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Sample records for bacterial drug resistance

  1. Drug resistance analysis of bacterial strains isolated from burn patients.

    PubMed

    Wang, L F; Li, J L; Ma, W H; Li, J Y

    2014-01-01

    This study aimed to analyze the spectrum and drug resistance of bacteria isolated from burn patients to provide a reference for rational clinical use of antibiotics. Up to 1914 bacterial strain specimens isolated from burn patients admitted to hospital between 2001 and 2010 were subjected to resistance monitoring by using the K-B paper disk method. Retrospective analysis was performed on drug resistance analysis of burn patients. The top eight bacterium strains according to detection rate. A total of 1355 strains of Gram-negative (G(-)) bacteria and 559 strains of Gram-positive (G(+)) bacteria were detected. The top eight bacterium strains, according to detection rate, were Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, and Enterococcus. Drug resistance rates were higher than 90% in A. baumannii, P. aeruginosa, S. epidermidis, and S. aureus, which accounted for 52.2, 21.7, 27.8, and 33.3%, respectively, of the entire sample. Those with drug resistance rates lower than 30% accounted for 4.3, 30.4, 16.7, and 16.7%, respectively. Multidrug-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE) accounted for 49.2 and 76.4% of the S. epidermis and S. aureus resistance, respectively. Antibacterial drugs that had drug resistance rates to MRSE and MRSA higher than 90% accounted for 38.9 and 72.2%, respectively, whereas those with lower than 30% drug resistance rates accounted for 11.1 and 16.7%, respectively. The burn patients enrolled in the study were mainly infected with G(-) bacteria. These results strongly suggest that clinicians should practice rational use of antibiotics based on drug susceptibility test results. PMID:24535909

  2. Whole-genome sequencing targets drug-resistant bacterial infections.

    PubMed

    Punina, N V; Makridakis, N M; Remnev, M A; Topunov, A F

    2015-01-01

    During the past two decades, the technological progress of whole-genome sequencing (WGS) had changed the fields of Environmental Microbiology and Biotechnology, and, currently, is changing the underlying principles, approaches, and fundamentals of Public Health, Epidemiology, Health Economics, and national productivity. Today's WGS technologies are able to compete with conventional techniques in cost, speed, accuracy, and resolution for day-to-day control of infectious diseases and outbreaks in clinical laboratories and in long-term epidemiological investigations. WGS gives rise to an exciting future direction for personalized Genomic Epidemiology. One of the most vital and growing public health problems is the emerging and re-emerging of multidrug-resistant (MDR) bacterial infections in the communities and healthcare settings, reinforced by a decline in antimicrobial drug discovery. In recent years, retrospective analysis provided by WGS has had a great impact on the identification and tracking of MDR microorganisms in hospitals and communities. The obtained genomic data are also important for developing novel easy-to-use diagnostic assays for clinics, as well as for antibiotic and therapeutic development at both the personal and population levels. At present, this technology has been successfully applied as an addendum to the real-time diagnostic methods currently used in clinical laboratories. However, the significance of WGS for public health may increase if: (a) unified and user-friendly bioinformatics toolsets for easy data interpretation and management are established, and (b) standards for data validation and verification are developed. Herein, we review the current and future impact of this technology on diagnosis, prevention, treatment, and control of MDR infectious bacteria in clinics and on the global scale. PMID:26243131

  3. An analogy between the evolution of drug resistance in bacterial communities and malignant tissues

    PubMed Central

    Lambert, Guillaume; Estévez-Salmeron, Luis; Oh, Steve; Liao, David; Emerson, Beverly M.; Tlsty, Thea D.; Austin, Robert H.

    2012-01-01

    Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance in bacterial communities. We propose that this evolution is the result of a programmed and collective stress response performed by interacting cells, and that, given this fundamental connection, studying bacterial communities can provide deeper insights into the dynamics of adaptation and the evolution of cells within tumours. PMID:21508974

  4. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/1/2016; last reviewed 3/1/2016) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  5. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens.

    PubMed

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F N; Sobreira, Tiago J P; Hedrick, Victoria E; Paul, Lake N; Seleem, Mohamed N

    2016-01-01

    Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin's antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin's ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID:26936660

  6. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2016-01-01

    Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID:26936660

  7. Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

    PubMed Central

    Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.

    2015-01-01

    SUMMARY Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR. PMID:25652543

  8. Aminomethyl spectinomycins as therapeutics for drug-resistant respiratory tract and sexually transmitted bacterial infections.

    PubMed

    Bruhn, David F; Waidyarachchi, Samanthi L; Madhura, Dora B; Shcherbakov, Dimitri; Zheng, Zhong; Liu, Jiuyu; Abdelrahman, Yasser M; Singh, Aman P; Duscha, Stefan; Rathi, Chetan; Lee, Robin B; Belland, Robert J; Meibohm, Bernd; Rosch, Jason W; Böttger, Erik C; Lee, Richard E

    2015-05-20

    The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A series of N-benzyl-substituted 3'-(R)-3'-aminomethyl-3'-hydroxy spectinomycins was developed on the basis of a computational analysis of the aminomethyl spectinomycin binding site and structure-guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against the common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis, as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome-binding 3'-(S) isomers of the lead compounds demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target against the ribosome. Compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series exhibited excellent chemical stability superior to spectinomycin; no interaction with a panel of human receptors and drug metabolism enzymes, suggesting low potential for adverse reactions or drug-drug interactions in vivo; activity in vitro against a panel of penicillin-, macrolide-, and cephalosporin-resistant S. pneumoniae clinical isolates; and the ability to cure mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate that N-benzyl aminomethyl spectinomycins are suitable for further development to treat drug-resistant respiratory tract and sexually transmitted bacterial infections. PMID:25995221

  9. Aminomethyl Spectinomycins as Novel Therapeutics for Drug Resistant Respiratory Tract and Sexually Transmitted Bacterial Infections

    PubMed Central

    Madhura, Dora B.; Shcherbakov, Dimitri; Zheng, Zhong; Liu, Jiuyu; Abdelrahman, Yasser M.; Singh, Aman P.; Duscha, Stefan; Rathi, Chetan; Lee, Robin B.; Belland, Robert J.; Meibohm, Bernd; Rosch, Jason W.; Böttger, Erik C.; Lee, Richard E.

    2015-01-01

    The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A novel series of N-benzyl substituted 3'-(R)- 3'-aminomethyl-3'-hydroxy spectinomycins was developed based on a computational analysis of the aminomethyl spectinomycin binding site and structure guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome binding 3'-(S) isomers of the leads demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target. In addition to improved antibacterial potency, compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series, compound 1, exhibited excellent chemical stability, which was superior to spectinomycin and had no significant interaction with a panel of human receptors and drug metabolism enzymes suggesting low potential for adverse reactions or drug-drug interactions in vivo. Compound 1 was active in vitro against a panel of penicillin, macrolide, and cephalosporin resistant S. pneumoniae clinical isolates and cured mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate N-benzyl aminomethyl spectinomycins possess suitable properties for further development as novel antibacterial agents to treat drug resistant respiratory tract and sexually transmitted bacterial infections. PMID:25995221

  10. Exposure to phages has little impact on the evolution of bacterial antibiotic resistance on drug concentration gradients

    PubMed Central

    Zhang, Quan-Guo

    2014-01-01

    The use of phages for treating bacterial pathogens has recently been advocated as an alternative to antibiotic therapy. Here, we test a hypothesis that bacteria treated with phages may show more limited evolution of antibiotic resistance as the fitness costs of resistance to phages may add to those of antibiotic resistance, further reducing the growth performance of antibiotic-resistant bacteria. We did this by studying the evolution of phage-exposed and phage-free Pseudomonas fluorescens cultures on concentration gradients of single drugs, including cefotaxime, chloramphenicol, and kanamycin. During drug treatment, the level of bacterial antibiotic resistance increased through time and was not affected by the phage treatment. Exposure to phages did not cause slower growth in antibiotic-resistant bacteria, although it did so in antibiotic-susceptible bacteria. We observed significant reversion of antibiotic resistance after drug use being terminated, and the rate of reversion was not affected by the phage treatment. The results suggest that the fitness costs caused by resistance to phages are unlikely to be an important constraint on the evolution of bacterial antibiotic resistance in heterogeneous drug environments. Further studies are needed for the interaction of fitness costs of antibiotic resistance with other factors. PMID:24665341

  11. Does the appearance of drug resistance during therapy alter bacterial susceptibility to opsonophagocytosis?

    PubMed

    Gemmell, C G

    1996-01-01

    Coagulase-negative staphylococci (CNS) are common causes of infection in patients undergoing chronic ambulatory peritoneal dialysis (CAPD). Their ability to survive intracellularly within peritoneal macrophages and to persist within the peritoneum during antibiotic therapy has led to the development of drug resistance during treatment. Strains of Staphylococcus epidermidis (SE) and Staphytococcus haemolyticus (SH) have been isolated from patients with CAPD during treatment with ciprofloxacin. The respective MIC values pre-and post-therapy were SE-0.25 and 128 mg/L and SH-0.50 and 64 mg/L. The susceptibility of each isolate to opsonophagocytosis was measured in vitro using isolated polymorphonuclear leucocytes (PMN) derived from fresh human blood donations. The bacteria were radiolabelled during growth, opsonised in either 1 or 10% serum and their uptake measured No differences were seen between the pre- and post therapy isolates when using 10% serum as opsonic source (18 vs. 21%); with 1% serum the corresponding values were lower (5 and 8% respectively). Similarly their ability to generate a respiratory burst as measured by chemiluminescence (CL) in the phagocytic cells was not diminished in the strains which had developed resistance to ciprofloxacin. The mean CL response to the strains isolated at outset of therapy ranged from 0.35-0.45 cpsc, and to the resistant strains following therapy from 0.36-0.50 cpsc. It is clear from the present investigation that although the bacterial strain became at least 10 times more resistant to ciprofloxacin during therapy, no change in their susceptibility to phagocytosis occurred refuting the idea that the emergence of drug resistant strains during therapy results in "super-bugs" of greater virulence. PMID:8879979

  12. Inhibition of bacterial growth by iron oxide nanoparticles with and without attached drug: Have we conquered the antibiotic resistance problem?

    NASA Astrophysics Data System (ADS)

    Armijo, Leisha M.; Jain, Priyanka; Malagodi, Angelina; Fornelli, F. Zuly; Hayat, Allison; Rivera, Antonio C.; French, Michael; Smyth, Hugh D. C.; Osiński, Marek

    2015-03-01

    Pseudomonas aeruginosa is among the top three leading causative opportunistic human pathogens, possessing one of the largest bacterial genomes and an exceptionally large proportion of regulatory genes therein. It has been known for more than a decade that the size and complexity of the P. aeruginosa genome is responsible for the adaptability and resilience of the bacteria to include its ability to resist many disinfectants and antibiotics. We have investigated the susceptibility of P. aeruginosa bacterial biofilms to iron oxide (magnetite) nanoparticles (NPs) with and without attached drug (tobramycin). We also characterized the susceptibility of zero-valent iron NPs, which are known to inactivate microbes. The particles, having an average diameter of 16 nm were capped with natural alginate, thus doubling the hydrodynamic size. Nanoparticle-drug conjugates were produced via cross-linking drug and alginate functional groups. Drug conjugates were investigated in the interest of determining dosage, during these dosage-curve experiments, NPs unbound to drug were tested in cultures as a negative control. Surprisingly, we found that the iron oxide NPs inhibited bacterial growth, and thus, biofilm formation without the addition of antibiotic drug. The inhibitory dosages of iron oxide NPs were investigated and the minimum inhibitory concentrations are presented. These findings suggest that NP-drug conjugates may overcome the antibiotic drug resistance common in P. aeruginosa infections.

