility testing, PCR amplification of the genetic determinants of resistance, and clonality were determined. Seventy-five unique patient isolates were included in this study: 53% were from bloodstream infections, 89% were resistant to at least three classes of antibiotics, and 15% were resistant to all nine antibiotics tested. Thirty-seven percent of the isolates were recovered from patients nosocomially infected or colonized at the WRAMC. Sixteen unique resistance genes or gene families and four mobile genetic elements were detected. In addition, this is the first report of bla(OXA-58)-like and bla(PER)-like genes in the U.S. MDR A. baumannii isolates with at least eight identified resistance determinants were recovered from 49 of the 75 patients. Molecular typing revealed multiple clones, with eight major clonal types being nosocomially acquired and with more than 60% of the isolates being related to three pan-European types. This report gives a "snapshot" of the complex genetic background responsible for antimicrobial resistance in Acinetobacter spp. from the WRAMC. Identifying genes associated with the MDR phenotype and defining patterns of transmission serve as a starting point for devising strategies to limit the clinical impact of these serious infections. PMID:17000742

  16. Anticancer effects of the organosilicon multidrug resistance modulator SILA 421.

    PubMed

    Olszewski, Ulrike; Zeillinger, Robert; Kars, Meltem Demirel; Zalatnai, Attila; Molnar, Jozsef; Hamilton, Gerhard

    2012-07-01

    1,3-dimethyl-1,3-bis(4-fluorophenyl)-1,3-bis{3-[1(4-butylpiperazinyl)]-propyl}-disiloxan-tetrahydrochlorid (SILA 421) is a compound that was developed as modulator of the ABC cassette transporter P-glycoprotein. Furthermore, it exerted antimicrobial toxicity, vascular effects, downregulation of chaperone induction and plasmid curing in bacterial cells. Here, this drug was found to possess cytotoxic activity against a panel of human cancer cell lines that do not overexpress P-gp, with 50% inhibitory concentrations ranging between 1.75±0.38 μM for GLC14 small cell lung cancer and 34.00±4.75 μM for PC-3 prostate cancer cells. HL-60 leukemia and MDA-MB-435 breast cancer cells exhibited cell cycle arrest and apoptotic cell death in response to SILA 421. Assessment of global gene expression of SILA 421-treated HL-60 cells was employed to identify cellular pathways affected by the compound and revealed disturbance of DNA replication, transcription and production of apparently misfolded proteins. Endoplasmatic reticulum stress and downregulation of cell cycle, cellular repair mechanisms and growth factor-related signaling cascades eventually resulted in induction of apoptosis in this cell line. In addition to the well established P-gp inhibitory effect of SILA compounds, reversal of resistance to taxanes, which had been reported for SILA 421 and the related molecule SILA 409, may be linked to downregulation of gene expression of kinesins. Interference with DNA replication and transcription seems to be the common denominator of antimicrobial activity and plasmid curing, as well as anticancer toxicity in human cell lines. Thus, in consideration of the full range of putative cellular targets found in the present work, the application of these SILA compounds for treatment of tumors should be further evaluated. PMID:22263791

  17. Amikacin Concentrations Predictive of Ototoxicity in Multidrug-Resistant Tuberculosis Patients

    PubMed Central

    Modongo, Chawangwa; Pasipanodya, Jotam G.; Zetola, Nicola M.; Williams, Scott M.; Sirugo, Giorgio

    2015-01-01

    Aminoglycosides, such as amikacin, are used to treat multidrug-resistant tuberculosis. However, ototoxicity is a common problem and is monitored using peak and trough amikacin concentrations based on World Health Organization recommendations. Our objective was to identify clinical factors predictive of ototoxicity using an agnostic machine learning method. We used classification and regression tree (CART) analyses to identify clinical factors, including amikacin concentration thresholds that predicted audiometry-confirmed ototoxicity among 28 multidrug-resistant pulmonary tuberculosis patients in Botswana. Amikacin concentrations were measured for all patients. The quantitative relationship between predictive factors and the probability of ototoxicity were then identified using probit analyses. The primary predictors of ototoxicity on CART analyses were cumulative days of therapy, followed by cumulative area under the concentration-time curve (AUC), which improved on the primary predictor by 87%. The area under the receiver operating curve was 0.97 on the test set. Peak and trough were not predictors in any tree. When algorithms were forced to pick peak and trough as primary predictors, the area under the receiver operating curve fell to 0.46. Probit analysis revealed that the probability of ototoxicity increased sharply starting after 6 months of therapy to near maximum at 9 months. A 10% probability of ototoxicity occurred with a threshold cumulative AUC of 87,232 days · mg · h/liter, while that of 20% occurred at 120,000 days · mg · h/liter. Thus, cumulative amikacin AUC and duration of therapy, and not peak and trough concentrations, should be used as the primary decision-making parameters to minimize the likelihood of ototoxicity in multidrug-resistant tuberculosis. PMID:26248372

  18. TPGS/Phospholipids Mixed Micelles for Delivery of Icariside II to Multidrug-Resistant Breast Cancer.

    PubMed

    Song, Jie; Huang, Houcai; Xia, Zhi; Wei, Yingjie; Yao, Nan; Zhang, Li; Yan, Hongmei; Jia, Xiaobin; Zhang, Zhenhai

    2016-09-01

    The biggest challenge for the treatment of multidrug resistant cancer is to deliver a high concentration of anticancer drugs to cancer cells. Icariside II is a flavonoid from Epimedium koreanum Nakai with remarkable anticancer properties, but poor solubility and significant efflux from cancer cells limited its clinical use. In our previous study, a self-assembled mixture of micelles (TPGS-Icariside II-phospholipid complex) was successfully constructed, which could substantially increase the solubility of Icariside II and inhibit the efflux on Caco-2 cells. In this study, we evaluate the anticancer effect of the mixed micelles encapsulating Icariside II (Icar-MC) on MCF-7/ADR, a multidrug-resistant breast cancer cell line. The cellular uptake of the micelles was confirmed by fluorescent coumarin-6-loaded micelles. The IC50 of Icar-MC in MCF-7/ADR was 2-fold less than the free drug. The in vitro study showed Icar-MC induced more apoptosis and lactate dehydrogenase release. Intravenous injection of Icar-MC into nude mice bearing MCF-7/ADR xenograft resulted in a better antitumor efficacy compared with the administration of free drug, without causing significant body weight changes in mice. The antitumor effect was further verified by magnetic resonance imaging and immunohistochemical assays for Ki-67, a proliferative indicator. Moreover, Icar-MC treatment also elevated Bax/Bcl-2 ratio and the expressions of cleaved caspase-3, -8, -9 and AIFM1 in tumors. This study suggests that phospholipid/TPGS mixed micelles might be a suitable drug delivery system for Icariside II to treat multidrug resistant breast cancer. PMID:26293804

  19. Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate.

    PubMed

    Homolya, László; Váradi, András; Sarkadi, Balázs

    2003-01-01

    Many endogenous or xenobiotic lipophilic substances are eliminated from the cells by the sequence of oxidation, conjugation to an anionic group (glutathione, glucuronate or sulfate) and transport across the plasma membrane into the extracellular space. The latter step is mediated by integral membrane glycoproteins belonging to the superfamily of ATP-Binding Cassette (ABC) transporters. A subfamily, referred as ABCC, includes the famous/infamous cystic fibrosis transmembrane regulator (CFTR), the sulfonylurea receptors (SUR 1 and 2), and the multidrug resistance-associated proteins (MRPs). The name of the MRPs refers to their potential role in clinical multidrug resistance, a phenomenon that hinders the effective chemotherapy of tumors. The MRPs that have been functionally characterized so far share the property of ATP-dependent export pumps for conjugates with glutathione (GSH), glucuronate or sulfate. MRP1 and MRP2 are also mediating the cotransport of unconjugated amphiphilic compounds together with free GSH. MRP3 preferentially transports glucuronides but not glutathione S-conjugates or free GSH. MRP1 and MRP2 also contribute to the control of the intracellular glutathione disulfide (GSSG) level. Although these proteins are low affinity GSSG transporters, they can play essential role in response to oxidative stress when the activity of GSSG reductase becomes rate limiting. The human MRP4, MRP5 and MRP6 have only partially been characterized. However, it has been revealed that MRP4 can function as an efflux pump for cyclic nucleotides and nucleoside analogues, used as anti-HIV drugs. MRP5 also transports GSH conjugates, nucleoside analogues, and possibly heavy metal complexes. Transport of glutathione S-conjugates mediated by MRP6, the mutation of which causes pseudoxantoma elasticum, has recently been shown. In summary, numerous members of the multidrug resistance-associated protein family serve as export pumps that prevent the accumulation of anionic conjugates

  20. Role of serum interleukin-6 in deciding therapy for multidrug resistant oral lichen planus

    PubMed Central

    Marwah, Akanksha; Kaushik, Smita; Garg, Vijay K.; Gupta, Sunita

    2015-01-01

    Background Oral lichen planus (OLP) is a T cell mediated immune response. T cells locally present in the involved tissues release cytokines like interleukin-6 (IL-6), which contributes to pathogenesis of OLP. Also IL-6 has been associated with multidrug resistance protein (MRP) expression by keratinocytes. Correspondingly, upregulation of MRP was found in OLP. We conducted this study to evaluate the effects of various drugs on serum IL-6 in OLP; and correlation of these effects with the nature of clinical response and resistance pattern seen in OLP lesions with various therapeutic modalities. Thus we evaluated the role of serum IL-6 in deciding therapy for multidrug resistant OLP. Material and Methods Serum IL-6 was evaluated in 42 erosive OLP (EOLP) patients and 10 normal mucosa and 10 oral squamous cell carcinoma cases using ELISA technique. OLP patients were randomly divided into 3 groups of 14 patients each and were subjected to Pimecrolimus local application, oral Mycophenolate Mofetil (MMF) and Methotrexate (MTX) alongwith Pimecrolimus local application. IL-6 levels were evaluated before and after treatment. Results Serum IL-6 levels were raised above 3pg/ml in 26.19% erosive OLP (EOLP) cases (mean- 3.72±8.14). EOLP (5%) cases with IL-6 levels above 5pg/ml were resistant in MTX group. However significant decrease in serum IL-6 corresponding with the clinical resolution was seen in MMF group. Conclusions Significantly raised IL-6 levels in EOLP reflect the chronic inflammatory nature of the disease. As serum IL-6 levels significantly decreased in MMF group, correspondingly no resistance to treatment was noted. However with MTX there was no significant decrease in IL-6 and resistance to treatment was noted in some, especially plaque type lesions. Thus IL-6 can be a possible biomarker in deciding the best possible therapy for treatment resistant OLP. Key words:Lichen planus, biological markers, cytokines, enzyme-linked immunosorbent assay, immunosuppressive

  1. Multidrug-Resistant Escherichia coli and Klebsiella pneumoniae Isolated From Patients in Kashan, Iran

    PubMed Central

    Moini, Atieh Sadat; Soltani, Babak; Taghavi Ardakani, Abbas; Moravveji, Alireza; Erami, Mahzad; Haji Rezaei, Mostafa; Namazi, Mansoor

    2015-01-01

    Background: Escherichia coli and Klebsiella pneumoniae are common human pathogens that cause a wide spectrum of infections. Antimicrobial resistance is a basic obstacle in the management of these infections which has different patterns in various regions. Objectives: In this study, the antibiotic resistance patterns and risk factors for multidrug-resistant (MDR) E. coli and K. pneumoniae were determined. Patients and Methods: In this cross-sectional study, a total of 250 isolates (134 E. coli and 116 K. pneumoniae) were collected and antimicrobial resistances to ampicillin, amoxicillin-clavulanic acid, amikacin, gentamycin, ceftriaxone, ceftazidime, ciprofloxacin and imipenem were evaluated by disc diffusion method and confirmed by E-test. Moreover, risk factors for MDR E. coli and K. pneumoniae were also detected. Results: The mean ages of the culture-positive cases of E. coli and K. pneumoniae were 33.39 ± 24.42 and 36.54 ± 24.66 years, respectively (P = 0.31); 137 (54.8%) cases were male and 113 (45.2%) were female (P = 0.53). Nineteen (14.2%) isolates of E. coli and 12 (10.3%) isolates of K. pneumoniae were sensitive to all the evaluated antibiotics. The prevalence of MDR E. coli and MDR K. pneumoniae was 50% and 46.6%, respectively (P = 0.59). The highest resistance for both strains was to ampicillin and no imipenem resistance was seen. The risk factors for MDR E. coli were admission history during the recent three months (P = 0.043) and antibiotic use in the previous month (P = 0.03); for MDR K. pneumoniae, they were admission in the pediatric ward (P = 0.016), surgical ward (P = 0.019), or gynecology ward (P = 0.12), admission duration of > seven days, and antibiotic use during the past month (P = 0.04). Conclusions: The prevalence of multidrug resistance was high compared with developed countries, and history of admission, antibiotic use, admission duration and admission wards were the risk factors for multidrug resistance. PMID:26587220

  2. Probenecid-resistant J774 cell expression of enhanced organic anion transport by a mechanism distinct from multidrug resistance.