  13. Antimicrobial potential of Halophilic actinomycetes against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens.

    PubMed

    Aslam, Sana; Sajid, Imran

    2016-03-01

    A collection of forty halophilic actinomycetes isolated from water and mud samples of the saline lake at Kalar Kahar, salt range, Pakistan, was screened to investigate their antimicrobial potential against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. The isolates exhibited significant tolerance to alkaline conditions and grew well at pH 9-11. The taxonomic status of the isolated strains was determined by morphological, biochemical and physiological characterization and by 16s rRNA gene sequencing. The results revealed that majority of the isolates (90%) belong to the genus Streptomyces. Most of the isolates exhibited remarkable antimicrobial activity up to 20mm zone of inhibition against MDR ventilator associated pneumonia causing bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Escherichia coli, Enterobacter and Acinetobacter spp. Additionally the isolates showed moderate to high cytotoxicity in the range of 40 to 80% larval mortality against Artemia salina in a micro well cytotoxicity assay. The chemical screening or the so called metabolic fingerprinting of the methanolic extracts of each isolate, by thin layer chromatography (TLC) using various staining reagents and by high performance liquid chromatography (HPLC-UV), indicated an impressive diversity of the compounds produced by these strains. The study reveals that these halophilic actinomycetes are a promising source of bioactive compounds. The preparative scale fermentation, isolation, purification and structure elucidation of the compounds produced by them may yield novel antimicrobial or chemotherapeutic agents. PMID:27087086

  14. Drug resistance of bacterial dental biofilm and the potential use of natural compounds as alternative for prevention and treatment.

    PubMed

    Kouidhi, Bochra; Al Qurashi, Yasir Mohammed A; Chaieb, Kamel

    2015-03-01

    Oral diseases, such as dental caries and periodontal disease are directly linked with the ability of bacteria to form biofilm. The development of dental caries involves acidogenic and aciduric Gram-positive bacteria colonizing the supragingival biofilm (Streptococcus, Lactobacillus and Actinomycetes). Periodontal diseases have been linked to anaerobic Gram-negative bacteria forming a subgingival plaque (Porphyromonas gingivalis, Actinobacillus, Prevotella and Fusobacterium). Cells embedded in biofilm are up to 1000-fold more resistant to antibiotics compared to their planctonic ones. Several mechanisms have been proposed to explain biofilms drug resistance. Given the increased bacterial resistance to antibiotics currently used in dentistry, a great importance is given to natural compounds for the prevention of oral bacterial growth, adhesion and colonization. Over the past decade, interest in drugs derived from medicinal plants has markedly increased. It has been well documented that medicinal plants and natural compounds confer considerable antibacterial activity against various microorganisms including cariogenic and periodontal pathogens. This paper provides a review of the literature focusing on the studies on (i) biofilm in the oral cavity, (ii) drug resistance of bacterial biofilm and (iii) the potential use of plant extracts, essential oils and natural compounds as biofilm preventive agents in dentistry, involving their origin and their mechanism of biofilm inhibition. PMID:25708507

  15. Bacterial quorum sensing inhibitors: attractive alternatives for control of infectious pathogens showing multiple drug resistance.

    PubMed

    Bhardwaj, Ashima K; Vinothkumar, Kittappa; Rajpara, Neha

    2013-04-01

    Quorum sensing (QS) is a bacterial communication process that depends on the bacterial population density. It involves small diffusible signaling molecules which activate the expression of myriad genes that control diverse array of functions like bioluminescence, virulence, biofilm formation, sporulation, to name a few. Since QS is responsible for virulence in the clinically relevant bacteria, inhibition of QS appears to be a promising strategy to control these pathogenic bacteria. With indiscriminate use of antibiotics, there has been an alarming increase in the number of antibiotic resistant pathogens. Antibiotics are no longer the magic bullets they were once thought to be and therefore there is a need for development of new antibiotics and/or other novel strategies to combat the infections caused by multidrug resistant organisms. Quorum sensing inhibition or quorum quenching has been pursued as one of such novel strategies. While antibiotics kill or slow down the growth of bacteria, quorum sensing inhibitors (QSIs) or quorum quenchers (QQs) attenuate bacterial virulence. A large body of work on QS has been carried out in deadly pathogens like Pseudomonas aeruginosa, Staphylococcus aureus, Vibrio fischeri, V. harveyi, Escherichia coli and V. cholerae etc to unravel the mechanisms of QS as well as identify and study QSIs. This review describes various aspects of QS, QSI, different model systems to study these phenomena and recent patents on various QSIs. It suggests QSIs as attractive alternatives for controlling human, animal and plant pathogens and their utility in agriculture and other industries. PMID:23394143

  16. A Copper-responsive Global Repressor Regulates Expression of Diverse Membrane-associated Transporters and Bacterial Drug Resistance in Mycobacteria*

    PubMed Central

    Rao, Muding; Liu, Huicong; Yang, Min; Zhao, Chunchao; He, Zheng-Guo

    2012-01-01

    Sequencing of entire bacterial genomes has led to the identification of many membrane-associated transporters, including several multidrug resistance transport proteins, in recent years. However, the regulators and signaling pathways involved in the expression of these genes remain largely unknown. In this study, we have identified Ms2173, a GntR/FadR family transcription factor, as a novel global regulator in Mycobacterium smegmatis. Ms2173 was found to specifically recognize a 15-bp palindromic motif and to broadly regulate expression of 292 genes, including 37 genes that encode membrane-associated transport proteins. Copper ions induced Ms2173 to form inactive proteins lacking DNA-binding activity. Ms2173 was shown to function as a repressor of its target genes. Interestingly, we found that the function of Ms2173 was linked to mycobacterial drug resistance. Compared with the substantially enhanced drug resistance in the Ms2173-deleted mutant strain, the strains overexpressing Ms2173 were more sensitive to anti-tuberculosis drugs than the wild-type strain. Additionally, copper ions could partially counteract the in vivo function of Ms2173. We have thus characterized the first mycobacterial GntR/Fad-like transcription factor that functions as a copper ion-responsive global repressor that we have renamed GfcR. These findings further enhance our understanding of membrane-associated transporter regulation and drug resistance in mycobacteria. PMID:23014988

  17. Drug Resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Drug resistance refers to both intrinsic and acquired abilities of cells or organisms to become insensitive or refractory to chemotherapeutic intervention. The advent of antibiotics is considered one of the most important medicinal developments in human history, which has led to significantly reduce...

  18. Bacterial energetics and antimicrobial resistance.

    PubMed

    Proctor, R A; von Humboldt, A

    1998-01-01

    Defining resistance to antimicrobics with specific terms is very useful as the precise mechanisms often lead to better susceptibility testing and improved treatment of bacterial infections. When one can characterize a class of phenotypic resistant organisms as electron transport variants, this has value in that it provides information about the basis for resistance and removes them from the non-specific categorization as phenotypically resistant. Studies of bacterial small colony variants (SCVs) has provided new insights into antimicrobial resistance as well as the connection between expression of virulence factors and energy metabolism. It also provides a framework for further studies which link antibiotic resistance to phase of growth, availability of nutrients, other environmental conditions, and adaptations to stress into a single model wherein the bacterial cell uses the products of energy metabolism to detect its sense of well being and to alter its response to antibiotics (Fig. I). Levels of NADH and ATP are able to act as signaling molecules in both gram positive an gram negative bacteria to activate stress sigma factors and two component systems. In the future, a full understanding of the signaling pathways in bacterial pathogens may provide new targets for the development of drugs to reduce bacterial virulence and to enhance the activity of existing antibiotics. PMID:16904405

  19. Predominance of multi-drug resistant bacterial pathogens causing surgical site infections in Muhimbili national hospital, Tanzania

    PubMed Central

    2014-01-01

    Background Surgical site infections (SSIs) remain a common and widespread problem contributing to a significant morbidity and mortality, attributed partly by the increase in antimicrobial resistance among the etiological agents. This study was done to determine the spectrum of bacterial isolates and their susceptibility patterns causing SSIs at Muhimbili National Hospital, Tanzania. Methods This descriptive cross sectional study was conducted between September, 2011 and February, 2012. Pus swabs or pus were cultured on blood agar (Oxoid, UK) and MacConkey agar (Oxoid, UK) and incubated aerobically at 37°C for 18–24 hours. Bacterial identification was done using API 20E and VITEK and antimicrobial susceptibility was determined by Kirby Bauer disc diffusion. Results Of the 100 patients, from whom wound swabs were collected, 90 (90%) had positive aerobic bacterial growth. A total of 147 pathogenic bacteria were isolated, including 114 (77.5%) gram negative and 33(22.5%) gram positive organisms. The most prevalent bacterial species were Pseudomonas aeruginosa (16.3%), followed by Staphylococcus aureus (12.2%) and Klebsiella pneumoniae (10.8%). Of the 18 S. aureus , 8 (44%) were methicillin resistant Staphylococcus aureus (MRSA) and three of them (17%) were carrying both MRSA and induced clindamycin resistance (ICR). Extended spectrum beta-lactamase (ESBL) producing Enterobacteriaceae were observed in 23 (79.3%) of the 29 isolates tested. Majority of Escherichia coli 12 (92.3%) and K. pneumoniae 11 (69%) isolates were ESBL producers. About 63% (93/147) were multiple-drug resistance (MDR) isolates, and the overall MDR among Gram positive and Gram negative bacteria was 60.6% (20/33) and 61.4%, (73/114), respectively. The prevalence of MDR for E. coli, A. baumannii and P. stuartii was 100% each. Majority (97%) of the Gram negative bacteria were resistant to more than four categories (classes) of antibiotics. Conclusion A high proportion (63%) of the isolates causing SSIs in this tertiary hospital were MDR, of which (90%) were resistant to more than four classes of antibiotics. In the light of these findings, an urgent and significant change in antibiotic prescription policy is required at this National hospital. PMID:25100042

  20. Epidemics of Drug-Resistant Bacterial Infections Observed in Infectious Disease Surveillance in Japan, 2001-2005

    PubMed Central

    Izumida, Michiko; Nagai, Masaki; Ohta, Akiko; Hashimoto, Shuji; Kawado, Miyuki; Murakami, Yoshitaka; Tada, Yuki; Shigematsu, Mika; Yasui, Yoshinori; Taniguchi, Kiyosu

    2008-01-01

    BACKGROUND Drug-resistant bacteria have been increasing together with advancement of antimicrobial chemotherapy in recent years. In Japan, the target diseases in the National Epidemiological Surveillance of Infectious Diseases (NESID) include some drug-resistant bacterial infections. METHODS We used the data in the NESID in Japan, 2001-2005. Target diseases were methicillin-resistant Staphylococcus aureus (MRSA), penicillin-resistant Streptococcus pneumoniae (PRSP) and multi-drug-resistant Pseudomonas aeruginosa (MDRPA) infections. The numbers of patients reported by sentinel hospitals (about 500) on a monthly basis were observed. RESULTS The numbers of patients per month per sentinel hospital of 2001-2005 were 3.37-3.98 in MRSA, 0.96-1.19 in PRSP, and 0.11-0.13 in MDRPA infections. The sex ratios (male / female) of patients were 1.69-1.82, 1.34-1.43, and 1.71-2.52, respectively. More than 50% of all patients were adults aged 70 years or older in MRSA and MDRPA infections, but more than 60% were children under 10 years in PRSP infections. The number of patients per sentinel hospital in MRSA infections showed little variation between months, but evidenced a large variation in PRSP and MDRPA infections. The annual trend in the number of patients per sentinel hospital was increasing significantly for the 5-year period in MRSA and PRSP infections, but not in MDRPA infections. CONCLUSIONS We revealed sex-age distributions of the patients reported to NESID in Japan, 2001-2005. An increasing incidence of MRSA and PRSP infections and monthly variation in PRSP and MDRPA infections were observed for the 5-year period. Extended observation would be necessary to confirm these trends and variations. PMID:18239341

  1. Host defenses and bacterial resistance.

    PubMed

    Yancey, M K

    1992-09-01

    The amount of knowledge and understanding about the human immune system has expanded rapidly in the past several decades. The ability of the physician to care for pregnant women, specifically those with infectious diseases, can be enhanced through a basic understanding of host defenses and the normal alterations of these defenses encountered during pregnancy. A general understanding of bacterial resistance to antimicrobial agents will also aid the practitioner in selecting the appropriate setting and agent when prescribing these drugs. PMID:1436921

  2. Globally dispersed mobile drug-resistance genes in Gram-negative bacterial isolates from patients with bloodstream infections in a US urban general hospital

    PubMed Central

    Adams-Sapper, S.; Sergeevna-Selezneva, J.; Tartof, S.; Raphael, E.; Diep, B. An; Perdreau-Remington, F.

    2012-01-01

    Mobile drug-resistance genes with identical nucleic acid sequences carried by multidrug-resistant Escherichia coli strains that cause community-acquired infections are becomingly increasingly dispersed worldwide. Over a 2-year period, we analysed Gram-negative bacterial (GNB) pathogens from the blood of inpatients at an urban public hospital to determine what proportion of these isolates carried such globally dispersed drug-resistance genes. Of 376 GNB isolates, 167 (44 %) were Escherichia coli, 50 (13 %) were Klebsiella pneumoniae, 25 (7 %) were Pseudomonas aeruginosa, 25 (7 %) were Proteus mirabilis and 20 (5 %) were Enterobacter cloacae; the remainder (24 %) comprised 26 different GNB species. Among E. coli isolates, class 1 integrons were detected in 64 (38 %). The most common integron gene cassette configuration was dfrA17-aadA5, found in 30 (25 %) of 119 drug-resistant E. coli isolates and in one isolate of Moraxella morganii. Extended-spectrum β-lactamase (ESBL) genes were found in 16 E. coli isolates (10 %). These genes with identical sequences were found in nearly 40 % of bloodstream E. coli isolates in the study hospital, as well as in a variety of bacterial species from clinical and non-clinical sources worldwide. Thus, a substantial proportion of bloodstream infections among hospitalized patients were caused by E. coli strains carrying drug-resistance genes that are dispersed globally in a wide variety of bacterial species. PMID:22493279

  3. Mechanisms of drug resistance: quinolone resistance.

    PubMed

    Hooper, David C; Jacoby, George A

    2015-09-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large. PMID:26190223

  4. Aloe vera extract functionalized zinc oxide nanoparticles as nanoantibiotics against multi-drug resistant clinical bacterial isolates.

    PubMed

    Ali, Khursheed; Dwivedi, Sourabh; Azam, Ameer; Saquib, Quaiser; Al-Said, Mansour S; Alkhedhairy, Abdulaziz A; Musarrat, Javed

    2016-06-15

    ZnO nanoparticles (ZnONPs) were synthesised through a simple and efficient biogenic synthesis approach, exploiting the reducing and capping potential of Aloe barbadensis Miller (A. vera) leaf extract (ALE). ALE-capped ZnO nanoparticles (ALE-ZnONPs) were characterized using UV-Vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM) analyses. XRD analysis provided the average size of ZnONPs as 15nm. FTIR spectral analysis suggested the role of phenolic compounds, terpenoids and proteins present in ALE, in nucleation and stability of ZnONPs. Flow cytometry and atomic absorption spectrophotometry (AAS) data analyses revealed the surface binding and internalization of ZnONPs in Gram +ve (Staphylococcus aureus) and Gram -ve (Escherichia coli) cells, respectively. Significant antibacterial activity of ALE-ZnONPs was observed against extended spectrum beta lactamases (ESBL) positive E. coli, Pseudomonas aeruginosa, and methicillin resistant S. aureus (MRSA) clinical isolates exhibiting the MIC and MBC values of 2200, 2400μg/ml and 2300, 2700μg/ml, respectively. Substantial inhibitory effects of ALE-ZnONPs on bacterial growth kinetics, exopolysaccharides and biofilm formation, unequivocally suggested the antibiotic and anti-biofilm potential. Overall, the results elucidated a rapid, environmentally benign, cost-effective, and convenient method for ALE-ZnONPs synthesis, for possible applications as nanoantibiotics or drug carriers. PMID:27031596

  5. Vancomycin pharmacokinetic models: informing the clinical management of drug-resistant bacterial infections.

    PubMed

    Stockmann, Chris; Roberts, Jessica K; Yu, Tian; Constance, Jonathan E; Knibbe, Catherijne A J; Spigarelli, Michael G; Sherwin, Catherine M T

    2014-11-01

    This review aims to critically evaluate the pharmacokinetic literature describing the use of vancomycin in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. Guidelines recommend that trough concentrations be used to guide vancomycin dosing for the treatment of MRSA infections; however, numerous in vitro, animal model and clinical studies have demonstrated that the therapeutic effectiveness of vancomycin is best described by the area under the concentration versus time curve (AUC) divided by the minimum inhibitory concentration (MIC) of the infecting organism (AUC/MIC). Among patients with lower respiratory tract infections, an AUC/MIC ≥400 was associated with a superior clinical and bacteriological response. Similarly, patients with MRSA bacteremia who achieved an Etest AUC/MIC ≥320 within 48 h were 50% less likely to experience treatment failure. For other patient populations and different clinical syndromes (e.g., children, the elderly, patients with osteomyelitis, etc.), pharmacokinetic/pharmacodynamic studies and prospective clinical trials are needed to establish appropriate therapeutic targets. PMID:25301231

  6. Bacterial strategies of resistance to antimicrobial peptides.

    PubMed

    Joo, Hwang-Soo; Fu, Chih-Iung; Otto, Michael

    2016-05-26

    Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'. PMID:27160595

  7. Synthetic interaction between the TipN polarity factor and an AcrAB-family efflux pump implicates cell polarity in bacterial drug resistance.

    PubMed

    Kirkpatrick, Clare L; Viollier, Patrick H

    2014-05-22

    Quinolone antibiotics are clinically important drugs that target bacterial DNA replication and chromosome segregation. Although the AcrAB-family efflux pumps generally protect bacteria from such drugs, the physiological role of these efflux systems and their interplay with other cellular events are poorly explored. Here, we report an intricate relationship between antibiotic resistance and cell polarity in the model bacterium Caulobacter crescentus. We show that a polarity landmark protein, TipN, identified by virtue of its ability to direct flagellum placement to the new cell pole, protects cells from toxic misregulation of an AcrAB efflux pump through a cis-encoded nalidixic acid-responsive transcriptional repressor. Alongside the importance of polarity in promoting the inheritance and activity of virulence functions including motility, we can now ascribe to it an additional role in drug resistance that is distinct from classical efflux mechanisms. PMID:24726830

  8. Polysaccharide-capped silver Nanoparticles inhibit biofilm formation and eliminate multi-drug-resistant bacteria by disrupting bacterial cytoskeleton with reduced cytotoxicity towards mammalian cells.

    PubMed

    Sanyasi, Sridhar; Majhi, Rakesh Kumar; Kumar, Satish; Mishra, Mitali; Ghosh, Arnab; Suar, Mrutyunjay; Satyam, Parlapalli Venkata; Mohapatra, Harapriya; Goswami, Chandan; Goswami, Luna

    2016-01-01

    Development of effective anti-microbial therapeutics has been hindered by the emergence of bacterial strains with multi-drug resistance and biofilm formation capabilities. In this article, we report an efficient green synthesis of silver nanoparticle (AgNP) by in situ reduction and capping with a semi-synthetic polysaccharide-based biopolymer (carboxymethyl tamarind polysaccharide). The CMT-capped AgNPs were characterized by UV, DLS, FE-SEM, EDX and HR-TEM. These AgNPs have average particle size of ~20-40 nm, and show long time stability, indicated by their unchanged SPR and Zeta-potential values. These AgNPs inhibit growth and biofilm formation of both Gram positive (B. subtilis) and Gram negative (E. coli and Salmonella typhimurium) bacterial strains even at concentrations much lower than the minimum inhibitory concentration (MIC) breakpoints of antibiotics, but show reduced or no cytotoxicity against mammalian cells. These AgNPs alter expression and positioning of bacterial cytoskeletal proteins FtsZ and FtsA. CMT-capped AgNPs can effectively block growth of several clinical isolates and MDR strains representing different genera and resistant towards multiple antibiotics belonging to different classes. We propose that the CMT-capped AgNPs can have potential bio-medical application against multi-drug-resistant microbes with minimal cytotoxicity towards mammalian cells. PMID:27125749

  9. Polysaccharide-capped silver Nanoparticles inhibit biofilm formation and eliminate multi-drug-resistant bacteria by disrupting bacterial cytoskeleton with reduced cytotoxicity towards mammalian cells

    PubMed Central

    Sanyasi, Sridhar; Majhi, Rakesh Kumar; Kumar, Satish; Mishra, Mitali; Ghosh, Arnab; Suar, Mrutyunjay; Satyam, Parlapalli Venkata; Mohapatra, Harapriya; Goswami, Chandan; Goswami, Luna

    2016-01-01

    Development of effective anti-microbial therapeutics has been hindered by the emergence of bacterial strains with multi-drug resistance and biofilm formation capabilities. In this article, we report an efficient green synthesis of silver nanoparticle (AgNP) by in situ reduction and capping with a semi-synthetic polysaccharide-based biopolymer (carboxymethyl tamarind polysaccharide). The CMT-capped AgNPs were characterized by UV, DLS, FE-SEM, EDX and HR-TEM. These AgNPs have average particle size of ~20–40 nm, and show long time stability, indicated by their unchanged SPR and Zeta-potential values. These AgNPs inhibit growth and biofilm formation of both Gram positive (B. subtilis) and Gram negative (E. coli and Salmonella typhimurium) bacterial strains even at concentrations much lower than the minimum inhibitory concentration (MIC) breakpoints of antibiotics, but show reduced or no cytotoxicity against mammalian cells. These AgNPs alter expression and positioning of bacterial cytoskeletal proteins FtsZ and FtsA. CMT-capped AgNPs can effectively block growth of several clinical isolates and MDR strains representing different genera and resistant towards multiple antibiotics belonging to different classes. We propose that the CMT-capped AgNPs can have potential bio-medical application against multi-drug-resistant microbes with minimal cytotoxicity towards mammalian cells. PMID:27125749

  10. Bacterial resistance to antimicrobial peptides: an evolving phenomenon.

    PubMed

    Fleitas, Osmel; Agbale, Caleb M; Franco, Octavio L

    2016-01-01

    Bacterial resistance to conventional antibiotics is currently a real problem all over the world, making novel antimicrobial compounds a real research priority. Some of the most promising compounds found to date are antimicrobial peptides (AMPs). The benefits of these drugs include their broad spectrum of activity that affects several microbial processes, making the emergence of resistance less likely. However, bacterial resistance to AMPs is an evolving phenomenon that compromises the therapeutic potential of these compounds. Therefore, it is mandatory to understand bacterial mechanisms of resistance to AMPs in depth, in order to develop more powerful AMPs that overcome the bacterial resistance response. PMID:27100488

  11. Transfer between an Algerian and a French hospital of four multi-drug resistant bacterial strains together via a single patient

    PubMed Central

    Moissenet, Didier; Richard, Patrick; Granados, Maria; Mérens, Audrey; Fournier, Damien; Fines-Guyon, Marguerite; Arlet, Guillaume; Vu-Thien, Hoang

    2015-01-01

    A 5 years-old girl, seriously burnt with fire, was first hospitalized during four days in an hospital at Alger, and then transferred to our hospital at Paris. Admitted in our intensive care burns unit, she was third degree burnt on 78% of total body surface area, already treated with imipenem and vancomycin at her arrival. Clinical aggravation was rapidly observed and death occurred within 24 hours. Cultures of blood and multiple wound swabs yielded 3 multi-drug resistant bacterial strains: Acinetobacter baumannii with carbapenemase OXA-23, Pseudomonas aeruginosa serotype O11 with metallo-ß-lactamase VIM-4 and Klebsiella pneumoniae with CTX-M-15 extended-spectrum ß-lactamase. Culture of a rectal swab showed colonization by Enterococcus faecium with vanA glycopeptides resistance. Patients colonized with one or two multi-drug-resistant strains were not rare in our burns unit, especially those transferred from Algeria, but this case of a single patient harboring four multi-drug-resistant strains is exceptional. PMID:26550534

  12. Transfer between an Algerian and a French hospital of four multi-drug resistant bacterial strains together via a single patient.