    PubMed

    Cao, C; Steinberg, T H; Neu, H C; Cohen, D; Horwitz, S B; Hickman, S; Silverstein, S C

    1993-08-01

    Macrophages possess organic anion transporters that carry membrane-impermeant fluorescent dyes, such as lucifer yellow (LY) and carboxy-fluorescein, from the cytoplasm into endosomes and out of the cells. Probenecid, an organic anion transport inhibitor, blocks these processes. Prolonged incubation of J774 cells in medium containing 2.5 mM probenecid eventually kills most of these cells. To identify J774 variants that express increased organic anion transport activity, we selected probenecid-resistant (PBR) J774 cells by growing them in medium containing increasing concentrations of probenecid. When PBR and unselected J774 cells were loaded with LY by ATP4- permeabilization, the amount of LY accumulated by the PBR cells was about half that in the unselected cells. This difference was abolished by adding 10 mM probenecid to the medium in which the cells were loaded, suggesting that the diminished LY accumulation in PBR cells was due to enhanced LY secretion and that the PBR cells expressed increased organic anion transport activity. Direct comparison of LY efflux from J774 and PBR J774 cells showed a faster initial rate of secretion of LY from PBR J774 cells than from unselected J774 cells. To determine whether LY efflux is mediated by P-glycoprotein, we compared LY efflux in unselected J774 cells, PBR J774 cells, and multidrug-resistant J774 cells (J7.C1). LY efflux from J7.C1 cells was not sensitive to verapamil, which inhibits multidrug-resistance transporters, and reverses the multidrug-resistant phenotype of J7.C1 cells. The rates of LY efflux from unselected J774 and J7.C1 cells were virtually identical.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7909709

  3. Differences in the motility phenotype of multidrug-resistant Salmonella enterica serovar Typhimurium exposed to various antibiotics

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the most prevalent foodborne-associated bacteria in humans and livestock, and over 35 per cent of these isolates are resistant to three or more antibiotics. This is a concern as multidrug-resistant (MDR) Salmonella has been associat...

  4. Draft Genome Sequence of a Multidrug-Resistant Klebsiella pneumoniae Strain Isolated from King Abdullah Medical City, Makkah, Saudi Arabia

    PubMed Central

    Algowaihi, Rayd; Ashgar, Sami; Sirag, Bashir; Shalam, Sheerin; Nassir, Anmar

    2016-01-01

    Multidrug-resistant (MDR) Gram-negative infections represent a growing problem and a serious global threat. Carbapenem-resistant Klebsiella pneumoniae is perhaps cause the most difficult infection to treat and is associated with increased morbidity and mortality. Here, we report the draft genome sequence of an MDR K. pneumoniae strain isolated from Makkah, Saudi Arabia. PMID:27198017

  5. Tetracycline can induce the expression of invasion factors in multidrug-resistant Salmonella during early-log phase

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The prevalence of multidrug-resistant (MDR) Salmonella continues to be an important health and safety concern in both humans and animals worldwide. Because the response of drug resistant bacteria exposed to antibiotics can affect a variety of cellular processes, such as motility, attachment, and in...

  6. Place of Colistin-Rifampicin Association in the Treatment of Multidrug-Resistant Acinetobacter Baumannii Meningitis: A Case Study

    PubMed Central

    Souhail, Dahraoui; Bouchra, Belefquih; Belarj, Badia; Laila, Rar; Mohammed, Frikh; Nassirou, Oumarou Mamane; Azeddine, Ibrahimi; Haimeur, Charki; Lemnouer, Abdelhay; Elouennass, Mostafa

    2016-01-01

    Treatment of Acinetobacter baumannii meningitis is an important challenge due to the accumulation of resistance of this bacteria and low meningeal diffusion of several antimicrobial requiring use of an antimicrobial effective combination to eradicate these species. We report a case of Acinetobacter baumannii multidrug-resistant nosocomial meningitis which was successfully treated with intravenous and intrathecal colistin associated with rifampicin. PMID:27064923

  7. Population genetics of multi-drug resistant (MDR) IncA/C plasmid in Salmonella enterica isolated from animals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Food animals harboring Multi-Drug Resistant (MDR) Salmonella enterica are a potential source for acquisition of zoonotic pathogens. Plasmids (small, self-replicating, extra-chromosomal DNA) are often associated with antimicrobial resistance and plasmids carrying MDR genes have been found to be a maj...

  8. Draft Genome Sequence of a Multidrug-Resistant Klebsiella quasipneumoniae subsp. similipneumoniae Isolate from a Clinical Source

    PubMed Central

    Morris, Andrew R.; Krapp, Fiorella; Henry, Christopher S.; Tyo, Keith E.; Hauser, Alan R.

    2016-01-01

    We report here the draft genome sequence of a multidrug-resistant clinical isolate of Klebsiella quasipneumoniae subsp. similipneumoniae, KP_Z4175. This strain, isolated as part of a hospital infection-control screening program, is resistant to multiple β-lactam antibiotics, aminoglycosides, and trimethoprim-sulfamethoxazole. PMID:27231362

  9. Effect of different agents onto multidrug resistant cells revealed by fluorescence correlation spectroscopy

    NASA Astrophysics Data System (ADS)

    Boutin, C.; Roche, Y.; Jaffiol, R.; Millot, J.-M.; Millot, C.; Plain, J.; Deturche, R.; Jeannesson, P.; Manfait, M.; Royer, P.

    Fluorescence correlation spectroscopy (FCS), which is a sensitive and non invasive technique, has been used to characterize the plasma membrane fluidity and heterogeneity of multidrug resistant living cells. At the single cell level, the effects of different membrane agents present in the extra-cellular medium have been analyzed. Firstly, we reveal a modification of plasma membrane microviscosity according to the addition of a fluidity modulator, benzyl alcohol. In the other hand, revertant such as verapamil and cyclosporin-A appears to act more specifically on the slow diffusion sites as microdomains.

  10. Spread of multidrug-resistant Pseudomonas aeruginosa clones in a university hospital.

    PubMed

    Koutsogiannou, Maria; Drougka, Eleanna; Liakopoulos, Apostolos; Jelastopulu, Eleni; Petinaki, Efthimia; Anastassiou, Evangelos D; Spiliopoulou, Iris; Christofidou, Myrto

    2013-02-01

    An outbreak of multidrug-resistant Pseudomonas aeruginosa (MDRPA) infections in a university hospital is described. Phenotypic and genotypic analysis of 240 isolates revealed that 152 patients, mainly in the intensive care unit (ICU), were colonized or infected with MDRPA, the majority with O11. All metallo-β-lactamase (MBL)-positive isolates carried the bla(VIM-2) or bla(VIM-1) gene. One or more type III secretion system toxin genes were detected in most isolates. Five dominant pulsed-field gel electrophoresis (PFGE) types were characterized, associated with ST235, ST111, ST253, ST309, and ST639. PMID:23241381

  11. [Monotherapy vs. combined therapy in the treatment of multi-drug resistance gramnegative bacteria].

    PubMed

    Martínez-Sagasti, F; González-Gallego, M A; Moneo-González, A

    2016-09-01

    The increasing number of multidrug resistant gram negative bacteria, particularly in patients with risk factors, but in those who suffer community infections as well, is doing more and more difficult to choose the appropriate treatment. The most challenging cases are due to the production of extended-spectrum-β-lactamases (ESBL) and carbapenemases. This mini-review will discuss the adequacy of administering carbapenems when suspecting infections due to ESBL that could be modified after knowing the MIC of the isolated bacteria and the combined therapy in cases of carbapenemases, being particularly important to include a carbapenem and/or colistine at high dosages in this combination. PMID:27608313

  12. The Race Is On To Shorten the Turnaround Time for Diagnosis of Multidrug-Resistant Tuberculosis

    PubMed Central

    Somoskovi, Akos

    2015-01-01

    To realize the most benefit from multidrug-resistant tuberculosis (MDR-TB) screening, all nucleic acid amplification test (NAAT)-positive respiratory specimens should be universally tested. Once an MDR-TB diagnosis is established, additional testing is warranted to provide details about the detected mutations. The lab-on-chip technology described by A. M. Cabibbe et al. (J Clin Microbiol 53:3876–3880, 2015, http://dx.doi.org/10.1128/JCM.01824-15) potentially provides this much needed information. PMID:26378276

  13. Genome sequencing and annotation of multidrug resistant Mycobacterium tuberculosis (MDR-TB) PR10 strain

    PubMed Central

    Halim, Mohd Zakihalani A.; Jaafar, Mohammad Maaruf; Teh, Lay Kek; Ismail, Mohamad Izwan; Lee, Lian Shien; Ngeow, Yun Fong; Nor, Norazmi Mohd; Zainuddin, Zainul Fadziruddin; Tang, Thean Hock; Najimudin, Mohd Nazalan Mohd; Salleh, Mohd Zaki

    2016-01-01

    Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10) isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968. PMID:26981419

  14. The multidrug resistance (mdr1) gene product functions as an ATP channel.

    PubMed Central

    Abraham, E H; Prat, A G; Gerweck, L; Seneveratne, T; Arceci, R J; Kramer, R; Guidotti, G; Cantiello, H F

    1993-01-01

    The multidrug resistance (mdr1) gene product, P-glycoprotein, is responsible for the ATP-dependent extrusion of a variety of compounds, including chemotherapeutic drugs, from cells. The data presented here show that cells with increased levels of the P-glycoprotein release ATP to the medium in proportion to the concentration of the protein in their plasma membrane. Furthermore, measurements of whole-cell and single-channel currents with patch-clamp electrodes indicate that the P-glycoprotein serves as an ATP-conducting channel in the plasma membrane. These findings suggest an unusual role for the P-glycoprotein. PMID:7678345

  15. Diterpene Constituents of Euphorbia exigua L. and Multidrug Resistance Reversing Activity of the Isolated Diterpenes.

    PubMed

    Rédei, Dóra; Boros, Klára; Forgo, Peter; Molnár, Joseph; Kele, Zoltán; Pálinkó, István; Pinke, Gyula; Hohmann, Judit

    2015-08-01

    Phytochemical investigation of the MeOH extract obtained from the aerial parts of the annual weed Euphorbia exigua L. resulted in the isolation of two novel (1, 2) and one known (3) jatrophane diterpenes. Their structures were established by extensive 1D- and 2D-NMR spectroscopy and HR-ESI-MS. The isolated compounds were evaluated for multidrug resistance (MDR) reversing activity on human MDR gene-transfected L5178 mouse lymphoma cells; and all three compounds were found to modulate the intracellular drug accumulation. PMID:26265573

  16. Management of emerging multidrug-resistant tuberculosis in a low-prevalence setting.

    PubMed

    Catho, G; Couraud, S; Grard, S; Bouaziz, A; Sénéchal, A; Valour, F; Perpoint, T; Braun, E; Biron, F; Ferry, T; Chidiac, C; Freymond, N; Perrot, E; Souquet, P-J; Maury, J-M; Tronc, F; Veziris, N; Lina, G; Dumitrescu, O; Ader, F

    2015-05-01

    Multidrug-resistant (MDR) tuberculosis (TB) is an emerging concern in communities with a low TB prevalence and a high standard of public health. Twenty-three consecutive adult MDR TB patients who were treated at our institution between 2007 and 2013 were reviewed for demographic characteristics and anti-TB treatment management, which included surgical procedures and long-term patient follow-up. This report of our experience emphasizes the need for an individualized approach as MDR TB brings mycobacterial disease management to a higher level of expertise, and for a balance to be found between international current guidelines and patient-tailored treatment strategies. PMID:25708551

  17. First Two Cases of Fungal Infections Associated with Multi-drug Resistant Yeast, Fereydounia khargensis.

    PubMed

    Tap, Ratna Mohd; Ramli, Nur Yasmin; Sabaratnam, Parameswari; Hashim, Rohaidah; Bakri, Ahmed Rafezzan Ahmed; Bee, Lim Bee; Ginsapu, Stephanie Jane; Ahmad, Rahimah; Razak, Mohd Fuat Abd; Ahmad, Norazah

    2016-08-01

    The number of new fungal pathogens is increasing due to growing population of immunocompromised patients and advanced identification techniques. Fereydounia khargensis is a yeast and was first described in 2014 from environmental samples. As far as we know, this is the first report of human infections associated with F. khargensis. The yeasts were isolated from blood of a HIV-positive patient and pleural fluid of chronic renal failure patient. Amplification and sequencing of the internal transcribed spacer and the large subunit regions confirmed the identity of the isolates. Both isolates showed multi-drug resistance to antifungal agents tested. PMID:27010640

  18. Genome sequencing and annotation of multidrug resistant Mycobacterium tuberculosis (MDR-TB) PR10 strain.

    PubMed

    Halim, Mohd Zakihalani A; Jaafar, Mohammad Maaruf; Teh, Lay Kek; Ismail, Mohamad Izwan; Lee, Lian Shien; Ngeow, Yun Fong; Nor, Norazmi Mohd; Zainuddin, Zainul Fadziruddin; Tang, Thean Hock; Najimudin, Mohd Nazalan Mohd; Salleh, Mohd Zaki

    2016-03-01

    Here, we report the draft genome sequence and annotation of a multidrug resistant Mycobacterium tuberculosis strain PR10 (MDR-TB PR10) isolated from a patient diagnosed with tuberculosis. The size of the draft genome MDR-TB PR10 is 4.34 Mbp with 65.6% of G + C content and consists of 4637 predicted genes. The determinants were categorized by RAST into 400 subsystems with 4286 coding sequences and 50 RNAs. The whole genome shotgun project has been deposited at DDBJ/EMBL/GenBank under the accession number CP010968. PMID:26981419

  19. [Molecular physiology of receptor mediated endocytosis and its role in overcoming multidrug resistance].