    PubMed

    Moissenet, Didier; Richard, Patrick; Granados, Maria; Mérens, Audrey; Fournier, Damien; Fines-Guyon, Marguerite; Arlet, Guillaume; Vu-Thien, Hoang

    2015-01-01

    A 5 years-old girl, seriously burnt with fire, was first hospitalized during four days in an hospital at Alger, and then transferred to our hospital at Paris. Admitted in our intensive care burns unit, she was third degree burnt on 78% of total body surface area, already treated with imipenem and vancomycin at her arrival. Clinical aggravation was rapidly observed and death occurred within 24 hours. Cultures of blood and multiple wound swabs yielded 3 multi-drug resistant bacterial strains: Acinetobacter baumannii with carbapenemase OXA-23, Pseudomonas aeruginosa serotype O11 with metallo-ß-lactamase VIM-4 and Klebsiella pneumoniae with CTX-M-15 extended-spectrum ß-lactamase. Culture of a rectal swab showed colonization by Enterococcus faecium with vanA glycopeptides resistance. Patients colonized with one or two multi-drug-resistant strains were not rare in our burns unit, especially those transferred from Algeria, but this case of a single patient harboring four multi-drug-resistant strains is exceptional. PMID:26550534

  13. Isolation and characterization of multiple drug resistance bacterial pathogens from waste water in hospital and non-hospital environments, Northwest Ethiopia

    PubMed Central

    2014-01-01

    Background The importance of bacterial isolates from waste water environment as a reservoir of antibiotic resistance and a potential source of novel resistance genes to clinical pathogens is underestimated. This study is aimed at to isolate and characterize public health important bacteria from waste water in hospital and non- hospital environments and evaluate the distribution of multiple drug resistance bacteria in the study area. Methods A cross-sectional study was conducted at Gondar from January-June 2012. The hospital waste water was taken from different sections of the Gondar University Teaching Hospital. Non- hospital environment samples were taken at different sites of the university campuses, Gondar College of Teachers education, and soft drink factory in Gondar. Samples were aseptically collected, transported and processed with in two hours following standard procedure. Identified organisms were assessed for different antibiotics following Kirby-Bauer disk diffusion method. All data was registered and entered in to SPSS version 16 computer program. P-values less than 0.05 were taken as statistically significant. Result A total of 60 waste water samples were processed for the presence of drug resistance pathogens. Among the total samples 113 bacterial isolates were recovered and of these 65 (57.5%) were from hospital environment and 48 (42.5%) were from non-hospital environment. The most frequently identified bacterium was Klebsiella spp. 30 (26.6%) followed by Pseudomonas spp. 19(16.8%), E. coli (11.5%) and Citrobacter spp (11.5%), and Staphylococcus aureus (8.2%). The over all prevalence of multiple drug resistance (MDR) in this study was 79/113 (69.9%). MDR in hospital environment was found to be 53/68 (81.5%) while in non hospital environment was found to be 26/48 (54.2%). Conclusions Multiple drug resistance to the commonly used antibiotics is high in the study area. The contamination of waste water by antibiotics or other pollutants lead to the rise of resistance due to selection pressure. The presence of antibiotic resistance organisms in this waste water should not be overlooked. Since this organisms may be vital to the safety and well-being of patients who are hospitalized and individual susceptible to infection. Therefore, proper waste water treatment plant should be established and improved sanitary measure should be practice. PMID:24708553

  14. Bacterial cheating limits antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Xiao Chao, Hui; Yurtsev, Eugene; Datta, Manoshi; Artemova, Tanya; Gore, Jeff

    2012-02-01

    The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain---which does not contribute to breaking down the antibiotic---may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors.

  15. Drug-resistant Diarrheogenic Escherichia coli, Mexico

    PubMed Central

    Cerna, Jorge F.; Paheco-Gil, Leova; Velázquez, Raúl F.; Ochoa, Theresa J.; Torres, Javier; DuPont, Herbert L.

    2005-01-01

    Diarrheogenic Escherichia coli isolates from 45 (73%) of 62 hospitalized patients were resistant to common antimicrobial drugs. Sixty-two percent were multidrug resistant, and >70% were resistant to trimethoprim-sulfamethoxazole and ampicillin. Ciprofloxacin and cefotaxime were uniformly active. Effective and safe oral agents are needed to treat children with bacterial diarrhea. PMID:16102327

  16. Regulation of Bacterial Drug Export Systems

    PubMed Central

    Grkovic, Steve; Brown, Melissa H.; Skurray, Ronald A.

    2002-01-01

    The active transport of toxic compounds by membrane-bound efflux proteins is becoming an increasingly frequent mechanism by which cells exhibit resistance to therapeutic drugs. This review examines the regulation of bacterial drug efflux systems, which occurs primarily at the level of transcription. Investigations into these regulatory networks have yielded a substantial volume of information that has either not been forthcoming from or complements that obtained by analysis of the transport proteins themselves. Several local regulatory proteins, including the activator BmrR from Bacillus subtilis and the repressors QacR from Staphylococcus aureus and TetR and EmrR from Escherichia coli, have been shown to mediate increases in the expression of drug efflux genes by directly sensing the presence of the toxic substrates exported by their cognate pump. This ability to bind transporter substrates has permitted detailed structural information to be gathered on protein-antimicrobial agent-ligand interactions. In addition, bacterial multidrug efflux determinants are frequently controlled at a global level and may belong to stress response regulons such as E. coli mar, expression of which is controlled by the MarA and MarR proteins. However, many regulatory systems are ill-adapted for detecting the presence of toxic pump substrates and instead are likely to respond to alternative signals related to unidentified physiological roles of the transporter. Hence, in a number of important pathogens, regulatory mutations that result in drug transporter overexpression and concomitant elevated antimicrobial resistance are often observed. PMID:12456787

  17. Antibiotic drugs targeting bacterial RNAs

    PubMed Central

    Hong, Weiling; Zeng, Jie; Xie, Jianping

    2014-01-01

    RNAs have diverse structures that include bulges and internal loops able to form tertiary contacts or serve as ligand binding sites. The recent increase in structural and functional information related to RNAs has put them in the limelight as a drug target for small molecule therapy. In addition, the recognition of the marked difference between prokaryotic and eukaryotic rRNA has led to the development of antibiotics that specifically target bacterial rRNA, reduce protein translation and thereby inhibit bacterial growth. To facilitate the development of new antibiotics targeting RNA, we here review the literature concerning such antibiotics, mRNA, riboswitch and tRNA and the key methodologies used for their screening. PMID:26579393

  18. Antimicrobial (Drug) Resistance Prevention

    MedlinePlus

    ... gov . Related Links Antibacterial Resistance Leadership Group (ARLG) Microbiology and Infectious Diseases Resources for Researchers NIAID Antimicrobial ... to properly dispose of unused medications, visit the Food and Drug Administration website . Healthy lifestyle habits, including ...

  19. Antimicrobial (Drug) Resistance

    MedlinePlus

    ... this site from a secured browser on the server. Please enable scripts and reload this page. Skip ... effective against drug-resistant microbes. Understanding Quick Facts Definitions of Terms Causes Diagnosis Treatment Prevention Examples of ...

  20. PCR amplfication on a microarray of gel-immobilized oligonucleotides : detection of bacterial toxin- and drug-resistent genes and their mutations.

    SciTech Connect

    Strizhkov, B. N.; Drobyshev, A. L.; Mikhailovich, V. M.; Mirzabekov, A. D.; Biochip Technology Center; Engelhardt Inst. of Molecular Biology

    2000-10-01

    PCR amplification on a microarray of gel-immobilized primers (microchip) has been developed. One of a pair of PCR primers was immobilized inside a separate microchip polyacrylamide porous gel pad of 0.1 x 0.1 x 0.02 (or 0.04) micron in size and 0.2 (or 0.4) nL in volume. The amplification was carried out simultaneously both in solution covering the microchip array and inside gel pads. Each gel pad contained the immobilized forward primers, while the fluorescently labeled reverse primers, as well as all components of the amplification reaction, diffused into the gel pads from the solution. To increase the amplification efficiency, the forward primers were also added into the solution. The kinetics of amplification was measured in real time in parallel for all gel pads with a fluorescent microscope equipped with a charge-coupled device (CCD) camera. The accuracy of the amplification was assessed by using the melting curves obtained for the duplexes formed by the labeled amplification product and the gel-immobilized primers during the amplification process; alternatively, the duplexes were produced by hybridization of the extended immobilized primers with labeled oligonucleotide probes. The on-chip amplification was applied to detect the anthrax toxin genes and the plasmid-borne beta-lactamase gene responsible for bacterial ampicillin resistance. The allele-specific type of PCR amplification was used to identify the Shiga toxin gene and discriminate it from the Shiga-like one. The genomic mutations responsible for rifampicin resistance of the Mycobacterium tuberculosis strains were detected by the same type of PCR amplification of the rpoB gene fragment isolated from sputum of tuberculosis patients. The on-chip PCR amplification has been shown to be a rapid, inexpensive and powerful tool to test genes responsible for bacterial toxin production and drug resistance, as well as to reveal point nucleotide mutations.

  1. Bacterial Enzymes and Antibiotic Resistance- Oral Presentation

    SciTech Connect

    Maltz, Lauren

    2015-08-25

    By using protein crystallography and X-ray diffraction, structures of bacterial enzymes were solved to gain a better understanding of how enzymatic modification acts as an antibacterial resistance mechanism. Aminoglycoside phosphotransferases (APHs) are one of three aminoglycoside modifying enzymes that confer resistance to the aminoglycoside antibiotics via enzymatic modification, rendering many drugs obsolete. Specifically, the APH(2”) family vary in their substrate specificities and also in their preference for the phosphate donor (ADP versus GDP). By solving the structures of members of the APH(2”) family of enzymes, we can see how domain movements are important to their substrate specificity. Our structure of the ternary complex of APH(2”)-IIIa with GDP and kanamycin, when compared to the known structures of APH(2”)-IVa, reveals that there are real physical differences between these two enzymes, a structural finding that explains why the two enzymes differ in their preferences for certain aminoglycosides. Another important group of bacterial resistance enzymes are the Class D β-lactamases. Oxacillinase carbapenemases (OXAs) are part of this enzyme class and have begun to confer resistance to ‘last resort’ drugs, most notably carbapenems. Our structure of OXA-143 shows that the conformational flexibility of a conserved hydrophobic residue in the active site (Val130) serves to control the entry of a transient water molecule responsible for a key step in the enzyme’s mechanism. Our results provide insight into the structural mechanisms of these two different enzymes.

  2. Overview perspective of bacterial resistance.

    PubMed

    Furtado, Guilherme H; Nicolau, David P

    2010-10-01

    The rapidly escalating prevalence of antimicrobial resistance is a global concern. This reduced susceptibility to currently available antimicrobial agents coupled with the progressive shortage of newly approved compounds is a worrisome situation. Major problems are encountered for a growing number of Gram-positive (i.e., Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus spp.) and Gram-negative pathogens (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae). We provide an overview of bacterial resistance focusing on the most common pathogens responsible for infection in both the community and healthcare settings. In addition, several strategies to curb antimicrobial resistance are also discussed. It is increasingly evident that without the introduction of novel antimicrobial agents, a return to the clinical outcomes associated with the pre-antibiotic era are inevitable. PMID:20687782

  3. Extensively drug-resistant bacteria are an independent predictive factor of mortality in 130 patients with spontaneous bacterial peritonitis or spontaneous bacteremia

    PubMed Central

    Alexopoulou, Alexandra; Vasilieva, Larisa; Agiasotelli, Danai; Siranidi, Kyriaki; Pouriki, Sophia; Tsiriga, Athanasia; Toutouza, Marina; Dourakis, Spyridon P

    2016-01-01

    AIM: To evaluate the epidemiology and outcomes of culture-positive spontaneous bacterial peritonitis (SBP) and spontaneous bacteremia (SB) in decompensated cirrhosis. METHODS: We prospectively collected clinical, laboratory characteristics, type of administered antibiotic, susceptibility and resistance of bacteria to antibiotics in one hundred thirty cases (68.5% males) with positive ascitic fluid and/or blood cultures during the period from January 1, 2012 to May 30, 2014. All patients with SBP had polymorphonuclear cell count in ascitic fluid > 250/mm3. In patients with SB a thorough study did not reveal any other cause of bacteremia. The patients were followed-up for a 30-d period following diagnosis of the infection. The final outcome of the patients was recorded in the end of follow-up and comparison among 3 groups of patients according to the pattern of drug resistance was performed. RESULTS: Gram-positive-cocci (GPC) were found in half of the cases. The most prevalent organisms in a descending order were Escherichia coli (33), Enterococcus spp (30), Streptococcus spp (25), Klebsiella pneumonia (16), S. aureus (8), Pseudomanas aeruginosa (5), other Gram-negative-bacteria (GNB) (11) and anaerobes (2). Overall, 20.8% of isolates were multidrug-resistant (MDR) and 10% extensively drug-resistant (XDR). Health-care-associated (HCA) and/or nosocomial infections were present in 100% of MDR/XDR and in 65.5% of non-DR cases. Meropenem was the empirically prescribed antibiotic in HCA/nosocomial infections showing a drug-resistance rate of 30.7% while third generation cephalosporins of 43.8%. Meropenem was ineffective on both XDR bacteria and Enterococcus faecium (E. faecium). All but one XDR were susceptible to colistin while all GPC (including E. faecium) and the 86% of GNB to tigecycline. Overall 30-d mortality was 37.7% (69.2% for XDR and 34.2% for the rest of the patients) (log rank, P = 0.015). In multivariate analysis, factors adversely affecting outcome included XDR infection (HR = 2.263, 95%CI: 1.005-5.095, P = 0.049), creatinine (HR = 1.125, 95%CI: 1.024-1.236, P = 0.015) and INR (HR =1.553, 95%CI: 1.106-2.180, P = 0.011). CONCLUSION: XDR bacteria are an independent life-threatening factor in SBP/SB. Strategies aiming at restricting antibiotic overuse and rapid identification of the responsible bacteria could help improve survival. PMID:27099449

  4. Clinical management of resistance evolution in a bacterial infection

    PubMed Central

    Woods, Robert J.; Read, Andrew F.

    2015-01-01

    We report the case of a patient with a chronic bacterial infection that could not be cured. Drug treatment became progressively less effective due to antibiotic resistance, and the patient died, in effect from overwhelming evolution. Even though the evolution of drug resistance was recognized as a major threat, and the fundamentals of drug resistance evolution are well understood, it was impossible to make evidence-based decisions about the evolutionary risks associated with the various treatment options. We present this case to illustrate the urgent need for translational research in the evolutionary medicine of antibiotic resistance. PMID:26454762

  5. Influenza drug resistance.

    PubMed

    Pizzorno, Andrés; Abed, Yacine; Boivin, Guy

    2011-08-01

    Influenza viruses are major human pathogens with a global distribution, accounting for more than 500,000 annual deaths worldwide and with considerable impact on the quality of life and productivity of the society. Due to the limited efficacy of vaccination, antiviral drugs constitute a complementary approach in the control and prevention of influenza infections and thus play an important role in the management of influenza outbreaks and pandemics. Currently, adamantanes and neuraminidase inhibitors (NAIs) are the only two classes of anti-influenza agents approved for clinical use. However, the worldwide emergence and high prevalence of adamantane-resistant virus variants has discouraged the use of the former drugs. NAIs have proved to be very effective against influenza A and B viruses. Nevertheless, oseltamivir-resistant strains have also been reported quite frequently, as in the case of seasonal H1N1 viruses that circulated between 2007 and 2009. Indeed, the emergence of drug-resistant virus variants is always a matter of concern because it could significantly compromise the usefulness of such intervention. This highlights the need for continuous monitoring of resistance markers, as well as the development of new anti-influenza drugs and combination therapies. PMID:21858746

  6. 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

  7. Dramatic increase of third-generation cephalosporin-resistant E. coli in German intensive care units: secular trends in antibiotic drug use and bacterial resistance, 2001 to 2008

    PubMed Central

    2010-01-01

    Introduction The objective of the present study was to analyse secular trends in antibiotic consumption and resistance data from a network of 53 intensive care units (ICUs). Methods The study involved prospective unit and laboratory-based surveillance in 53 German ICUs from 2001 through 2008. Data were calculated on the basis of proportions of nonduplicate resistant isolates, resistance densities (that is, the number of resistant isolates of a species per 1,000 patient-days) and an antimicrobial usage density (AD) expressed as daily defined doses (DDD) and normalised per 1,000 patient-days. Results Total mean antibiotic use remained stable over time and amounted to 1,172 DDD/1,000 patient-days (range 531 to 2,471). Carbapenem use almost doubled to an AD of 151 in 2008. Significant increases were also calculated for quinolone (AD of 163 in 2008) and third-generation and fourth-generation cephalosporin use (AD of 117 in 2008). Aminoglycoside consumption decreased substantially (AD of 86 in 2001 and 24 in 2008). Resistance proportions were as follows in 2001 and 2008, respectively: methicillin-resistant Staphylococcus aureus (MRSA) 26% and 20% (P = 0.006; trend test showed a significant decrease), vancomycin-resistant enterococcus (VRE) faecium 2.3% and 8.2% (P = 0.008), third-generation cephalosporin (3GC)-resistant Escherichia. coli 1.2% and 19.7% (P < 0.001), 3GC-resistant Klebsiella pneumoniae 3.8% and 25.5% (P < 0.001), imipenem-resistant Acinetobacter baumannii 1.1% and 4.5% (P = 0.002), and imipenem-resistant K. pneumoniae 0.4% and 1.1%. The resistance densities did not change for MRSA but increased significantly for VRE faecium and 3GC-resistant E. coli and K. pneumoniae. In 2008, the resistance density for MRSA was 3.73, 0.48 for VRE, 1.39 for 3GC-resistant E. coli and 0.82 for K. pneumoniae. Conclusions Although total antibiotic use did not change over time in German ICUs, carbapenem use doubled. This is probably due to the rise in 3GC-resistant E. coli and K. pneumoniae. Increased carbapenem consumption was associated with carbapenem-resistant K. pneumoniae carbapenemase-producing bacteria and imipenem-resistant A. baumannii. PMID:20546564

  8. Antibacterial drug discovery in the resistance era.

    PubMed

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era. PMID:26791724

  9. Antimalarial drug resistance: An overview

    PubMed Central

    Antony, Hiasindh Ashmi; Parija, Subhash Chandra

    2016-01-01

    Malaria is a major public health burden throughout the world. Resistance to the antimalarial drugs has increased the mortality and morbidity rate that is achieved so far through the malaria control program. Monitoring the drug resistance to the available antimalarial drugs helps to implement effective drug policy, through the in vivo efficacy studies, in vitro drug susceptibility tests and detection of molecular markers. It is important to understand the mechanism of the antimalarial drugs, as it is one of the key factors in the emergence and spread of drug resistance. This review summarizes the commonly used antimalarial drugs, their mechanism of action and the genetic markers validated so far for the detection of drug-resistant parasites. PMID:26998432

  10. 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

  11. Bacterial resistance in biofilm-associated bacteria.

    PubMed

    Venkatesan, Nandakumar; Perumal, Govindaraj; Doble, Mukesh

    2015-01-01

    Biofilms are structured groups of different bacterial species that are responsible for most chronic and recurrent infections. Biofilm-related infections reoccur in approximately 65-80% of cases. Bacteria associated with the biofilm are highly resistant to antibiotics. Knowledge of biofilm formation, its propagation and the resistance associated with it is scant and a multidisciplinary approach is followed to understand the science and develop strategies to address this problem. This article discusses the role of various biochemical factors, molecular mechanisms and altered host environment causes associated with bacterial resistance in biofilm. It also reveals the target sites and different multidisciplinary strategies adapted for destroying or preventing the formation of biofilms. PMID:26517598

  12. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    PubMed Central

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals. PMID:27092125

  13. Potential of novel antimicrobial peptide P3 from bovine erythrocytes and its analogs to disrupt bacterial membranes in vitro and display activity against drug-resistant bacteria in a mouse model.

    PubMed

    Zhang, Qinghua; Xu, Yanzhao; Wang, Qing; Hang, Bolin; Sun, Yawei; Wei, Xiaoxiao; Hu, Jianhe

    2015-05-01

    With the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activity in vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, both in vitro and in vivo. The MICs of P3 and JH-3 ranged from 3.125 μg/ml to 50 μg/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an α-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD50) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria. PMID:25753638

  14. Potential of Novel Antimicrobial Peptide P3 from Bovine Erythrocytes and Its Analogs To Disrupt Bacterial Membranes In Vitro and Display Activity against Drug-Resistant Bacteria in a Mouse Model

    PubMed Central

    Zhang, Qinghua; Wang, Qing; Hang, Bolin; Sun, Yawei; Wei, Xiaoxiao

    2015-01-01

    With the emergence of many antibiotic-resistant strains worldwide, antimicrobial peptides (AMPs) are being evaluated as promising alternatives to conventional antibiotics. P3, a novel hemoglobin peptide derived from bovine erythrocytes, exhibited modest antimicrobial activity in vitro. We evaluated the antimicrobial activities of P3 and an analog, JH-3, both in vitro and in vivo. The MICs of P3 and JH-3 ranged from 3.125 ?g/ml to 50 ?g/ml when a wide spectrum of bacteria was tested, including multidrug-resistant strains. P3 killed bacteria within 30 min by disrupting the bacterial cytoplasmic membrane and disturbing the intracellular calcium balance. Circular dichroism (CD) spectrometry showed that P3 assumed an ?-helical conformation in bacterial lipid membranes, which was indispensable for antimicrobial activity. Importantly, the 50% lethal dose (LD50) of JH-3 was 180 mg/kg of mouse body weight after intraperitoneal (i.p.) injection, and no death was observed at any dose up to 240 mg/kg body weight following subcutaneous (s.c.) injection. Furthermore, JH-3 significantly decreased the bacterial count and rescued infected mice in a model of mouse bacteremia. In conclusion, P3 and an analog exhibited potent antimicrobial activities and relatively low toxicities in a mouse model, indicating that they may be useful for treating infections caused by drug-resistant bacteria. PMID:25753638

  15. Antibiotics and Bacterial Resistance in the 21st Century

    PubMed Central

    Fair, Richard J; Tor, Yitzhak

    2014-01-01

    Dangerous, antibiotic resistant bacteria have been observed with increasing frequency over the past several decades. In this review the factors that have been linked to this phenomenon are addressed. Profiles of bacterial species that are deemed to be particularly concerning at the present time are illustrated. Factors including economic impact, intrinsic and acquired drug resistance, morbidity and mortality rates, and means of infection are taken into account. Synchronously with the waxing of bacterial resistance there has been waning antibiotic development. The approaches that scientists are employing in the pursuit of new antibacterial agents are briefly described. The standings of established antibiotic classes as well as potentially emerging classes are assessed with an emphasis on molecules that have been clinically approved or are in advanced stages of development. Historical perspectives, mechanisms of action and resistance, spectrum of activity, and preeminent members of each class are discussed. PMID:25232278

  16. Mechanisms of bacterial resistance to antimicrobial agents.

    PubMed

    Stratton, C W

    2000-01-01

    The 20th century has been considered the antimicrobial era--whereas the 21st century may well represent the post-antimicrobial era. The reason for this dramatic change, should it come to pass, is the development of bacterial resistance to antimicrobial agents. This emerging resistance is now challenging the clinical utility of many antimicrobial agents such that the chemotherapy of hospitalized patients with serious infections has been compromised. If the problem with resistance is to be successfully dealt with by clinicians, the mechanisms of such resistance must be known and understood. This paper thus reviews the most important mechanisms of resistance as well as some of the most important pathogens having these mechanisms. An understanding of these important microbial resistance mechanisms will help the clinician identify circumstances in which resistance may be a problem as well as evaluating the potential usefulness of an alternate antimicrobial agent against resistant microbes. PMID:11214188

  17. Communicating trends in resistance using a drug resistance index

    PubMed Central

    Klugman, Keith P

    2011-01-01

    Background Antibiotic resistance is a growing problem worldwide, but communicating this challenge to policymakers and non-experts is complicated by the multiplicity of bacterial pathogens and the distinct classes of antibiotics used to treat them. It is difficult, even for experts aware of the pharmacodynamics of antibiotics, to infer the seriousness of resistance without information on how commonly the antibiotic is being used and whether alternative antibiotics are available. Difficulty in aggregating resistance to multiple drugs to assess trends poses a further challenge to quantifying and communicating changes in resistance over time and across locations. Methods We developed a method for aggregating bacterial resistance to multiple antibiotics, creating an index comparable to the composite economic indices that measure consumer prices and stock market values. The resulting drug resistance index (DRI) and various subindices show antibiotic resistance and consumption trends in the USA but can be applied at any geographical level. Findings The DRI based on use patterns in 1999 for Escherichia coli rose from 0.25 (95% CI 0.23 to 0.26) to 0.30 (95% CI 0.29 to 0.32) between 1999 and 2006. However, the adaptive DRI, which includes treatment of baseline resistant strains with alternative agents, climbed from 0.25 to 0.27 (95% CI 0.25 to 0.28) during that period. In contrast, both the static-use and the adaptive DRIs for Acinetobacter spp. rose from 0.41 (95% CI 0.4 to 0.42) to 0.48 (95% CI 0.46 to 0.49) between 1999 and 2006. Interpretation Divergence between the static-use and the adaptive-use DRIs for E coli reflects the ability of physicians to adapt to increasing resistance. However, antibiotic use patterns did not change much in response to growing resistance to Acinetobacter spp. because physicians were unable to adapt; new drugs for Acinetobacter spp. are therefore needed. Composite indices that aggregate resistance to various drugs can be useful for assessing changes in drug resistance across time and space. PMID:22102636