    PubMed

    Severin, E S; Posypanova, G A

    2011-06-01

    Receptor-mediated endocytosis plays important role in the selective uptake of proteins at the plasma membrane of eukaryotic cells. Endocytosis regulates many processes of cell signalling by controlling the number of functional receptors on the cell surface. The article reviews the mechanism of clathrin-dependent endocytosis and the possibility of using this phenomenon for the targeted delivery of drugs. Use of certain proteins as targeting component of drug delivery systems can significantly improve the selectivity of this drug, as well as to overcome the multidrug resistance of cells resulting from the activity of the ABC-transporters. PMID:21874867

  20. Two pimarane diterpenoids from Ephemerantha lonchophylla and their evaluation as modulators of the multidrug resistance phenotype.

    PubMed

    Na, G X; Wang, T S; Yin, L; Pan, Y; Guo, Y L; LeBlanc, G A; Reinecke, M G; Watson, W H; Krawiec, M

    1998-01-01

    Two new pimarane diterpenoids, lonchophylloids A (1) and B (2), were isolated from the stems of Ephemerantha lonchophylla. The structures of 1 and 2 were established predominantly through the application of extensive 1H-and 13C-NMR, 1D- and 2D-homonuclear and heteronuclear correlation NMR experiments, and X-ray diffraction methods. Consistent with structure--activity predictions, both compounds were capable of sensitizing cells that expressed the multidrug resistance phenotype to the toxicity of the anticancer drug doxorubicin. PMID:9461658

  1. Identification of selenocompounds with promising properties to reverse cancer multidrug resistance.

    PubMed

    Domínguez-Álvarez, Enrique; Gajdács, Márió; Spengler, Gabriella; Palop, Juan Antonio; Marć, Małgorzata Anna; Kieć-Kononowicz, Katarzyna; Amaral, Leonard; Molnár, Joseph; Jacob, Claus; Handzlik, Jadwiga; Sanmartín, Carmen

    2016-06-15

    In previous studies, 56 novel selenoesters and one cyclic selenoanhydride with chemopreventive, antiproliferative and cytotoxic activity were described. Herein, the selenoanhydride and selected selenoesters were evaluated for their ability to reverse the cancer multidrug resistance (MDR) using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. Results showed that the selenoanhydride (1) and the selenoesters with ketone terminal fragments (9-11) exerted (1.7-3.6)-fold stronger efflux pump inhibitory action than the reference verapamil. In addition, those four derivatives triggered apoptotic events in more than 80% of the examined MDR mouse cells. PMID:27156771

  2. Multidrug-resistant Gram-negative bacteria in solid organ transplant recipients with bacteremias.

    PubMed

    Wan, Q Q; Ye, Q F; Yuan, H

    2015-03-01

    Bloodstream infections (BSIs) remain as life-threatening complications and are associated with significant morbidity and mortality among solid organ transplant (SOT) recipients. Multidrug-resistant (MDR) Gram-negative bacteria can cause serious bacteremias in these recipients. Reviews have aimed to investigate MDR Gram-negative bacteremias; however, they were lacking in SOT recipients in the past. To better understand the characteristics of bacteremias due to MDR Gram-negative bacteria, optimize preventive and therapeutic strategies, and improve the outcomes of SOT recipients, this review summarize the epidemiology, clinical and laboratory characteristics, and explores the mechanisms, prevention, and treatment of MDR Gram-negative bacteria. PMID:25388855

  3. Multidrug-resistant tuberculosis outbreak on an HIV ward--Madrid, Spain, 1991-1995.

    PubMed

    1996-04-26

    Beginning in 1990, outbreaks of multidrug-resistant tuberculosis (MDR-TB) have been reported in hospitals and prisons in the eastern United States (1). During June 1991-January 1995, MDR-TB was diagnosed in 47 patients and one health-care worker at a 120-bed, infectious disease referral hospital in urban Madrid; on April 19, 1995, the Spanish Field Epidemiology Training Program was asked to investigate this outbreak. This report summarizes the findings of this investigation, which suggested that nosocomial transmission of MDR-TB occurred on a hospital ward for patients with human immunodeficiency virus (HIV) infection. PMID:8602134

  4. Partial synthesis and biological evaluation of bisbenzylisoquinoline alkaloids derivatives: potential modulators of multidrug resistance in cancer.

    PubMed

    He, Ping; Sun, Hua; Jian, Xi-Xian; Chen, Qiao-Hong; Chen, Dong-Lin; Liu, Geng-Tao; Wang, Feng-Peng

    2012-01-01

    A series of new bisbenzylisoquinoline alkaloids was partially synthesized from tetrandrine and fangchinoline and evaluated for their ability to reverse P-glycoprotein-mediated multidrug resistance (MDR) in cancer cells. All the test compounds increased the intracellular accumulation rate of rhodamine 123 in MDR cells (Bel7402 and HCT8), and most exhibited more potent MDR-reversing activity relative to the reference compound verapamil. Compounds 8, 10, 13, and 14 enhanced intracellular accumulation of doxorubicin in Bel7402 and HCT8 cells. PMID:22587798

  5. Multidrug-Resistant Pseudomonas aeruginosa Strain That Caused an Outbreak in a Neurosurgery Ward and Its aac(6′)-Iae Gene Cassette Encoding a Novel Aminoglycoside Acetyltransferase

    PubMed Central

    Sekiguchi, Jun-ichiro; Asagi, Tsukasa; Miyoshi-Akiyama, Tohru; Fujino, Tomoko; Kobayashi, Intetsu; Morita, Koji; Kikuchi, Yoshihiro; Kuratsuji, Tadatoshi; Kirikae, Teruo

    2005-01-01

    We characterized multidrug-resistant Pseudomonas aeruginosa strains isolated from patients involved in an outbreak of catheter-associated urinary tract infections that occurred in a neurosurgery ward of a hospital in Sendai, Japan. Pulsed-field gel electrophoresis of SpeI-, XbaI-, or HpaI-digested genomic DNAs from the isolates revealed that clonal expansion of a P. aeruginosa strain designated IMCJ2.S1 had occurred in the ward. This strain possessed broad-spectrum resistance to aminoglycosides, β-lactams, fluoroquinolones, tetracyclines, sulfonamides, and chlorhexidine. Strain IMCJ2.S1 showed a level of resistance to some kinds of disinfectants similar to that of a control strain of P. aeruginosa, ATCC 27853. IMCJ2.S1 contained a novel class 1 integron, In113, in the chromosome but not on a plasmid. In113 contains an array of three gene cassettes of blaIMP-1, a novel aminoglycoside resistance gene, and the aadA1 gene. The aminoglycoside resistance gene, designated aac(6′)-Iae, encoded a 183-amino-acid protein that shared 57.1% identity with AAC(6′)-Iq. Recombinant AAC(6′)-Iae protein showed aminoglycoside 6′-N-acetyltransferase activity by thin-layer chromatography. Escherichia coli expressing exogenous aac(6′)-Iae showed resistance to amikacin, dibekacin, isepamicin, kanamycin, netilmicin, sisomicin, and tobramycin but not to arbekacin, gentamicins, or streptomycin. Alterations of gyrA and parC at the amino acid sequence level were detected in IMCJ2.S1, suggesting that such mutations confer the resistance to fluoroquinolones observed for this strain. These results indicate that P. aeruginosa IMCJ2.S1 has developed multidrug resistance by acquiring resistance determinants, including a novel member of the aac(6′)-I family and mutations in drug resistance genes. PMID:16127047

  6. Long-term molecular surveillance of multidrug-resistant tuberculosis in Spain.

    PubMed

    Gavín, Patricia; Iglesias, María José; Jiménez, María Soledad; Rodríguez-Valín, Elena; Ibarz, Daniel; Lezcano, María Antonia; Revillo, María José; Martín, Carlos; Samper, Sofía

    2012-06-01

    The data presented here span 11 years (1998-2008) of monitoring of multidrug-resistant tuberculosis (MDR-TB) clustering through molecular typing techniques in Spain. The molecular and epidemiological data of 480 multidrug-resistant Mycobacterium tuberculosis complex isolates were analyzed. Thirty-one clusters involving 157 (32.7%) patients were identified. The proportion of immigrants increased substantially over the study period reaching 65% in 2008; however, the clustering rate remained stable indicating that local transmission was little influenced by imported MDR-TB. The three major clusters respond to the persistence of two autochthonous strains throughout the study period and an extensively drug-resistant (XDR) Mycobacterium bovis outbreak with only two cases was reported since 2002. Molecular and epidemiological evidence for the importation of new strains and their spread within the community was found. Immigrant-only clusters most often grouped patients infected abroad with strains belonging to rare spoligotypes. Conversely, widespread spoligotypes of the Latin-American and Mediterranean (LAM) and Haarlem families were responsible for the majority of the MDR-TB local transmission. The demonstration of clusters spanning several Spanish regions that have been ongoing throughout the study period makes it advisable to maintain a continuous molecular surveillance in order to monitor the spread of MDR-TB. PMID:21669301

  7. Non-cytotoxic nanomaterials enhance antimicrobial activities of cefmetazole against multidrug-resistant Neisseria gonorrhoeae.

    PubMed

    Li, Lan-Hui; Yen, Muh-Yong; Ho, Chao-Chi; Wu, Ping; Wang, Chien-Chun; Maurya, Pawan Kumar; Chen, Pai-Shan; Chen, Wei; Hsieh, Wan-Yu; Chen, Huei-Wen

    2013-01-01

    The emergence and spread of antibiotic-resistant Neisseria gonorrhoeae has led to difficulties in treating patients, and novel strategies to prevent and treat this infection are urgently needed. Here, we examined 21 different nanomaterials for their potential activity against N. gonorrhoeae (ATCC 49226). Silver nanoparticles (Ag NPs, 120 nm) showed the greatest potency for reducing N. gonorrhoeae colony formation (MIC: 12.5 µg/ml) and possessed the dominant influence on the antibacterial activity with their properties of the nanoparticles within a concentration range that did not induce cytotoxicity in human fibroblasts or epithelial cells. Electron microscopy revealed that the Ag NPs significantly reduced bacterial cell membrane integrity. Furthermore, the use of clinical isolates of multidrug-resistant N. gonorrhoeae showed that combined treatment with 120 nm Ag NPs and cefmetazole produced additive effects. This is the first report to screen the effectiveness of nanomaterials against N. gonorrhoeae, and our results indicate that 120 nm Ag NPs deliver low levels of toxicity to human epithelial cells and could be used as an adjuvant with antibiotic therapy, either for topical use or as a coating for biomaterials, to prevent or treat multidrug-resistant N. gonorrhoeae. PMID:23705013

  8. Genetic diversity of multidrug resistant Staphylococcus aureus isolated from clinical and non clinical samples in Egypt.