  18. Communicating trends in resistance using a drug resistance index.

    PubMed

    Laxminarayan, Ramanan; Klugman, Keith P

    2011-01-01

    Background Antibiotic resistance is a growing problem worldwide, but communicating this challenge to policymakers and non-experts is complicated by the multiplicity of bacterial pathogens and the distinct classes of antibiotics used to treat them. It is difficult, even for experts aware of the pharmacodynamics of antibiotics, to infer the seriousness of resistance without information on how commonly the antibiotic is being used and whether alternative antibiotics are available. Difficulty in aggregating resistance to multiple drugs to assess trends poses a further challenge to quantifying and communicating changes in resistance over time and across locations. Methods We developed a method for aggregating bacterial resistance to multiple antibiotics, creating an index comparable to the composite economic indices that measure consumer prices and stock market values. The resulting drug resistance index (DRI) and various subindices show antibiotic resistance and consumption trends in the USA but can be applied at any geographical level. Findings The DRI based on use patterns in 1999 for Escherichia coli rose from 0.25 (95% CI 0.23 to 0.26) to 0.30 (95% CI 0.29 to 0.32) between 1999 and 2006. However, the adaptive DRI, which includes treatment of baseline resistant strains with alternative agents, climbed from 0.25 to 0.27 (95% CI 0.25 to 0.28) during that period. In contrast, both the static-use and the adaptive DRIs for Acinetobacter spp. rose from 0.41 (95% CI 0.4 to 0.42) to 0.48 (95% CI 0.46 to 0.49) between 1999 and 2006. Interpretation Divergence between the static-use and the adaptive-use DRIs for E coli reflects the ability of physicians to adapt to increasing resistance. However, antibiotic use patterns did not change much in response to growing resistance to Acinetobacter spp. because physicians were unable to adapt; new drugs for Acinetobacter spp. are therefore needed. Composite indices that aggregate resistance to various drugs can be useful for assessing changes in drug resistance across time and space. PMID:22102636

  19. Bacterial charity work leads to population-wide resistance.

    PubMed

    Lee, Henry H; Molla, Michael N; Cantor, Charles R; Collins, James J

    2010-09-01

    Bacteria show remarkable adaptability in the face of antibiotic therapeutics. Resistance alleles in drug target-specific sites and general stress responses have been identified in individual end-point isolates. Less is known, however, about the population dynamics during the development of antibiotic-resistant strains. Here we follow a continuous culture of Escherichia coli facing increasing levels of antibiotic and show that the vast majority of isolates are less resistant than the population as a whole. We find that the few highly resistant mutants improve the survival of the population's less resistant constituents, in part by producing indole, a signalling molecule generated by actively growing, unstressed cells. We show, through transcriptional profiling, that indole serves to turn on drug efflux pumps and oxidative-stress protective mechanisms. The indole production comes at a fitness cost to the highly resistant isolates, and whole-genome sequencing reveals that this bacterial altruism is made possible by drug-resistance mutations unrelated to indole production. This work establishes a population-based resistance mechanism constituting a form of kin selection whereby a small number of resistant mutants can, at some cost to themselves, provide protection to other, more vulnerable, cells, enhancing the survival capacity of the overall population in stressful environments. PMID:20811456

  20. Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

    PubMed

    Andersson, D I; Hughes, D; Kubicek-Sutherland, J Z

    2016-05-01

    Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings. PMID:27180309

  1. How drug resistance takes shape

    PubMed Central

    Jeselsohn, Rinath

    2016-01-01

    Mutations in a hormone receptor can lead to therapeutic resistance by making it less able to bind and respond to hormone blocking drugs and by making it active, even when the hormome is not present. PMID:27010172

  2. Bacterial genome sequencing and drug discovery.

    PubMed

    Allsop, A E

    1998-12-01

    The availability of bacterial genome sequence information has opened up many new strategies for antibacterial drug hunting. There are obvious benefits for the identification and evaluation of new drug targets, but genomic-based technology is also beginning to provide new tools for the downstream, preclinical, optimisation of compounds. The greatest benefit from these new approaches lies in the ability to examine the entire genome (or several genomes) simultaneously and in total. In this way, one potential target can be evaluated against another, and either the total effects of functional impairment can be established or the effects of a compound can be compared across species. PMID:9889137

  3. Antibiotic resistance in prevalent bacterial and protozoan sexually transmitted infections

    PubMed Central

    Krupp, Karl; Madhivanan, Purnima

    2015-01-01

    The emergence of multi-drug resistant sexually transmitted infections (STIs) is causing a treatment crisis across the globe. While cephalosporin-resistant gonorrhea is one of the most pressing issues, extensively antibiotic resistant Chlamydia trachomatis and Mycoplasma hominis are also becoming commonplace. Experts have suggested that the failure of current treatment regimens are “largely inevitable” and have called for entirely new classes of antimicrobial agents. With the exception of several new classes of drugs primarily targeting nosocomial infections, progress has been slow. While pharmaceutical companies continue to introduce new drugs, they are based on decade-old discoveries. While there is disagreement about what constitutes new classes of antibiotics, many experts suggest that the last truly new family of antimicrobials was discovered in 1987. This review summarizes the existing literature on antibiotic resistance in common bacterial and protozoal STIs. It also briefly discusses several of the most promising alternatives to current therapies, and further examines how advances in drug delivery, formulation, concentration, and timing are improving the efficacy of existing treatments. Finally, the paper discusses the current state of pharmaceutical development for multidrug-resistant STI. PMID:26392647

  4. Antibiotic resistance in prevalent bacterial and protozoan sexually transmitted infections.

    PubMed

    Krupp, Karl; Madhivanan, Purnima

    2015-01-01

    The emergence of multi-drug resistant sexually transmitted infections (STIs) is causing a treatment crisis across the globe. While cephalosporin-resistant gonorrhea is one of the most pressing issues, extensively antibiotic resistant Chlamydia trachomatis and Mycoplasma hominis are also becoming commonplace. Experts have suggested that the failure of current treatment regimens are "largely inevitable" and have called for entirely new classes of antimicrobial agents. With the exception of several new classes of drugs primarily targeting nosocomial infections, progress has been slow. While pharmaceutical companies continue to introduce new drugs, they are based on decade-old discoveries. While there is disagreement about what constitutes new classes of antibiotics, many experts suggest that the last truly new family of antimicrobials was discovered in 1987. This review summarizes the existing literature on antibiotic resistance in common bacterial and protozoal STIs. It also briefly discusses several of the most promising alternatives to current therapies, and further examines how advances in drug delivery, formulation, concentration, and timing are improving the efficacy of existing treatments. Finally, the paper discusses the current state of pharmaceutical development for multidrug-resistant STI. PMID:26392647

  5. Repurposing Salicylanilide Anthelmintic Drugs to Combat Drug Resistant Staphylococcus aureus

    PubMed Central

    Rajamuthiah, Rajmohan; Fuchs, Beth Burgwyn; Conery, Annie L.; Kim, Wooseong; Jayamani, Elamparithi; Kwon, Bumsup; Ausubel, Frederick M.; Mylonakis, Eleftherios

    2015-01-01

    Staphylococcus aureus is a Gram-positive bacterium that has become the leading cause of hospital acquired infections in the US. Repurposing Food and Drug Administration (FDA) approved drugs for antimicrobial therapy involves lower risks and costs compared to de novo development of novel antimicrobial agents. In this study, we examined the antimicrobial properties of two commercially available anthelmintic drugs. The FDA approved drug niclosamide and the veterinary drug oxyclozanide displayed strong in vivo and in vitro activity against methicillin resistant S. aureus (minimum inhibitory concentration (MIC): 0.125 and 0.5 μg/ml respectively; minimum effective concentration: ≤ 0.78 μg/ml for both drugs). The two drugs were also effective against another Gram-positive bacteria Enterococcus faecium (MIC 0.25 and 2 μg/ml respectively), but not against the Gram-negative species Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter aerogenes. The in vitro antimicrobial activity of niclosamide and oxyclozanide were determined against methicillin, vancomycin, linezolid or daptomycin resistant S. aureus clinical isolates, with MICs at 0.0625-0.5 and 0.125-2 μg/ml for niclosamide and oxyclozanide respectively. A time-kill study demonstrated that niclosamide is bacteriostatic, whereas oxyclozanide is bactericidal. Interestingly, oxyclozanide permeabilized the bacterial membrane but neither of the anthelmintic drugs exhibited demonstrable toxicity to sheep erythrocytes. Oxyclozanide was non-toxic to HepG2 human liver carcinoma cells within the range of its in vitro MICs but niclosamide displayed toxicity even at low concentrations. These data show that the salicylanilide anthelmintic drugs niclosamide and oxyclozanide are suitable candidates for mechanism of action studies and further clinical evaluation for treatment of staphylococcal infections. PMID:25897961

  6. Evaluation of antibacterial efficacy of phyto fabricated silver nanoparticles using Mukia scabrella (Musumusukkai) against drug resistance nosocomial gram negative bacterial pathogens.

    PubMed

    Prabakar, Kandasamy; Sivalingam, Periyasamy; Mohamed Rabeek, Siyed Ibrahim; Muthuselvam, Manickam; Devarajan, Naresh; Arjunan, Annavi; Karthick, Rajamanickam; Suresh, Micky Maray; Wembonyama, John Pote

    2013-04-01

    Given the fact in the limitation of the therapeutic options for emerging multidrug resistance gram-negative bacteria (MDR-GNB) of respiratory tract infections, the present study was focused on green synthesis of antimicrobial silver nanoparticles (AgNPs) using leaf extract of Mukia scabrella. An obvious color change to brown color and surface plasmon resonance by UV-visible spectroscopy (UV-vis) indicated a well observable peak at 440 nm confirming the synthesis of AgNPs. Fourier transform infra-red spectroscopy (FTIR) analysis indicates protein as possible capping agents. Energy dispersive X-ray (EDAX) spectroscopy results showed major signal for elemental silver. X-ray diffraction (XRD) analysis indicates the formation of metallic silver nanomaterials. Transmission electron microscopic (TEM) study showed the nanoparticles in the size range of 18-21 nm with spherical shape. Zeta potential analysis showed -21.7 mV characteristic for stable AgNPs. The biosynthesized AgNPs exhibited significant antimicrobial activity against MDR-GNB nosocomial pathogens of Acinetobacter sp., Klebsiella pneumoniae and Pseudomonas aeruginosa. Results from the current study suggested that M. scabrella material could be exploited for the fabrication of AgNPs with potential therapeutic applications in nanomedicine especially for nosocomial bacterial infections. PMID:23334182

  7. Antibacterial Mechanisms of Polymyxin and Bacterial Resistance

    PubMed Central

    Qin, Wangrong; Fang, Shisong; Qiu, Juanping

    2015-01-01

    Multidrug resistance in pathogens is an increasingly significant threat for human health. Indeed, some strains are resistant to almost all currently available antibiotics, leaving very limited choices for antimicrobial clinical therapy. In many such cases, polymyxins are the last option available, although their use increases the risk of developing resistant strains. This review mainly aims to discuss advances in unraveling the mechanisms of antibacterial activity of polymyxins and bacterial tolerance together with the description of polymyxin structure, synthesis, and structural modification. These are expected to help researchers not only develop a series of new polymyxin derivatives necessary for future medical care, but also optimize the clinical use of polymyxins with minimal resistance development. PMID:25664322

  8. Persistence of antibiotic resistance in bacterial populations.

    PubMed

    Andersson, Dan I; Hughes, Diarmaid

    2011-09-01

    Unfortunately for mankind, it is very likely that the antibiotic resistance problem we have generated during the last 60 years due to the extensive use and misuse of antibiotics is here to stay for the foreseeable future. This view is based on theoretical arguments, mathematical modeling, experiments and clinical interventions, suggesting that even if we could reduce antibiotic use, resistant clones would remain persistent and only slowly (if at all) be outcompeted by their susceptible relatives. In this review, we discuss the multitude of mechanisms and processes that are involved in causing the persistence of chromosomal and plasmid-borne resistance determinants and how we might use them to our advantage to increase the likelihood of reversing the problem. Of particular interest is the recent demonstration that a very low antibiotic concentration can be enriching for resistant bacteria and the implication that antibiotic release into the environment could contribute to the selection for resistance. Several mechanisms are contributing to the stability of antibiotic resistance in bacterial populations and even if antibiotic use is reduced it is likely that most resistance mechanisms will persist for considerable times. PMID:21707669

  9. Mechanisms of drug resistance: daptomycin resistance.

    PubMed

    Tran, Truc T; Munita, Jose M; Arias, Cesar A

    2015-09-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp., and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP-R are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have provided novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope, such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID:26495887

  10. 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

  11. Drug-resistant tuberculosis: pediatric guidelines.

    PubMed

    Poorana Ganga Devi, Navaneetha Pandian; Swaminathan, Soumya

    2013-10-01

    The World Health Organization estimates that there are 650,000 prevalent cases of multidrug-resistant (MDR) tuberculosis (TB) globally, and since children (<15 years of age) constitute up to 20 % of the TB caseload in high-burden settings, the number of children with drug-resistant (DR) TB is likely to be substantial. Because bacterial burden at the site of disease is often low, diagnosis involves collection of multiple specimens and a laboratory capable of performing culture, although the Xpert MTB/RIF assay has improved sensitivity over smear examination. The basic principles of treatment for children are the same as those for adults with MDR-TB; however, the treatment regimen is often empiric and based on the drug susceptibility pattern of the source case, if available, or on past history of treatment. Additional challenges arise when MDR-TB is diagnosed and managed in the context of HIV coinfection. HIV-infected children are also treated with antiretroviral therapy medications, which have the potential to interact with second-line anti-TB drugs. Lack of pediatric formulations of second-line drugs and paucity of pharmacokinetic data make dosage challenging. However, when treated appropriately, children with DR TB have good outcomes. PMID:23990343

  12. Drug resistance in Giardia duodenalis.

    PubMed

    Ansell, Brendan R E; McConville, Malcolm J; Ma'ayeh, Showgy Y; Dagley, Michael J; Gasser, Robin B; Svärd, Staffan G; Jex, Aaron R

    2015-11-01

    Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protist's unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen. PMID:25922317

  13. Clinical management of resistance evolution in a bacterial infection: A case study.

    PubMed

    Woods, Robert J; Read, Andrew F

    2015-01-01

    We report the case of a patient with a chronic bacterial infection that could not be cured. Drug treatment became progressively less effective due to antibiotic resistance, and the patient died, in effect from overwhelming evolution. Even though the evolution of drug resistance was recognized as a major threat, and the fundamentals of drug resistance evolution are well understood, it was impossible to make evidence-based decisions about the evolutionary risks associated with the various treatment options. We present this case to illustrate the urgent need for translational research in the evolutionary medicine of antibiotic resistance. PMID:26454762

  14. YAP and the drug resistance highway

    PubMed Central

    Keren-Paz, Alona; Emmanuel, Rafi

    2016-01-01

    Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target. PMID:25711863

  15. YAP and the drug resistance highway.

    PubMed

    Keren-Paz, Alona; Emmanuel, Rafi; Samuels, Yardena

    2015-03-01

    Deciphering mechanisms of drug resistance is crucial to winning the battle against cancer. A new study points to an unexpected function of YAP in drug resistance and illuminates its potential role as a therapeutic target. PMID:25711863

  16. Drug Resistance in Cancer: An Overview

    PubMed Central

    Housman, Genevieve; Byler, Shannon; Heerboth, Sarah; Lapinska, Karolina; Longacre, Mckenna; Snyder, Nicole; Sarkar, Sibaji

    2014-01-01

    Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study. PMID:25198391

  17. Drug Resistance Mechanisms in Mycobacterium tuberculosis

    PubMed Central

    Palomino, Juan Carlos; Martin, Anandi

    2014-01-01

    Tuberculosis (TB) is a serious public health problem worldwide. Its situation is worsened by the presence of multidrug resistant (MDR) strains of Mycobacterium tuberculosis, the causative agent of the disease. In recent years, even more serious forms of drug resistance have been reported. A better knowledge of the mechanisms of drug resistance of M. tuberculosis and the relevant molecular mechanisms involved will improve the available techniques for rapid drug resistance detection and will help to explore new targets for drug activity and development. This review article discusses the mechanisms of action of anti-tuberculosis drugs and the molecular basis of drug resistance in M. tuberculosis. PMID:27025748

  18. Cancer Metabolism and Drug Resistance

    PubMed Central

    Rahman, Mahbuba; Hasan, Mohammad Rubayet

    2015-01-01

    Metabolic alterations, driven by genetic and epigenetic factors, have long been known to be associated with the etiology of cancer. Furthermore, accumulating evidence suggest that cancer metabolism is intimately linked to drug resistance, which is currently one of the most important challenges in cancer treatment. Altered metabolic pathways help cancer cells to proliferate at a rate higher than normal, adapt to nutrient limited conditions, and develop drug resistance phenotypes. Application of systems biology, boosted by recent advancement of novel high-throughput technologies to obtain cancer-associated, transcriptomic, proteomic and metabolomic data, is expected to make a significant contribution to our understanding of metabolic properties related to malignancy. Indeed, despite being at a very early stage, quantitative data obtained from the omics platforms and through applications of 13C metabolic flux analysis (MFA) in in vitro studies, researchers have already began to gain insight into the complex metabolic mechanisms of cancer, paving the way for selection of molecular targets for therapeutic interventions. In this review, we discuss some of the major findings associated with the metabolic pathways in cancer cells and also discuss new evidences and achievements on specific metabolic enzyme targets and target-directed small molecules that can potentially be used as anti-cancer drugs. PMID:26437434

  19. Suppression of Drug Resistance in Dengue Virus

    PubMed Central

    Mateo, Roberto; Nagamine, Claude M.

    2015-01-01

    ABSTRACT Dengue virus is a major human pathogen responsible for 400 million infections yearly. As with other RNA viruses, daunting challenges to antiviral design exist due to the high error rates of RNA-dependent RNA synthesis. Indeed, treatment of dengue virus infection with a nucleoside analog resulted in the expected genetic selection of resistant viruses in tissue culture and in mice. However, when the function of the oligomeric core protein was inhibited, no detectable selection of drug resistance in tissue culture or in mice was detected, despite the presence of drug-resistant variants in the population. Suppressed selection of drug-resistant virus correlated with cooligomerization of the targeted drug-susceptible and drug-resistant core proteins. The concept of “dominant drug targets,” in which inhibition of oligomeric viral assemblages leads to the formation of drug-susceptible chimeras, can therefore be used to prevent the outgrowth of drug resistance during dengue virus infection. PMID:26670386

  20. Socioeconomic and behavioral factors leading to acquired bacterial resistance to antibiotics in developing countries.

    PubMed Central

    Okeke, I. N.; Lamikanra, A.; Edelman, R.

    1999-01-01

    In developing countries, acquired bacterial resistance to antimicrobial agents is common in isolates from healthy persons and from persons with community-acquired infections. Complex socioeconomic and behavioral factors associated with antibiotic resistance, particularly regarding diarrheal and respiratory pathogens, in developing tropical countries, include misuse of antibiotics by health professionals, unskilled practitioners, and laypersons; poor drug quality; unhygienic conditions accounting for spread of resistant bacteria; and inadequate surveillance. PMID:10081668

  1. Bacterial and archaeal resistance to ionizing radiation

    NASA Astrophysics Data System (ADS)

    Confalonieri, F.; Sommer, S.

    2011-01-01

    Organisms living in extreme environments must cope with large fluctuations of temperature, high levels of radiation and/or desiccation, conditions that can induce DNA damage ranging from base modifications to DNA double-strand breaks. The bacterium Deinococcus radiodurans is known for its resistance to extremely high doses of ionizing radiation and for its ability to reconstruct a functional genome from hundreds of radiation-induced chromosomal fragments. Recently, extreme ionizing radiation resistance was also generated by directed evolution of an apparently radiation-sensitive bacterial species, Escherichia coli. Radioresistant organisms are not only found among the Eubacteria but also among the Archaea that represent the third kingdom of life. They present a set of particular features that differentiate them from the Eubacteria and eukaryotes. Moreover, Archaea are often isolated from extreme environments where they live under severe conditions of temperature, pressure, pH, salts or toxic compounds that are lethal for the large majority of living organisms. Thus, Archaea offer the opportunity to understand how cells are able to cope with such harsh conditions. Among them, the halophilic archaeon Halobacterium sp and several Pyrococcus or Thermococcus species, such as Thermococcus gammatolerans, were also shown to display high level of radiation resistance. The dispersion, in the phylogenetic tree, of radioresistant prokaryotes suggests that they have independently acquired radioresistance. Different strategies were selected during evolution including several mechanisms of radiation byproduct detoxification and subtle cellular metabolism modifications to help cells recover from radiation-induced injuries, protection of proteins against oxidation, an efficient DNA repair tool box, an original pathway of DNA double-strand break repair, a condensed nucleoid that may prevent the dispersion of the DNA fragments and specific radiation-induced proteins involved in radioresistance. Here, we compare mechanisms and discuss hypotheses suggested to contribute to radioresistance in several Archaea and Eubacteria.

  2. Understanding drug resistance in human intestinal protozoa.

    PubMed

    El-Taweel, Hend Aly

    2015-05-01

    Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents. PMID:25782683

  3. Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics?

    PubMed Central

    Supuran, Claudiu T.

    2011-01-01

    Carbonic anhydrases (CAs, EC 4.2.1.1) are metalloenzymes which catalyze the hydration of carbon dioxide to bicarbonate and protons. Many pathogenic bacteria encode such enzymes belonging to the ?-, ?-, and/or ?-CA families. In the last decade, the ?-CAs from Neisseria spp. and Helicobacter pylori as well as the ?-class enzymes from Escherichia coli, H. pylori, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, and Haemophilus influenzae have been cloned and characterized in detail. For some of these enzymes the X-ray crystal structures were determined, and in vitro and in vivo inhibition studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates reported. Although efficient inhibitors have been reported for many such enzymes, only for Neisseria spp., H. pylori, B. suis, and S. pneumoniae enzymes it has been possible to evidence inhibition of bacterial growth in vivo. Thus, bacterial CAs represent promising targets for obtaining antibacterials devoid of the resistance problems of the clinically used such agents but further studies are needed to validate these and other less investigated enzymes as novel drug targets. PMID:21779249

  4. Surgery for drug-resistant focal epilepsy

    PubMed Central

    Rao, Malla Bhaskara; Arivazhagan, Arimappamagan; Sinha, Sanjib; Bharath, Rose Dawn; Mahadevan, Anita; Bhat, Maya; Satishchandra, Parthasarthy

    2014-01-01

    During the colloquium on drug-resistant epilepsy (DRE) at National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore on August 16-18, 2013, a number of presentations were made on the surgically remediable lesional epilepsy syndromes, presurgical evaluation, surgical techniques, neuropathology of drug resistance focal epilepsy and surgical outcome. This pictorial essay with the illustrative case examples provides an overview of the various surgical techniques for the management of drug-resistant focal epilepsy. PMID:24791080

  5. Drug Abuse Resistance Education. Administrative Orientation. Revised.

    ERIC Educational Resources Information Center

    North Carolina State Dept. of Justice, Raleigh.