    PubMed

    Bendary, M M; Solyman, S M; Azab, M M; Mahmoud, N F; Hanora, A M

    2016-01-01

    In recent years, the increasing incidence of diseases caused by Staphylococcus aureus (S. aureus) has been noted in the university hospitals of El-Sharkia and Assuit governorates - Egypt. Therefore, we studied the genetic relatedness of multidrug resistant S. aureus isolates from different sources in the above mentioned governorates. One hundred and fifty six S. aureus isolates were divided into 5 different groups, 1 non clinical isolates from different food products and 4 different clinical isolates of human and animal sources in the 2 different governorates. Epidemiological characteristics of 156 S. aureus isolates were determined by phenotypic methods including quantitative antibiogram typing and biofilm production. Genetic typing of 35 multidrug resistant (MDR) isolates (7 from each group) based on 16S rRNA gene sequence, virulence and antimicrobial resistance gene profiles was done. The genetic relatedness of the highest virulent strain from each group was detected based on different single locus sequence typing and multi-locus sequence typing (MLST). S. aureus strains isolated from different sources and geographical areas showed high diversity. The genetic typing revealed different sequence types and different sequences of coa and spa genes. S. aureus isolates were found highly diverse in Egypt. PMID:27609475

  9. Mixed Micelles of Doxorubicin Overcome Multidrug Resistance by Inhibiting the Expression of P-Glycoprotein.

    PubMed

    Jin, Yan; Zhang, Zhijie; Zhao, Tie; Liu, Xiaodong; Jian, Lingyan

    2015-08-01

    With the goal of overcoming multidrug resistance, DSPE-PEG (polyethylene glycol 2000 grafted with distearoyl phosphatidylethanolamine) and TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) were combined, each with a different inhibiting mechanism for P-glycoprotein (P-gp) expression, to create mixed micelles with the purpose of encapsulating the water-soluble drug, doxorubicin (Dox). As the molar ratio of Dox/DSPE-PEG/TPGS was 1:1:0.2, the encapsulation efficiency and particle size of the micelles were 98.2% and 12.8 nm respectively. Compared to Dox/DSPE-PEG micelles, Dox/DSPE-PEG/TPGS mixed micelles demonstrated enhanced in vitro cytotoxicity, drug uptake, and apoptosis for drug resistant H460/TaxR cancer cells. Western blot results showed that the expression level of P-gp significantly decreased as H460/TaxR cells were incubated with Dox/DSPE-PEG/TPGS mixed micelles. The anti-tumor efficacy in vivo was evaluated using H460/TaxR-bearing mice and showed that Dox/DSPE-PEG/TPGS mixed micelles were more effective at inhibiting tumor growth than Dox/DSPE-PEG micelles and free Dox solution. It was also found that the high efficacy of mixed micelles was associated with the ability to induce dramatic apoptosis of the tumor cells. In summary, through combining different P-gp inhibiting mechanisms, mixed micelles could be a promising nanocarrier for anti-cancer drugs in overcoming multidrug resistance. PMID:26295136

  10. Plasma membrane microorganization of LR73 multidrug-resistant cells revealed by FCS

    NASA Astrophysics Data System (ADS)

    Winckler, Pascale; Jaffiol, Rodolphe; Cailler, Aurélie; Morjani, Hamid; Jeannesson, Pierre; Deturche, Régis

    2011-03-01

    Tumoral cells could present a multidrug resistance (MDR) to chemotherapeutic treatments. This drug resistance would be associated to biomechanisms occurring at the plasma membrane level, involving modification of membrane fluidity, drug permeability, presence of microdomains (rafts, caveolae...), and membrane proteins overexpression such as Pglycoprotein. Fluorescence correlation spectroscopy (FCS) is the relevant method to investigate locally the fluidity of biological membranes through the lateral diffusion of a fluorescent membrane probe. Thus, we use FCS to monitor the plasma membrane local organization of LR73 carcinoma cells and three derived multidrug-resistant cancer cells lines. Measurements were conducted at the single cell level, which enabled us to get a detailed overview of the plasma membrane microviscosity distribution of each cell line studied. Moreover, we propose 2D diffusion simulation based on a Monte Carlo model to investigate the membrane organisation in terms of microdomains. This simulation allows us to relate the differences in the fluidity distributions with microorganization changes in plasma membrane of MDR cells.

  11. Non-Cytotoxic Nanomaterials Enhance Antimicrobial Activities of Cefmetazole against Multidrug-Resistant Neisseria gonorrhoeae

    PubMed Central

    Li, Lan-Hui; Yen, Muh-Yong; Ho, Chao-Chi; Wu, Ping; Wang, Chien-Chun; Maurya, Pawan Kumar; Chen, Pai-Shan; Chen, Wei; Hsieh, Wan-Yu; Chen, Huei-Wen

    2013-01-01

    The emergence and spread of antibiotic-resistant Neisseria gonorrhoeae has led to difficulties in treating patients, and novel strategies to prevent and treat this infection are urgently needed. Here, we examined 21 different nanomaterials for their potential activity against N. gonorrhoeae (ATCC 49226). Silver nanoparticles (Ag NPs, 120 nm) showed the greatest potency for reducing N. gonorrhoeae colony formation (MIC: 12.5 µg/ml) and possessed the dominant influence on the antibacterial activity with their properties of the nanoparticles within a concentration range that did not induce cytotoxicity in human fibroblasts or epithelial cells. Electron microscopy revealed that the Ag NPs significantly reduced bacterial cell membrane integrity. Furthermore, the use of clinical isolates of multidrug-resistant N. gonorrhoeae showed that combined treatment with 120 nm Ag NPs and cefmetazole produced additive effects. This is the first report to screen the effectiveness of nanomaterials against N. gonorrhoeae, and our results indicate that 120 nm Ag NPs deliver low levels of toxicity to human epithelial cells and could be used as an adjuvant with antibiotic therapy, either for topical use or as a coating for biomaterials, to prevent or treat multidrug-resistant N. gonorrhoeae. PMID:23705013

  12. Modulation of function of multidrug resistance associated-proteins by Kaempferia parviflora extracts and their components.

    PubMed

    Patanasethanont, Denpong; Nagai, Junya; Matsuura, Chie; Fukui, Kyoko; Sutthanut, Khaetthareeya; Sripanidkulchai, Bung-orn; Yumoto, Ryoko; Takano, Mikihisa

    2007-07-01

    In this study, the effects of extracts and flavone derivatives from the rhizome of Kaempferia parviflora on multidrug resistance associated-proteins (MRP)-mediated transport in A549 cells were examined. The cells employed express MRP1 and MRP2, but not P-glycoprotein. The cellular accumulation of calcein, an MRP substrate, was significantly increased by various MRP inhibitors without being affected by verapamil, a typical P-glycoprotein inhibitor. Ethanol and aqueous extracts from K. parviflora rhizome increased the accumulation of calcein and doxorubicin in A549 cells in a concentration-dependent manner. The inhibitory potency of the ethanol extract for MRP function was greater than that of the aqueous extract. Among six flavone derivatives isolated from K. parviflora rhizome, 5,7-dimethoxyflavone exhibited a maximal stimulatory effect on the accumulation of doxorubicin in A549 cells. The accumulation of doxorubicin was increased by four flavone derivatives without 5-hydroxy group, but not by the other two flavone derivatives with 5-hydroxy group. In addition, 5,7-dimethoxyflavone and 3,5,7,3',4'-pentamethoxyflavone decreased resistance to doxorubicin in A549 cells. These findings indicate that extracts and flavone derivatives from the rhizome of K. parviflora suppress MRP function, and therefore may be useful as modulators of multidrug resistance in cancer cells. PMID:17481606

  13. Pyrrolopyrimidine Derivatives as Novel Inhibitors of Multidrug Resistance-Associated Protein 1 (MRP1, ABCC1).

    PubMed

    Schmitt, Sven Marcel; Stefan, Katja; Wiese, Michael

    2016-04-14

    Five series of pyrrolo[3,2-d]pyrimidines were synthesized and evaluated with respect to potency and selectivity toward multidrug resistance-associated protein 1 (MRP1, ABCC1). This transport protein is a major target to overcome multidrug resistance in cancer patients. We investigated differently substituted pyrrolopyrimidines using the doxorubicin selected and MRP1 overexpressing small cell lung cancer cell line H69 AR in a calcein AM and daunorubicin cell accumulation assay. New compounds with high potency and selectivity were identified. Piperazine residues at position 4 bearing large phenylalkyl side chains proved to be beneficial for MRP1 inhibition. Its replacement by an amino group led to decreased activity. Aliphatic and aliphatic-aromatic variations at position 5 and 6 revealed compounds with IC50 values in high nanomolar range. All investigated compounds had low affinity toward P-glycoprotein (P-gp, ABCB1). Pyrrolopyrimidines with small substituents showed moderate inhibition against breast cancer resistance protein (BCRP, ABCG2). PMID:26943020

  14. Global Introduction of New Multidrug-Resistant Tuberculosis Drugs—Balancing Regulation with Urgent Patient Needs

    PubMed Central

    Sullivan, Timothy

    2016-01-01

    New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations. PMID:26889711

  15. Whole genome sequencing of emerging multidrug resistant Candida auris isolates in India demonstrates low genetic variation.

    PubMed

    Sharma, C; Kumar, N; Pandey, R; Meis, J F; Chowdhary, A

    2016-09-01

    Candida auris is an emerging multidrug resistant yeast that causes nosocomial fungaemia and deep-seated infections. Notably, the emergence of this yeast is alarming as it exhibits resistance to azoles, amphotericin B and caspofungin, which may lead to clinical failure in patients. The multigene phylogeny and amplified fragment length polymorphism typing methods report the C. auris population as clonal. Here, using whole genome sequencing analysis, we decipher for the first time that C. auris strains from four Indian hospitals were highly related, suggesting clonal transmission. Further, all C. auris isolates originated from cases of fungaemia and were resistant to fluconazole (MIC >64 mg/L). PMID:27617098

  16. Do mobile phones of patients, companions and visitors carry multidrug-resistant hospital pathogens?

    PubMed

    Tekerekoǧlu, Mehmet Sait; Duman, Yucel; Serindağ, Ayfer; Cuǧlan, Serpil Semiha; Kaysadu, Halim; Tunc, Emine; Yakupogullari, Yusuf

    2011-06-01

    A cross-sectional study was conducted to determine bacterial colonization on the mobile phones (MPs) used by patients, patients' companions, visitors, and health care workers (HCWs). Significantly higher rates of pathogens (39.6% vs 20.6%, respectively; P = .02) were found in MPs of patients' (n = 48) versus the HCWs' (n = 12). There were also more multidrug pathogens in the patents' MPs including methicillin-resistant Staphylococcus aureus, extended-spectrum β-lactamase-producing Escherichia coli, and Klebsiella spp, high-level aminoglycoside-resistant Enterococcus spp, and carabepenem-resistant Acinetobacter baumanii. Our findings suggest that mobile phones of patients, patients' companions, and visitors represent higher risk for nosocomial pathogen colonization than those of HCWs. Specific infection control measures may be required for this threat. PMID:21624635

  17. Reversion of multidrug resistance with polyalkylcyanoacrylate nanoparticles: towards a mechanism of action.

    PubMed Central

    de Verdière, A. C.; Dubernet, C.; Némati, F.; Soma, E.; Appel, M.; Ferté, J.; Bernard, S.; Puisieux, F.; Couvreur, P.

    1997-01-01

    Polyalkylcyanoacrylate (PACA) nanoparticles loaded with doxorubicin allowed multidrug resistance to be overcome in vitro. However, increased cytotoxicity is not always correlated with an increased level of intracellular drug. Although we have previously shown that PACA nanoparticles are not endocytosed by tumour cells, we report here that a direct interaction between nanoparticles and cells is a necessary requirement for overcoming resistance. In addition, the results showed that the degradation products of PACA (mainly polycyanoacrylic acid) in the presence of doxorubicin are able to increase both accumulation and cytotoxicity, thus suggesting the formation of a doxorubicin-polycyanoacrylic acid ion pair. It is therefore concluded that resistance is overcome as a result of both the adsorption of nanoparticles to the cell surface and increased doxorubicin diffusion by the accumulation of an ion pair at the plasma membrane. PMID:9231919

  18. Global Introduction of New Multidrug-Resistant Tuberculosis Drugs-Balancing Regulation with Urgent Patient Needs.

    PubMed

    Sullivan, Timothy; Ben Amor, Yanis

    2016-03-01

    New treatments for multidrug-resistant tuberculosis (MDR TB) are urgently needed. Two new drugs, bedaquiline and delamanid, have recently been released, and several new drugs and treatment regimens are in the pipeline. Misuse of TB drugs is a principal cause of drug resistance. As new drugs and regimens reach the market, the need to make them available to patients must be balanced with regulation of their use so that resistance to the new drugs can be prevented. To foster the rational use of new drugs, we propose 1) expanding/strengthening the capacity for drug susceptibility testing, beginning with countries with a high TB burden; 2) regulating prescribing practices by banning over-the-counter sale of TB drugs and enacting an accreditation system whereby providers must be certified to prescribe new drugs; and 3) decentralizing MDR TB care in rural communities by employing trained community health workers, using promising mobile technologies, and enlisting the aid of civil society organizations. PMID:26889711

  19. Multi-drug resistant tuberculosis burden and risk factors: an update.

    PubMed

    Marahatta, S B

    2010-01-01

    Multi-drug resistant (MDR) tuberculosis is defined as disease caused by Mycobacterium tuberculosis with resistance to at least two anti-tubercular drugs Isoniazid and Rifampicin. Recent surveillance data have revealed that prevalence of the drug resistant tuberculosis has risen to the highest rate ever recorded in the history. Drug resistant tuberculosis generally arises through the selection of mutated strains by inadequate therapy. The most powerful predictor of the presence of MDR-TB is a history of treatment of TB. Shortage of drugs has been one of the most common reasons for the inadequacy of the initial anti-TB regimen, especially in resource poor settings. Other major issues significantly contributing to the higher complexity of the treatment of MDR-TB is the increased cost of treatment. Other factors also play important role in the development of MDR-TB such as poor administrative control on purchase and distribution of the drugs with no proper mechanism on quality control and bioavailability tests. Tuberculosis control program implemented in past has also partially contributed to the development of drug resistance due to poor follow up and infrastructure. The association known for centuries between TB and poverty also applies to MDR-TB, a rather significant inverse association with MDR-TB. Various treatment strategies have been employed, including the use of standardised treatment regimens based upon representative local susceptibility patterns, empirical treatment based upon previous treatment history and local Drug Susceptibility Test (DST) patterns, and individualised treatment designed on the basis of individual DST results.Treatment outcomes among MDR-TB cases have varied widely; a recent survey of five Green Line Committee (GLC) approved sites in resource-limited countries found treatment success rates of 70%. Treatment continues to be limited in the resource poor countries where the demand is high. The ultimate strategy to control multidrug

  20. Antimicrobial hydrogels: a new weapon in the arsenal against multidrug-resistant infections.

    PubMed

    Ng, Victor W L; Chan, Julian M W; Sardon, Haritz; Ono, Robert J; García, Jeannette M; Yang, Yi Yan; Hedrick, James L

    2014-11-30

    The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Treatment with conventional antibiotics often leads to resistance development as the majority of these antibiotics act on intracellular targets, leaving the bacterial morphology intact. Thus, they are highly prone to develop resistance through mutation. Much effort has been made to develop macromolecular antimicrobial agents that are less susceptible to resistance as they function by microbial membrane disruption. Antimicrobial hydrogels constitute an important class of macromolecular antimicrobial agents, which have been shown to be effective in preventing and treating multidrug-resistant infections. Advances in synthetic chemistry have made it possible to tailor molecular structure and functionality to impart broad-spectrum antimicrobial activity as well as predictable mechanical and rheological properties. This has significantly broadened the scope of potential applications that range from medical device and implant coating, sterilization, wound dressing, to antimicrobial creams for the prevention and treatment of multidrug-resistant infections. In this review, advances in both chemically and physically cross-linked natural and synthetic hydrogels possessing intrinsic antimicrobial properties or loaded with antibiotics, antimicrobial polymers/peptides and metal nanoparticles are highlighted. Relationships between physicochemical properties and antimicrobial activity/selectivity, and possible antimicrobial mechanisms of the hydrogels are discussed. Approaches to mitigating toxicity of metal nanoparticles that are encapsulated in hydrogels are reviewed. In addition, challenges and future perspectives in the development of safe and effective antimicrobial hydrogel systems especially involving co-delivery of antimicrobial polymers/peptides and conventional antimicrobial agents for eventual clinical applications are presented. PMID:25450263

  1. Simple Method for Markerless Gene Deletion in Multidrug-Resistant Acinetobacter baumannii.

    PubMed

    Oh, Man Hwan; Lee, Je Chul; Kim, Jungmin; Choi, Chul Hee; Han, Kyudong

    2015-05-15

    The traditional markerless gene deletion technique based on overlap extension PCR has been used for generating gene deletions in multidrug-resistant Acinetobacter baumannii. However, the method is time-consuming because it requires restriction digestion of the PCR products in DNA cloning and the construction of new vectors containing a suitable antibiotic resistance cassette for the selection of A. baumannii merodiploids. Moreover, the availability of restriction sites and the selection of recombinant bacteria harboring the desired chimeric plasmid are limited, making the construction of a chimeric plasmid more difficult. We describe a rapid and easy cloning method for markerless gene deletion in A. baumannii, which has no limitation in the availability of restriction sites and allows for easy selection of the clones carrying the desired chimeric plasmid. Notably, it is not necessary to construct new vectors in our method. This method utilizes direct cloning of blunt-end DNA fragments, in which upstream and downstream regions of the target gene are fused with an antibiotic resistance cassette via overlap extension PCR and are inserted into a blunt-end suicide vector developed for blunt-end cloning. Importantly, the antibiotic resistance cassette is placed outside the downstream region in order to enable easy selection of the recombinants carrying the desired plasmid, to eliminate the antibiotic resistance cassette via homologous recombination, and to avoid the necessity of constructing new vectors. This strategy was successfully applied to functional analysis of the genes associated with iron acquisition by A. baumannii ATCC 19606 and to ompA gene deletion in other A. baumannii strains. Consequently, the proposed method is invaluable for markerless gene deletion in multidrug-resistant A. baumannii. PMID:25746991

  2. LL-37-Derived Peptides Eradicate Multidrug-Resistant Staphylococcus aureus from Thermally Wounded Human Skin Equivalents

    PubMed Central

    de Breij, Anna; Chan, Heelam; van Dissel, Jaap T.; Drijfhout, Jan W.; Hiemstra, Pieter S.; El Ghalbzouri, Abdoelwaheb; Nibbering, Peter H.

    2014-01-01

    Burn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistant Staphylococcus aureus (MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains of S. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria. PMID:24841266

  3. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer.

    PubMed

    Lv, Yingqian; Zhao, Shan; Han, Jinzhu; Zheng, Likang; Yang, Zixin; Zhao, Li

    2015-01-01

    Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1) were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1α by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at -378 to -373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well. PMID:26251616

  4. Molecular characterization of multidrug-resistant avian pathogenic Escherichia coli isolated from septicemic broilers.

    PubMed

    Li, Yurong; Chen, Ligong; Wu, Xianjun; Huo, Shuying

    2015-04-01

    Avian pathogenic Escherichia coli (APEC) causes extensive mortality in poultry flocks, leading to extensive economic losses. To date, little information has been available on the molecular basis of antimicrobial resistance in APEC in Hebei, China. Therefore, the objective of this study was to characterize the virulence and antimicrobial resistance of multidrug-resistant APEC isolated from septicemic broilers at the molecular level. Among 87 nonrepetitive E. coli isolates, 41 (47.1%) carried 3 or more of the APEC virulence genes iroN, ompT, iss, iutA, and hlyF. All 87 APEC isolates showed multidrug-resistant phenotypes, particularly against ampicillin, kanamycin, ciprofloxacin, levofloxacin, streptomycin, gentamycin, ofloxacin, norfloxacin, and ceftriaxone. The β-lactamase-encoding genes blaTEM, blaCMY-2, blaOXA-30, blaCTX-M-15, and blaSHV-2; the aminoglycoside-modifying enzymes (AME) strA, strB, aph(3')-IIa, aac(3)-IIa, aac(6')-Ib, and ant(3″)-Ia; and the plasmid-mediated quinolone resistance (PMQR) genes qnrA, qnrB, and qnrS, were also identified in 66 (75.9%), 65 (74.7%), and 6 (6.9%) isolates, respectively. All isolates were evaluated in terms of replicon type. The plasmid replicons were identified in 63 (72.4%) isolates, and the FIB, B/O, and K replicons were the most present. To the best of our knowledge, this is the first report of molecular characterization of antimicrobial resistance in APEC strains from China. PMID:25667425

  5. Enhancement of antibiotic activity by efflux inhibitors against multidrug resistant Mycobacterium tuberculosis clinical isolates from Brazil

    PubMed Central

    Coelho, Tatiane; Machado, Diana; Couto, Isabel; Maschmann, Raquel; Ramos, Daniela; von Groll, Andrea; Rossetti, Maria L.; Silva, Pedro A.; Viveiros, Miguel

    2015-01-01

    Drug resistant tuberculosis continues to increase and new approaches for its treatment are necessary. The identification of M. tuberculosis clinical isolates presenting efflux as part of their resistant phenotype has a major impact in tuberculosis treatment. In this work, we used a checkerboard procedure combined with the tetrazolium microplate-based assay (TEMA) to study single combinations between antituberculosis drugs and efflux inhibitors (EIs) against multidrug resistant M. tuberculosis clinical isolates using the fully susceptible strain H37Rv as reference. Efflux activity was studied on a real-time basis by a fluorometric method that uses ethidium bromide as efflux substrate. Quantification of efflux pump genes mRNA transcriptional levels were performed by RT-qPCR. The fractional inhibitory concentrations (FIC) indicated synergistic activity for the interactions between isoniazid, rifampicin, amikacin, ofloxacin, and ethidium bromide plus the EIs verapamil, thioridazine and chlorpromazine. The FICs ranged from 0.25, indicating a four-fold reduction on the MICs, to 0.015, 64-fold reduction. The detection of active efflux by real-time fluorometry showed that all strains presented intrinsic efflux activity that contributes to the overall resistance which can be inhibited in the presence of the EIs. The quantification of the mRNA levels of the most important efflux pump genes on these strains shows that they are intrinsically predisposed to expel toxic compounds as the exposure to subinhibitory concentrations of antibiotics were not necessary to increase the pump mRNA levels when compared with the non-exposed counterpart. The results obtained in this study confirm that the intrinsic efflux activity contributes to the overall resistance in multidrug resistant clinical isolates of M. tuberculosis and that the inhibition of efflux pumps by the EIs can enhance the clinical effect of antibiotics that are their substrates. PMID:25972842

  6. LL-37-derived peptides eradicate multidrug-resistant Staphylococcus aureus from thermally wounded human skin equivalents.

    PubMed

    Haisma, Elisabeth M; de Breij, Anna; Chan, Heelam; van Dissel, Jaap T; Drijfhout, Jan W; Hiemstra, Pieter S; El Ghalbzouri, Abdoelwaheb; Nibbering, Peter H

    2014-08-01

    Burn wound infections are often difficult to treat due to the presence of multidrug-resistant bacterial strains and biofilms. Currently, mupirocin is used to eradicate methicillin-resistant Staphylococcus aureus (MRSA) from colonized persons; however, mupirocin resistance is also emerging. Since we consider antimicrobial peptides to be promising candidates for the development of novel anti-infective agents, we studied the antibacterial activities of a set of synthetic peptides against different strains of S. aureus, including mupirocin-resistant MRSA strains. The peptides were derived from P60.4Ac, a peptide based on the human cathelicidin LL-37. The results showed that peptide 10 (P10) was the only peptide more efficient than P60.4Ac, which is better than LL-37, in killing MRSA strain LUH14616. All three peptides displayed good antibiofilm activities. However, both P10 and P60.4Ac were more efficient than LL-37 in eliminating biofilm-associated bacteria. No toxic effects of these three peptides on human epidermal models were detected, as observed morphologically and by staining for mitochondrial activity. In addition, P60.4Ac and P10, but not LL-37, eradicated MRSA LUH14616 and the mupirocin-resistant MRSA strain LUH15051 from thermally wounded human skin equivalents (HSE). Interestingly, P60.4Ac and P10, but not mupirocin, eradicated LUH15051 from the HSEs. None of the peptides affected the excretion of interleukin 8 (IL-8) by thermally wounded HSEs upon MRSA exposure. In conclusion, the synthetic peptides P60.4Ac and P10 appear to be attractive candidates for the development of novel local therapies to treat patients with burn wounds infected with multidrug-resistant bacteria. PMID:24841266

  7. Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer

    PubMed Central

    Lv, Yingqian; Zhao, Shan; Han, Jinzhu; Zheng, Likang; Yang, Zixin; Zhao, Li

    2015-01-01

    Multidrug resistance is the major cause of chemotherapy failure in many solid tumors, including colon cancer. Hypoxic environment is a feature for all solid tumors and is important for the development of tumor resistance to chemotherapy. Hypoxia-inducible factor (HIF)-1α is the key transcription factor that mediates cellular response to hypoxia. HIF-1α has been shown to play an important role in tumor resistance; however, the mechanism is still not fully understood. Here, we found that HIF-1α and the drug resistance-associated gene multidrug resistance associated protein 1 (MRP1) were induced by treatment of colon cancer cells with the hypoxia-mimetic agent cobalt chloride. Inhibition of HIF-1α by RNA interference and dominant-negative protein can significantly reduce the induction of MRP1 by hypoxia. Bioinformatics analysis showed that a hypoxia response element is located at −378 to −373 bp upstream of the transcription start site of MRP1 gene. Luciferase reporter assay combined with mutation analysis confirmed that this element is essential for hypoxia-mediated activation of MRP gene. Furthermore, RNA interference revealed that HIF-1α is necessary for this hypoxia-driven activation of MRP1 promoter. Importantly, chromatin immunoprecipitation analysis demonstrated that HIF-1α could directly bind to this HRE site in vivo. Together, these data suggest that MRP1 is a downstream target gene of HIF-1α, which provides a potential novel mechanism for HIF-1α-mediated drug resistance in colon cancer and maybe other solid tumors as well. PMID:26251616

  8. Simple Method for Markerless Gene Deletion in Multidrug-Resistant Acinetobacter baumannii

    PubMed Central

    Oh, Man Hwan; Lee, Je Chul; Kim, Jungmin

    2015-01-01

    The traditional markerless gene deletion technique based on overlap extension PCR has been used for generating gene deletions in multidrug-resistant Acinetobacter baumannii. However, the method is time-consuming because it requires restriction digestion of the PCR products in DNA cloning and the construction of new vectors containing a suitable antibiotic resistance cassette for the selection of A. baumannii merodiploids. Moreover, the availability of restriction sites and the selection of recombinant bacteria harboring the desired chimeric plasmid are limited, making the construction of a chimeric plasmid more difficult. We describe a rapid and easy cloning method for markerless gene deletion in A. baumannii, which has no limitation in the availability of restriction sites and allows for easy selection of the clones carrying the desired chimeric plasmid. Notably, it is not necessary to construct new vectors in our method. This method utilizes direct cloning of blunt-end DNA fragments, in which upstream and downstream regions of the target gene are fused with an antibiotic resistance cassette via overlap extension PCR and are inserted into a blunt-end suicide vector developed for blunt-end cloning. Importantly, the antibiotic resistance cassette is placed outside the downstream region in order to enable easy selection of the recombinants carrying the desired plasmid, to eliminate the antibiotic resistance cassette via homologous recombination, and to avoid the necessity of constructing new vectors. This strategy was successfully applied to functional analysis of the genes associated with iron acquisition by A. baumannii ATCC 19606 and to ompA gene deletion in other A. baumannii strains. Consequently, the proposed method is invaluable for markerless gene deletion in multidrug-resistant A. baumannii. PMID:25746991

  9. Molecular Characterization of Multidrug-Resistant Mycobacterium tuberculosis Isolates from China

    PubMed Central

    Zhao, Li-Li; Chen, Yan; Liu, Hai-Can; Xia, Qiang; Wu, Xiao-Cui; Sun, Qing; Zhao, Xiu-Qin; Li, Gui-Lian; Liu, Zhi-Guang

    2014-01-01

    To investigate the molecular characterization of multidrug-resistant tuberculosis (MDR-TB) isolates from China and the association of specific mutations conferring drug resistance with strains of different genotypes, we performed spoligotyping and sequenced nine loci (katG, inhA, the oxyR-ahpC intergenic region, rpoB, tlyA, eis, rrs, gyrA, and gyrB) for 128 MDR-TB isolates. Our results showed that 108 isolates (84.4%) were Beijing family strains, 64 (59.3%) of which were identified as modern Beijing strains. Compared with the phenotypic data, the sensitivity and specificity of DNA sequencing were 89.1% and 100.0%, respectively, for isoniazid (INH) resistance, 93.8% and 100.0% for rifampin (RIF) resistance, 60.0% and 99.4% for capreomycin (CAP) resistance, 84.6% and 99.4% for kanamycin (KAN) resistance, and 90.0% and 100.0% for ofloxacin (OFX) resistance. The most prevalent mutations among the MDR-TB isolates were katG315, inhA15, rpoB531, -526, and -516, rrs1401, eis-10, and gyrA94, -90, and -91. Furthermore, there was no association between specific resistance-conferring mutations and the strain genotype. These findings will be helpful for the establishment of rapid molecular diagnostic methods to be implemented in China. PMID:24419342

  10. High prevalence of multidrug-resistance uropathogenic Escherichia coli strains, Isfahan, Iran

    PubMed Central

    Dehbanipour, Razieh; Rastaghi, Sedighe; Sedighi, Mansour; Maleki, Nafiseh; Faghri, Jamshid

    2016-01-01

    Background and Objectives: Urinary tract infection (UTI) is one of the most frequent infectious diseases and can occur in all age groups. Escherichia coli is the main cause of this infection. Multiple resistances to antimicrobial agents are increasing quickly in E. coli isolates and may complicate therapeutic strategies for UTI. The aim of this study was to determine the antibiotic resistance pattern and the multidrug-resistance (MDR) phenotypes in uropathogenic E. coli (UPEC). Materials and Methods: A total of 135 UPEC isolates were collected from both outpatients (91 isolates) and inpatients (44 isolates) between September, 2012 and February, 2013. In order to determine the MDR among UPEC isolates, we have tested 15 antimicrobial agents and antibiotic susceptibility was done by Kirby-Bauer disk diffusion method. Results: The percentage of MDR isolates (resistant to at least three drug classes such as aminoglycosides, fluoroquinolones, penicillins, cephalosporins, or carbapenems) was 68% in the inpatients and 61% in the outpatients. Antibiotic resistance to ampicillin, ceftazidim, nalidixic acid, and trimethoprim/sulfamethoxazole were higher than 50%. Amikacin, nitrofurantoin, and gentamicin showed markedly greater activity (89.1%, 85.9%, and 82.4% sensitivity, respectively) than other antimicrobial agents. Resistance to meropenem did show either in outpatients or in inpatients. Interpretation and Conclusions: The high prevalence of drug resistance among UTI patients calls for continuous monitoring of the incidence of drug resistance for appropriate empiric selection of antibiotic therapy. Empirical treatment of UTIs should be relied on susceptibility patterns from local studies. PMID:27003964

  11. Diverse Genetic Background of Multidrug-Resistant Pseudomonas aeruginosa from Mainland China, and Emergence of an Extensively Drug-Resistant ST292 Clone in Kunming.

    PubMed

    Fan, Xin; Wu, Yue; Xiao, Meng; Xu, Zhi-Peng; Kudinha, Timothy; Bazaj, Alda; Kong, Fanrong; Xu, Ying-Chun

    2016-01-01

    For a better understanding of the multidrug resistant Pseudomonas aeruginosa (MDR-PA) epidemiology in mainland China, a nationwide surveillance network of 27 tertiary hospitals was established. Non-duplicate MDR-PA isolates from 254 cases of nosocomial infections, were collected during the period August 2011 to July 2012. Minimum inhibitory concentrations (MICs) of nine antimicrobial agents were determined by broth micro-dilution method according to the CLSI guidelines [M7-A10]. Genotyping analysis was performed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). The presence of acquired carbapenemases was also determined by molecular approaches for 233 carbapenem-resistant isolates. Carbapenemase genes were detected in 19 (8.2%) isolates, with 13 of these isolates encoding IMP-type enzymes, five with VIM-2, and one with KPC-2. MLST analysis revealed significant genetic diversity among the MDR-PA isolates studied, and 91 STs (including 17 novel STs) were identified. However, a long-term outbreak of an emerging extensively drug-resistant (XDR) ST292/PFGE genotype A clone was detected in a hospital from Southwest China. This study has demonstrated that MDR-PA in mainland China have evolved from diverse genetic backgrounds. Evidence of clonal dissemination of the organism and nosocomial outbreaks in some regions, suggest a need to strengthen existing infection control measures. PMID:27198004

  12. Homologues of the human multidrug resistance genes MRP and MDR contribute to heavy metal resistance in the soil nematode Caenorhabditis elegans.

    PubMed Central

    Broeks, A; Gerrard, B; Allikmets, R; Dean, M; Plasterk, R H

    1996-01-01

    Acquired resistance of mammalian cells to multiple chemotherapeutic drugs can result from enhanced expression of the multidrug resistance-associated protein (MRP), which belongs to the ABC transporter superfamily. ABC transporters play a role in the protection of organisms against exogenous toxins by cellular detoxification processes. We have identified four MRP homologues in the soil nematode Caenorhabditis elegans, and we have studied one member, mrp-1, in detail. Using an mrp::lacZ gene fusion, mrp-l expression was found in cells of the pharynx, the pharynx-intestinal valve and the anterior intestinal cells, the rectum-intestinal valve and the epithelial cells of the vulva. Targeted inactivation of mrp-l resulted in increased sensitivity to the heavy metal ions cadmium and arsenite, to which wild-type worms are highly tolerant. The most pronounced effect of the mrp-1 mutation is on the ability of animals to recover from temporary exposure to high concentrations of heavy metals. Nematodes were found to be hypersensitive to heavy metals when both the MRP homologue, mrp-1, and a member of the P-glycoprotein (Pgp) gene family, pgp-1, were deleted. We conclude that nematodes have multiple proteins, homologues of mammalian proteins involved in the cellular resistance to chemotherapeutic drugs, that protect them against heavy metals. Images PMID:8947035

  13. Diverse Genetic Background of Multidrug-Resistant Pseudomonas aeruginosa from Mainland China, and Emergence of an Extensively Drug-Resistant ST292 Clone in Kunming

    PubMed Central

    Fan, Xin; Wu, Yue; Xiao, Meng; Xu, Zhi-Peng; Kudinha, Timothy; Bazaj, Alda; Kong, Fanrong; Xu, Ying-Chun

    2016-01-01

    For a better understanding of the multidrug resistant Pseudomonas aeruginosa (MDR-PA) epidemiology in mainland China, a nationwide surveillance network of 27 tertiary hospitals was established. Non-duplicate MDR-PA isolates from 254 cases of nosocomial infections, were collected during the period August 2011 to July 2012. Minimum inhibitory concentrations (MICs) of nine antimicrobial agents were determined by broth micro-dilution method according to the CLSI guidelines [M7-A10]. Genotyping analysis was performed by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). The presence of acquired carbapenemases was also determined by molecular approaches for 233 carbapenem-resistant isolates. Carbapenemase genes were detected in 19 (8.2%) isolates, with 13 of these isolates encoding IMP-type enzymes, five with VIM-2, and one with KPC-2. MLST analysis revealed significant genetic diversity among the MDR-PA isolates studied, and 91 STs (including 17 novel STs) were identified. However, a long-term outbreak of an emerging extensively drug-resistant (XDR) ST292/PFGE genotype A clone was detected in a hospital from Southwest China. This study has demonstrated that MDR-PA in mainland China have evolved from diverse genetic backgrounds. Evidence of clonal dissemination of the organism and nosocomial outbreaks in some regions, suggest a need to strengthen existing infection control measures. PMID:27198004

  14. Identifying candidate causal variants responsible for altered activity of the ABCB1 multidrug resistance gene.

    PubMed

    Soranzo, Nicole; Cavalleri, Gianpiero L; Weale, Michael E; Wood, Nicholas W; Depondt, Chantal; Marguerie, Richard; Sisodiya, Sanjay M; Goldstein, David B

    2004-07-01

    The difficulty of fine localizing the polymorphisms responsible for genotype-phenotype correlations is emerging as an important constraint in the implementation and interpretation of genetic association studies, and calls for the definition of protocols for the follow-up of associated variants. One recent example is the 3435C>T polymorphism in the multidrug transporter gene ABCB1, associated with protein expression and activity, and with several clinical conditions. Available data suggest that 3435C>T may not directly cause altered transport activity, but may be associated with one or more causal variants in the poorly characterized stretch of linkage disequilibrium (LD) surrounding it. Here we describe a strategy for the follow-up of reported associations, including a Bayesian formalization of the associated interval concept previously described by Goldstein. We focus on the region of high LD around 3435C>T to compile an exhaustive list of variants by (1) using a relatively coarse set of marker typings to assess the pattern of LD, and (2) resequencing derived and ancestral chromosomes at 3435C>T through the associated interval. We identified three intronic sites that are strongly associated with the 3435C>T polymorphism. One of them is associated with multidrug resistance in patients with epilepsy (chi2 = 3.78, P = 0.052), and sits within a stretch of significant evolutionary conservation. We argue that these variants represent additional candidates for influencing multidrug resistance due to P-glycoprotein activity, with the IVS 26+80 T>C being the best candidate among the three intronic sites. Finally, we describe a set of six haplotype tagging single-nucleotide polymorphisms that represent common ABCB1 variation surrounding 3435C>T in Europeans. PMID:15197162

  15. Solution Binding and Structural Analyses Reveal Potential Multidrug Resistance Functions for SAV2435 and CTR107 and Other GyrI-like Proteins.

    PubMed

    Moreno, Andrew; Froehlig, John R; Bachas, Sharrol; Gunio, Drew; Alexander, Teressa; Vanya, Aaron; Wade, Herschel

    2016-08-30

    Multidrug resistance (MDR) refers to the acquired ability of cells to tolerate a broad range of toxic compounds. One mechanism cells employ is to increase the level of expression of efflux pumps for the expulsion of xenobiotics. A key feature uniting efflux-related mechanisms is multidrug (MD) recognition, either by efflux pumps themselves or by their transcriptional regulators. However, models describing MD binding by MDR effectors are incomplete, underscoring the importance of studies focused on the recognition elements and key motifs that dictate polyspecific binding. One such motif is the GyrI-like domain, which is found in several MDR proteins and is postulated to have been adapted for small-molecule binding and signaling. Here we report the solution binding properties and crystal structures of two proteins containing GyrI-like domains, SAV2435 and CTR107, bound to various ligands. Furthermore, we provide a comparison with deposited crystal structures of GyrI-like proteins, revealing key features of GyrI-like domains that not only support polyspecific binding but also are conserved among GyrI-like domains. Together, our studies suggest that GyrI-like domains perform evolutionarily conserved functions connected to multidrug binding and highlight the utility of these types of studies for elucidating mechanisms of MDR. PMID:27505298

  16. Carbapenem-resistant Acinetobacter baumannii acquired before liver transplantation: Impact on recipient outcomes.

    PubMed

    Freire, Maristela Pinheiro; Pierrotti, Ligia Câmera; Oshiro, Isabel Cristina Villela Soares; Bonazzi, Patrícia Rodrigues; Oliveira, Larissa Marques de; Machado, Anna Silva; Van Der Heijden, Inneke Marie; Rossi, Flavia; Costa, Silvia Figueiredo; D'Albuquerque, Luiz Augusto Carneiro; Abdala, Edson

    2016-05-01

    Infection with carbapenem-resistant Acinetobacter baumannii (CRAB) after liver transplantation (LT) is associated with high mortality. This study aimed to identify risk factors for post-LT CRAB infection, as well as to evaluate the impact of pre-LT CRAB acquisition on the incidence of post-LT CRAB infection. This was a prospective cohort study of all patients undergoing LT at our facility between October 2009 and October 2011. Surveillance cultures (SCs) were collected immediately before LT and weekly thereafter, until discharge. We analyzed 196 patients who were submitted to 222 LTs. CRAB was identified in 105 (53.6%); 24 (22.9%) of these patients were found to have acquired CRAB before LT, and 85 (81.0%) tested positive on SCs. Post-LT CRAB infection occurred in 56 (28.6%), the most common site being the surgical wound. Multivariate analysis showed that the risk factors for developing CRAB infection were prolonged cold ischemia, post-LT dialysis, LT due to fulminant hepatitis, and pre-LT CRAB acquisition with pre-LT CRAB acquisition showing a considerable trend toward significance (P = 0.06). Among the recipients with CRAB infection, 60-day mortality was 46.4%, significantly higher than among those without (P < 0.001). Mortality risk factors were post-LT infection with multidrug-resistant bacteria, LT performed because of fulminant hepatitis, retransplantation, prolonged cold ischemia, longer LT surgical time, and pre-LT CRAB acquisition, the last showing a trend toward significance (P = 0.08). In conclusion, pre-LT CRAB acquisition appears to increase the risk of post-LT CRAB infection, which has a negative impact on recipient survival. Liver Transplantation 22 615-626 2016 AASLD. PMID:26684547

  17. In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture

    PubMed Central

    Follit, Courtney A; Brewer, Frances K; Wise, John G; Vogel, Pia D

    2015-01-01

    Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P-glycoprotein (P-gp). P-gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P-gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P-gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P-gp inhibitors for use as co-therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716–726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug-like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P-gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P-gp-mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P-gp inhibition are excellent leads for the development of co-therapeutics for the treatment of multidrug resistances. PMID:26516582

  18. Signaling by small metabolites in systemic acquired resistance.

    PubMed

    Shah, Jyoti; Chaturvedi, Ratnesh; Chowdhury, Zulkarnain; Venables, Barney; Petros, Robby A

    2014-08-01

    Plants can retain the memory of a prior encounter with a pest. This memory confers upon a plant the ability to subsequently activate defenses more robustly when challenged by a pest. In plants that have retained the memory of a prior, localized, foliar infection by a pathogen, the pathogen-free distal organs develop immunity against subsequent infections by a broad-spectrum of pathogens. The long-term immunity conferred by this mechanism, which is termed systemic acquired resistance (SAR), is inheritable over a few generations. Signaling mediated by the phenolic metabolite salicylic acid (SA) is critical for the manifestation of SAR. Recent studies have described the involvement of additional small metabolites in SAR signaling, including methyl salicylate, the abietane diterpenoid dehydroabietinal, the lysine catabolite pipecolic acid, a glycerol-3-phosphate-dependent factor and the dicarboxylic acid azelaic acid. Many of these metabolites can be systemically transported through the plant and probably facilitate communication by the primary infected tissue with the distal tissues, which is essential for the activation of SAR. Some of these metabolites have been implicated in the SAR-associated rapid activation of defenses in response to subsequent exposure to the pathogen, a mechanism termed priming. Here, we summarize the role of these signaling metabolites in SAR, and the relationship between them and SA signaling in SAR. PMID:24506415

  19. Prolongation of acquired cellular resistance to Listeria monocytogenes

    PubMed Central

    Willers, J. M. N.; Hofhuis, F. M. A.; Meer, C. Vander

    1982-01-01

    Intracutaneous immunization of mice with 105 or 106 viable listeria resulted in acquired cellular resistance (ACR) of short duration (7 days) and in delayed-type hypersensitivity (DH) lasting at least 27 days. The ACR was partially non-specific, as 50% of the mice were also protected against a lethal challenge with Salmonella enteritidis. The specific element of the ACR could be transferred by non-adherent spleen cells from immune mice to normal recipient mice. Such transfer was not possible with adherent spleen cells from immune mice or with spleen cells from normal mice. Two systems of multiple immunizations to extend the period during which mice were protected against a challenge with 50 LD50 listeria were used. In the first system, mice were immunized with 106 viable listeria and subsequently challenged with 50 LD50 (= 107) viable listeria. Mice surviving the challenge were actually boosted at the challenge injection for ACR. In the second system mice were immunized and boosted with 108 killed listeria mixed with the adjuvant dimethyl dioctadecyl ammonium bromide (DDA). In the former system after each booster injection with viable listeria the interval during which the mice were protected doubled and reached a maximum of 31 days. In the latter system all intervals between two booster injections were equally long and never exceeded 28 days. In both systems the existence of immunological memory was suggested. The difference in results obtained after immunization with viable listeria and killed listeria mixed with DDA are discussed. PMID:6809603

  20. Mesoporous silica nanoparticles loading doxorubicin reverse multidrug resistance: performance and mechanism

    NASA Astrophysics Data System (ADS)

    Shen, Jianan; He, Qianjun; Gao, Yu; Shi, Jianlin; Li, Yaping

    2011-10-01

    Multidrug resistance (MDR) is one of the major obstacles for successful chemotherapy in cancer. One of the effective approaches to overcome MDR is to use nanoparticle-mediated drug delivery to increase drug accumulation in drug resistant cancer cells. In this work, we first report that the performance and mechanism of an inorganic engineered delivery system based on mesoporous silica nanoparticles (MSNs) loading doxorubicin (DMNs) to overcome the MDR of MCF-7/ADR (a DOX-resistant and P-glycoprotein (P-gp) over-expression cancer cell line). The experimental results showed that DMNs could enhance the cellular uptake of doxorubicin (DOX) and increase the cell proliferation suppression effect of DOX against MCF-7/ADR cells. The IC50 of DMNs against MCF-7/ADR cells was 8-fold lower than that of free DOX. However, an improved effect of DOX in DMNs against MCF-7 cells (a DOX-sensitive cancer cell line) was not found. The increased cellular uptake and nuclear accumulation of DOX delivered by DMNs in MCF-7/ADR cells was confirmed by confocal laser scanning microscopy, and could result from the down-regulation of P-gp and bypassing the efflux action by MSNs themselves. The cellular uptake mechanism of DMNs indicated that the macropinocytosis was one of the pathways for the uptake of DMNs by MCF-7/ADR cells. The in vivo biodistribution showed that DMNs induced a higher accumulation of DOX in drug resistant tumors than free DOX. These results suggested that MSNs could be an effective delivery system to overcome multidrug resistance.

  1. A data-driven approach to modeling the tripartite structure of multidrug resistance efflux pumps.

    PubMed

    Phillips, Joshua L; Gnanakaran, S

    2015-01-01

    Many bacterial pathogens are becoming increasingly resistant to antibiotic treatments, and a detailed understanding of the molecular basis of antibiotic resistance is critical for the development of next-generation approaches for combating bacterial infections. Studies focusing on pathogens have revealed the profile of resistance in these organisms to be due primarily to the presence of multidrug resistance efflux pumps: tripartite protein complexes which span the periplasm bridging the inner and outer membranes of Gram-negative bacteria. An atomic-level resolution tripartite structure remains imperative to advancing our understanding of the molecular mechanisms of pump function using both theoretical and experimental approaches. We develop a fast and consistent method for constructing tripartite structures which leverages existing data-driven models and provide molecular modeling approaches for constructing tripartite structures of multidrug resistance efflux pumps. Our modeling studies reveal that conformational changes in the inner membrane component responsible for drug translocation have limited impact on the conformations of the other pump components, and that two distinct models derived from conflicting experimental data are both consistent with all currently available measurements. Additionally, we investigate putative drug translocation pathways via geometric simulations based on the available crystal structures of the inner membrane pump component, AcrB, bound to two drugs which occupy distinct binding sites: doxorubicin and linezolid. These simulations suggest that smaller drugs may enter the pump through a channel from the cytoplasmic leaflet of the inner membrane, while both smaller and larger drug molecules may enter through a vestibule accessible from the periplasm. PMID:24957790

  2. Carbapenemase Genes among Multidrug Resistant Gram Negative Clinical Isolates from a Tertiary Hospital in Mwanza, Tanzania

    PubMed Central

    Mushi, Martha F.; Mshana, Stephen E.; Imirzalioglu, Can; Bwanga, Freddie

    2014-01-01

    The burden of antimicrobial resistance (AMR) is rapidly growing across antibiotic classes, with increased detection of isolates resistant to carbapenems. Data on the prevalence of carbapenem resistance in developing countries is limited; therefore, in this study, we determined the prevalence of carbapenemase genes among multidrug resistant gram negative bacteria (MDR-GNB) isolated from clinical specimens in a tertiary hospital in Mwanza, Tanzania. A total of 227 MDR-GNB isolates were analyzed for carbapenem resistance genes. For each isolate, five different PCR assays were performed, allowing for the detection of the major carbapenemase genes, including those encoding the VIM-, IMP-, and NDM-type metallo-beta-lactamases, the class A KPC-type carbapenemases, and the class D OXA-48 enzyme. Of 227 isolates, 80 (35%) were positive for one or more carbapenemase gene. IMP-types were the most predominant gene followed by VIM, in 49 (21.59%) and 28 (12%) isolates, respectively. Carbapenemase genes were most detected in K. pneumoniae 24 (11%), followed by P. aeruginosa 23 (10%), and E. coli with 19 isolates (8%). We have demonstrated for the first time a high prevalence of MDR-GNB clinical isolates having carbapenem resistance genes in Tanzania. We recommend routine testing for carbapenem resistance among the MDR-GNB particularly in systemic infections. PMID:24707481

  3. Inhibition of the Multidrug Resistance P-Glycoprotein: Time for a Change of Strategy?

    PubMed Central

    Luk, Frederick; Bebawy, Mary

    2014-01-01

    P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to “block” P-gp–mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high-dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application. PMID:24492893

  4. Interferon-Gamma Improves Macrophages Function against M. tuberculosis in Multidrug-Resistant Tuberculosis Patients

    PubMed Central

    Mazhar, Humaira; Muhammad, Niaz; Abbas, Muhammad Nasser

    2016-01-01

    Background. Mycobacterium tuberculosis (M. tuberculosis) that causes tuberculosis (TB) kills millions of infected people annually especially multidrug-resistant tuberculosis (MDR-TB). On infection, macrophages recognize the mycobacteria by toll-like receptor (TLR) followed by phagocytosis and control of mycobacteria. In addition, macrophages also secrete IL-12 to induce IFN-γ production by T, which, in turn, increases the phagocytosis and oxidative burst. Individuals with defects in innate or adaptive immunity exhibit increased susceptibility to M. tuberculosis. Understanding these immunologic mechanisms will help in TB control. We aimed to investigate the immunopathologic mechanisms in MDR-TB and role of recombinant human interferon-gamma (rhIFN-γ). Study Design and Methods. Monocyte-derived macrophages (MDMs) were generated from peripheral blood mononuclear cells of MDR-TB patients and healthy subjects and were investigated for immunologic response by ELISA and flow cytometry. Results. Different functional and molecular anomalies were observed in macrophages. In addition, a defective immune response to M. tuberculosis from the patient's MDMs was characterized, which in turn improved by pretreatment with rhIFN-γ. Conclusion. This work highlights the fact that rhIFN-γ improves macrophages function against M. tuberculosis and treatment of patients with poor responsiveness to TB therapy may be needed in future to include IFN-γ as adjuvant therapy after the full characterization of pathological and molecular mechanisms in these and in other more multidrug-resistant TB patients. PMID:27478636

  5. A Potato cDNA Encoding a Homologue of Mammalian Multidrug Resistant P-Glycoprotein

    NASA Technical Reports Server (NTRS)

    Wang, W.; Takezawa, D.; Poovaiah, B. W.

    1996-01-01

    A homologue of the multidrug resistance (MDR) gene was obtained while screening a potato stolon tip cDNA expression library with S-15-labeled calmodulin. The mammalian MDR gene codes for a membrane-bound P-glycoprotein (170-180 kDa) which imparts multidrug resistance to cancerous cells. The potato cDNA (PMDR1) codes for a polypeptide of 1313 amino acid residues (ca. 144 kDa) and its structural features are very similar to the MDR P-glycoprotein. The N-terminal half of the PMDR1-encoded protein shares striking homology with its C-terminal half, and each half contains a conserved ATP-binding site and six putative transmembrane domains. Southern blot analysis indicated that potato has one or two MDR-like genes. PMDR1 mRNA is constitutively expressed in all organs studied with higher expression in the stem and stolon tip. The PMDR1 expression was highest during tuber initiation and decreased during tuber development.

  6. Expression of a multidrug-resistance gene in human tumors and tissues

    SciTech Connect

    Fojo, A.T.; Ueda, K.; Slamon, D.J.; Poplack, D.G.; Gottesman, M.M.; Pastan, I.

    1987-01-01

    The identification and cloning of a segment of a human multidrug resistance gene (mdr1) was reported recently. To examine, the molecular basis of one type of multidrug resistance, the authors have prepared RNA from human tumors and normal tissues and measured their content of mdr1 RNA. They find that the mdr1 gene is expressed at a very high level in the adrenal gland; at a high level in the kidney; at intermediate levels in the lung, liver, lower jejunum, colon, and rectum; and at low levels in many other tissues. The mdr1 gene is also expressed in several human tumors, including many but not all tumors derived from the adrenal gland and the colon. In addition, increased expression was detected in a few tumors at the time of relapse following initial chemotherapy. Although controlled clinical studies will be required, the results suggest that measurement of mdr1 RNA may prove to be a valuable tool in the design of chemotherapy protocols.

  7. Chloramphenicol – A Potent Armament Against Multi-Drug Resistant (MDR) Gram Negative Bacilli?

    PubMed Central

    2016-01-01

    Introduction Multidrug-resistant gram-negative bacteria cause infections which are hard to treat and cause high morbidity and mortality. Due to limited therapeutic options there is a renewed interest upon older antimicrobials which had fallen into disuse as a result of toxic side effects. One such antibiotic is chloramphenicol which was sidelined due to reports linking its use with the development of aplastic anaemia. Aim A study was conducted to evaluate the susceptibility of chloramphenicol in light of the emerging problem of multi-drug resistant gram negative bacteria (MDR GNB). Materials and Methods A total of 483 MDR GNB of the 650 consecutive Gram Negative Bacteria isolated from various clinical samples of patients admitted at a tertiary care hospital in Jaipur between January-June 2014 were screened for chloramphenicol susceptibility by the disc diffusion method as per CLSI guidelines. Results The MDR GNB isolates were obtained from 217 (45%) urine, 163 (34%) from respiratory samples, 52(11%) from pus, 42 (9%) from blood and 9 (2%) from body fluids. A 68% of the MDR GNB isolates were found to be sensitive to chloramphenicol. Conclusion Clinicians should always check for the local susceptibility of Gram-negative bacteria to chloramphenicol. This antibiotic has a potential to play a role in the therapeutic management of infections due to MDR GNB pathogens. PMID:27042458

  8. A polyphenolic flavonoid glabridin: Oxidative stress response in multidrug-resistant Staphylococcus aureus.

    PubMed

    Singh, Vigyasa; Pal, Anirban; Darokar, Mahendra P

    2015-10-01

    Glabridin a polyphenolic flavonoid from Glycyrrhiza glabra is known to possess several therapeutic properties. In the present study, we report for the first time the in vitro antibacterial activity (MIC values ranging from 3.12 to 25 μg/mL) of glabridin against multidrug-resistant clinical isolates of S. aureus by inducing oxidative stress. Increased levels of H2O2 and NO were observed in a dose-dependent manner after treatment of glabridin that further affected macromolecules such as DNA, lipids, and proteins. Surprisingly, glabridin was found to possess antioxidant properties when used at lower concentrations using three different methods including DPPH, FRAP, and SOD assays. These observations were further validated through the expression analysis of oxidative stress-responsive genes using qRT-PCR wherein glabridin was observed to up- and down-regulate these genes at lower and higher concentrations, respectively. In in vitro combination experiments, glabridin was found to reduce the MIC of different antibiotics such as norfloxacin, oxacillin, and vancomycin by up to 4-fold, while the MIC of glabridin itself was found to be reduced by up to 8-fold in the presence of antibiotics. A synergistic interaction was observed between norfloxacin and glabridin when used in combination against multidrug-resistant clinical isolate SA 4627 of Staphylococcus aureus at much lower concentrations, indicating the suitability of glabridin in combination therapy. PMID:26117328

  9. Imaging Features of Pulmonary CT in Type 2 Diabetic Patients with Multidrug-Resistant Tuberculosis

    PubMed Central

    Jiang, Hongbo; Ren, Yanwei; Lu, Xiwei

    2016-01-01

    Background Until now, radiographic manifestations of multidrug-resistant pulmonary tuberculosis (MDR- TB) in patients with diabetes mellitus (DM) have not been reported. We conducted a study to investigate the imaging features of pulmonary computed tomography (CT) for type 2 diabetic (T2DM) patients with MDR-TB. Methods The clinical data and pulmonary CT findings of 39 type 2 diabetic patients with MDR-TB, 46 type 2 diabetic patients with drug-susceptible tuberculosis (DS-TB), and 72 pure drug-susceptible TB cases (without T2DM and MDR) treated at Dalian Tuberculosis Hospital from 2012 to 2015 were collected, and the clinical features and imaging differences of the three groups were compared. Results The clinical characteristics of the three groups of patients were not significantly different except with respect to age and previous treatment history. However, on imaging, the patients with MDR-TB showed consolidation in and above the pulmonary segments was significantly more extensive than that seen in the DS-TB group with or without T2DM. Conclusion Consolidation in or above multiple pulmonary segments with multiple mouth-eaten cavities and bronchial damage on pulmonary CT images in type 2 diabetic patients with tuberculosis suggests the possibility of multi-drug resistance. PMID:27022735

  10. Short-course treatment for multidrug-resistant tuberculosis: the STREAM trials.

    PubMed

    Moodley, Riya; Godec, Thomas R

    2016-03-01

    Multidrug-resistant (MDR) tuberculosis (TB) is a threat to global TB control, as suboptimal and poorly tolerated treatment options have resulted in largely unfavourable outcomes for these patients. The last of six cohort studies conducted in Bangladesh which assessed a new shorter regimen using currently available TB drugs showed promising results and offered the possibility of a more acceptable and more effective regimen than the one recommended by the World Health Organization (WHO). The aims of stage 1 of the STREAM (Evaluation of a Standardised Treatment Regimen of Anti-tuberculosis Drugs for Patients with Multidrug-resistant Tuberculosis) trial are to evaluate the efficacy and safety of this regimen, compared to the current WHO-recommended standard of care. Stage 2 evaluates two new bedaquiline-containing regimens: one an all-oral regimen and the second a further shortened and simplified version of the stage 1 study regimen, comparing the efficacy and safety of each to that of the stage 1 study regimen and also to the WHO-recommended standard of care. Success of the stage 1 study regimen would in all probability provide a new standard of care for MDR-TB patients, while positive results from the bedaquiline-containing regimens in stage 2 may allow for even greater progress in the management of this difficult population. PMID:26929418

  11. Discovering Natural Product Modulators to Overcome Multidrug Resistance in Cancer Chemotherapy

    PubMed Central

    Wu, Chung-Pu; Ohnuma, Shinobu; Ambudkar, Suresh V.

    2012-01-01

    Multidrug resistance caused by the overexpression of ABC drug transporters is a major obstacle in clinical cancer chemotherapy. For several years, it appeared that direct inhibition of ABC transporters would be the cheapest and most efficient way to combat this problem. Unfortunately, progress in finding a potent, selective inhibitor to modulate ABC transporters and restore drug sensitivity in multidrug-resistant cancer cells has been slow and challenging. Candidate drugs should ideally be selective, potent and relatively non-toxic. Many researchers in recent years have turned their attention to utilizing natural products as the building blocks for the development of the next generation of inhibitors, especially after the disappointing results obtained from inhibitors of the first three generations at the clinical trial stage. The first step is to discover natural substances (distinct from the first three generation inhibitors) that are potent, selective and relatively non-toxic in order to be used clinically. Here, we present a brief overview of the prospect of using natural products to modulate the function of ABC drug transporters clinically and their impact on human physiology and pharmacology. PMID:21118092

  12. A nanoparticulate pre-chemosensitizer for efficacious chemotherapy of multidrug resistant breast cancer

    PubMed Central

    Guo, Shengrong; Lv, Li; Shen, Yuanyuan; Hu, Zhongliang; He, Qianjun; Chen, Xiaoyuan

    2016-01-01

    Small-molecule chemosensitizers can reverse cancer multidrug resistance (MDR), thus significantly improving the in vitro effect of chemotherapy drugs for MDR cancer cells, however, their in vivo effects are not always very good, because they are difficult to effectively accumulate in tumor and enter the same cancer with chemotherapy drugs after systemic administration due to individual biopharmaceutical properties. To overcome these limitations, here we study a novel nanoparticular pre-chemosensitizer which can be also used as nanocarrier of chemotherapy drugs. We take an ‘all in one’ approach to develop a self-assembled nanoparticle formula of amphiphilic poly(curcumin-dithiodipropionic acid)-b-poly(ethylene glycol)-biotin. The nanoparticle is capable of tumor-targeted delivery, responsive degradation at the intracellular level of glutathione and subsequent intracellular co-release of the chemosensitizer curcumin and the encapsulated chemotherapeutic drug doxorubicin to maximize a synergistic effect of chemosensitization and chemotherapy. We demonstrate that the antitumor efficacy of nanoparticle is much superior to that of doxorubicin in the multidrug resistant MCF-7/ADR xenografted nude mice. PMID:26875787

  13. Engineered Endolysin-Based “Artilysins” To Combat Multidrug-Resistant Gram-Negative Pathogens

    PubMed Central

    Briers, Yves; Walmagh, Maarten; Van Puyenbroeck, Victor; Cornelissen, Anneleen; Cenens, William; Aertsen, Abram; Oliveira, Hugo; Azeredo, Joana; Verween, Gunther; Pirnay, Jean-Paul; Miller, Stefan; Volckaert, Guido

    2014-01-01

    ABSTRACT The global threat to public health posed by emerging multidrug-resistant bacteria in the past few years necessitates the development of novel approaches to combat bacterial infections. Endolysins encoded by bacterial viruses (or phages) represent one promising avenue of investigation. These enzyme-based antibacterials efficiently kill Gram-positive bacteria upon contact by specific cell wall hydrolysis. However, a major hurdle in their exploitation as antibacterials against Gram-negative pathogens is the impermeable lipopolysaccharide layer surrounding their cell wall. Therefore, we developed and optimized an approach to engineer these enzymes as outer membrane-penetrating endolysins (Artilysins), rendering them highly bactericidal against Gram-negative pathogens, including Pseudomonas aeruginosa and Acinetobacter baumannii. Artilysins combining a polycationic nonapeptide and a modular endolysin are able to kill these (multidrug-resistant) strains in vitro with a 4 to 5 log reduction within 30 min. We show that the activity of Artilysins can be further enhanced by the presence of a linker of increasing length between the peptide and endolysin or by a combination of both polycationic and hydrophobic/amphipathic peptides. Time-lapse microscopy confirmed the mode of action of polycationic Artilysins, showing that they pass the outer membrane to degrade the peptidoglycan with subsequent cell lysis. Artilysins are effective in vitro (human keratinocytes) and in vivo (Caenorhabditis elegans). PMID:24987094

  14. Reversal of Multidrug Resistance in Mouse Lymphoma Cells by Extracts and Flavonoids from Pistacia integerrima.

    PubMed

    Rauf, Abdur; Uddin, Ghias; Raza, Muslim; Ahmad, Bashir; Jehan, Noor; Siddiqui, Bina S; Molnar, Joseph; Csonka, Akos; Szabo, Diana

    2016-01-01

    Phytochemical investigation of Pistacia integerrima has highlighted isolation of two known compounds naringenin (1) and dihydrokaempferol (2). A crude extract and these isolated compounds were here evaluated for their effects on reversion of multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). The multidrug resistance P-glycoprotein is a target for chemotherapeutic drugs from cancer cells. In the present study rhodamine- 123 exclusion screening test on human mdr1 gene transfected mouse gene transfected L5178 and L5178Y mouse T-cell