    The goal of the Drug Abuse Resistance Education (DARE) Program is to prevent drug abuse among school children, by targeting children at an age (K-6) when they are most receptive to drug prevention education and before they are likely to have been led by their peers to experiment with tobacco, alcohol, and other drugs. Project DARE seeks to prevent…

  6. Drug-Resistant Tuberculosis: Challenges and Progress.

    PubMed

    Kurz, Sebastian G; Furin, Jennifer J; Bark, Charles M

    2016-06-01

    Antimicrobial resistance is a natural evolutionary process, which in the case of Mycobacterium tuberculosis is based on spontaneous chromosomal mutations, meaning that well-designed combination drug regimens provided under supervised therapy will prevent the emergence of drug-resistant strains. Unfortunately, limited resources, poverty, and neglect have led to the emergence of drug-resistant tuberculosis throughout the world. The international community has responded with financial and scientific support, leading to new rapid diagnostics, new drugs and regimens in advanced clinical development, and an increasingly sophisticated understanding of resistance mechanisms and their application to all aspects of TB control and treatment. PMID:27208770

  7. Preventing drug resistance in severe influenza

    NASA Astrophysics Data System (ADS)

    Dobrovolny, Hana; Deecke, Lucas

    2015-03-01

    Severe, long-lasting influenza infections are often caused by new strains of influenza. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic for new strains of influenza since there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply periodic treatment. During treatment the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. We combine a mathematical model of severe influenza with a model of drug resistance to study emergence of drug resistance during a long-lasting infection. We apply periodic treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. We compare the efficacy of the two drugs in reducing emergence of drug resistant mutants and examine the effect of treatment frequency on the emergence of drug resistant mutants.

  8. HIV Drug Resistance: Problems and Perspectives

    PubMed Central

    Pennings, Pleuni S.

    2013-01-01

    Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis. PMID:24470969

  9. Architecture and Conservation of the Bacterial DNA Replication Machinery, an Underexploited Drug Target

    PubMed Central

    Robinson, Andrew; Causer, Rebecca J; Dixon, Nicholas E

    2012-01-01

    New antibiotics with novel modes of action are required to combat the growing threat posed by multi-drug resistant bacteria. Over the last decade, genome sequencing and other high-throughput techniques have provided tremendous insight into the molecular processes underlying cellular functions in a wide range of bacterial species. We can now use these data to assess the degree of conservation of certain aspects of bacterial physiology, to help choose the best cellular targets for development of new broad-spectrum antibacterials. DNA replication is a conserved and essential process, and the large number of proteins that interact to replicate DNA in bacteria are distinct from those in eukaryotes and archaea; yet none of the antibiotics in current clinical use acts directly on the replication machinery. Bacterial DNA synthesis thus appears to be an underexploited drug target. However, before this system can be targeted for drug design, it is important to understand which parts are conserved and which are not, as this will have implications for the spectrum of activity of any new inhibitors against bacterial species, as well as the potential for development of drug resistance. In this review we assess similarities and differences in replication components and mechanisms across the bacteria, highlight current progress towards the discovery of novel replication inhibitors, and suggest those aspects of the replication machinery that have the greatest potential as drug targets. PMID:22206257

  10. SCREENING OF TRANSGENIC ANTHURIUMS FOR BACTERIAL BLIGHT AND NEMATODE RESISTANCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Anthuriums exhibit limited resistance to bacterial blight caused by Xanthomonas axonopodis pv. dieffenbachiae and to the nematodes Radopholus simile and Meloidogyne javanica. Agrobacterium tumefaciens transformation of embryogenic calli with strains LBA4404, EHA105, and AGLO resulted in transgenic p...

  11. Multidrug-resistant bacterial ingluvitis associated with squamous cell carcinoma in a budgerigar (Melopsittacus undulatus).

    PubMed

    Youl, Jennifer M; Gartrell, Brett D

    2006-09-01

    A 2-year-old budgerigar (Melopsittacus undulatus) was presented to the Massey University Veterinary Teaching Hospital for chronic regurgitation. Multiple drug-resistant Klebsiella oxytoca was cultured from the crop. Necropsy revealed a mass in the crop that was histologically diagnosed as squamous cell carcinoma (SCC). To the authors' knowledge, this is the first report of SCC in a budgerigar associated with a multidrug-resistant bacterial ingluvitis. PMID:16931374

  12. A guide to antibiotic resistance in bacterial skin infections.

    PubMed

    Perera, G; Hay, R

    2005-09-01

    The emergence of bacterial resistance to commonly used antibiotics is not new. In this review we have tried to cover the ever increasing problems facing the treatment and containment of bacterial skin infections. We have tried to give an overview of the varied mechanisms by which bacteria gain and spread antimicrobial resistance, whilst dealing with the patterns of resistance exhibited by some of the commonly encountered organisms. Where there is evidence, we have formulated an approach on how to tackle antibiotic resistance. Where there is a lack of evidence we have formulated what we perceive to be appropriate guidelines. PMID:16164705

  13. MULTIPLE DRUG RESISTANCE: TRENDS AND IMPLICATIONS

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Antimicrobial resistance (AR) has emerged as a global problem. Although AR occurs shortly after the introduction and use of an antimicrobial, resistance levels vary over time. Historically, antimicrobials were regarded as wonder drugs and for years, when resistance to a single antimicrobial occurr...

  14. The role of glucuronidation in drug resistance.

    PubMed

    Mazerska, Zofia; Mróz, Anna; Pawłowska, Monika; Augustin, Ewa

    2016-03-01

    The final therapeutic effect of a drug candidate, which is directed to a specific molecular target strongly depends on its absorption, distribution, metabolism and excretion (ADME). The disruption of at least one element of ADME may result in serious drug resistance. In this work we described the role of one element of this resistance: phase II metabolism with UDP-glucuronosyltransferases (UGTs). UGT function is the transformation of their substrates into more polar metabolites, which are better substrates for the ABC transporters, MDR1, MRP and BCRP, than the native drug. UGT-mediated drug resistance can be associated with (i) inherent overexpression of the enzyme, named intrinsic drug resistance or (ii) induced expression of the enzyme, named acquired drug resistance observed when enzyme expression is induced by the drug or other factors, as food-derived compounds. Very often this induction occurs via ligand binding receptors including AhR (aryl hydrocarbon receptor) PXR (pregnane X receptor), or other transcription factors. The effect of UGT dependent resistance is strengthened by coordinate action and also a coordinate regulation of the expression of UGTs and ABC transporters. This coupling of UGT and multidrug resistance proteins has been intensively studied, particularly in the case of antitumor treatment, when this resistance is "improved" by differences in UGT expression between tumor and healthy tissue. Multidrug resistance coordinated with glucuronidation has also been described here for drugs used in the management of epilepsy, psychiatric diseases, HIV infections, hypertension and hypercholesterolemia. Proposals to reverse UGT-mediated drug resistance should consider the endogenous functions of UGT. PMID:26808161

  15. Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections

    PubMed Central

    Rangel-Vega, Adrián; Bernstein, Lawrence R.; Mandujano-Tinoco, Edna Ayerim; García-Contreras, Silvia Julieta; García-Contreras, Rodolfo

    2015-01-01

    Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell–cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy. PMID:25914685

  16. Drug repurposing as an alternative for the treatment of recalcitrant bacterial infections.

    PubMed

    Rangel-Vega, Adrián; Bernstein, Lawrence R; Mandujano-Tinoco, Edna Ayerim; García-Contreras, Silvia Julieta; García-Contreras, Rodolfo

    2015-01-01

    Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell-cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy. PMID:25914685

  17. Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells

    PubMed Central

    Pu, Yingying; Zhao, Zhilun; Li, Yingxing; Zou, Jin; Ma, Qi; Zhao, Yanna; Ke, Yuehua; Zhu, Yun; Chen, Huiyi; Baker, Matthew A.B.; Ge, Hao; Sun, Yujie; Xie, Xiaoliang Sunney; Bai, Fan

    2016-01-01

    Summary Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance. PMID:27105118

  18. Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells.

    PubMed

    Pu, Yingying; Zhao, Zhilun; Li, Yingxing; Zou, Jin; Ma, Qi; Zhao, Yanna; Ke, Yuehua; Zhu, Yun; Chen, Huiyi; Baker, Matthew A B; Ge, Hao; Sun, Yujie; Xie, Xiaoliang Sunney; Bai, Fan

    2016-04-21

    Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance. PMID:27105118

  19. Types and drug susceptibility patterns of bacterial isolates from eye discharge samples at Gondar University Hospital, Northwest Ethiopia

    PubMed Central

    2014-01-01

    Background The type and pattern of organisms that cause ocular infection changes over time. Moreover, the causative organisms have developed increased drug resistance. Therefore, the aim of this study was to determine the prevalent bacterial agents of eye discharge and their drug susceptibility patterns to commonly used antimicrobial agents. Methods A retrospective study was conducted at Gondar University Hospital, Northwest Ethiopia from September, 2009 to August, 2012. Culture and drug susceptibility test results of patients who had eye infections were taken for analysis. Eye discharge samples were cultured on MacConkey agar, blood agar and chocolate agar plates. A standard biochemical procedure was used for full identification of bacterial isolates. Antimicrobial susceptibility tests were done on Mueller-Hinton agar by using disk diffusion method. Data was entered and analyzed by using SPSS version 16 software. Result A total of 102 eye discharges were submitted for microbiological evaluation, of which (60.8%) had bacterial growth. The most frequently isolated bacterial isolates were gram-positive bacteria (74.2%). The predominant bacterial species isolated was Coagulase-negative staphylococci (27.4%) followed by S. aureus (21%). Within the age group of 1day-2years old, (66.1%) of bacteria were isolated. Most of the bacterial isolates were resistance to ampicilin (71%), amoxicilin (62.9%), erythromycin (43.5%), gentamicin (45.2%), penicillin (71%), trimethoprim-sulphamethoxazole (58.1%), and tetracycline (64.6%) while Ceftriaxon and Ciprofloxacin showed (75.8%) and (80%) susceptibility respectively. From the total bacterial isolates, (87.1%) were showed multi drug resistance (MDR) to two or more drugs. Conclusion The prevalence of bacterial isolates in eye discharge was high in the study area and majority of isolates were gram-positive bacteria. Most of the bacterial isolates were resistant to frequently used antimicrobials. Therefore, drug susceptibility test is necessary before prescribing any antimicrobials. PMID:24885599

  20. The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru

    PubMed Central

    Grandjean, Louis; Iwamoto, Tomotada; Lithgow, Anna; Gilman, Robert H; Arikawa, Kentaro; Nakanishi, Noriko; Martin, Laura; Castillo, Edith; Alarcon, Valentina; Coronel, Jorge; Solano, Walter; Aminian, Minoo; Guezala, Claudia; Rastogi, Nalin; Couvin, David; Sheen, Patricia; Zimic, Mirko; Moore, David AJ

    2015-01-01

    Background The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis. Methods To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census. Results The Latin American Mediterranean (LAM) clade (OR 2.4, p<0.001) was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively). Conclusions Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs. PMID:25984723

  1. Plasmodium falciparum drug resistance in Angola.

    PubMed

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-01-01

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination. PMID:26858018

  2. Antimicrobial Drug Resistance, Regulation, and Research1

    PubMed Central

    Powers, John H.; Dudley, Michael N.; Christiansen, Keryn; Finch, Roger G.

    2006-01-01

    Innovative regulatory and legislative measures to stimulate and facilitate the development of new antimicrobial drugs are needed. We discuss research approaches that can aid regulatory decision making on the treatment of resistant infections and minimization of resistance selection. We also outline current and future measures that regulatory agencies may employ to help control resistance and promote drug development. Pharmacokinetic/pharmacodynamic research models offer promising approaches to define the determinants of resistance selection and drug doses that optimize efficacy and reduce resistance selection. Internationally, variations exist in how regulators use drug scheduling, subsidy restrictions, central directives, educational guidelines, amendments to prescribing information, and indication review. Recent consultations and collaborations between regulators, academics, and industry are welcome. Efforts to coordinate regulatory measures would benefit from greater levels of international dialogue. PMID:16494740

  3. Antimicrobial drug resistance, regulation, and research.

    PubMed

    Metlay, Joshua P; Powers, John H; Dudley, Michael N; Christiansen, Keryn; Finch, Roger G

    2006-02-01

    Innovative regulatory and legislative measures to stimulate and facilitate the development of new antimicrobial drugs are needed. We discuss research approaches that can aid regulatory decision making on the treatment of resistant infections and minimization of resistance selection. We also outline current and future measures that regulatory agencies may employ to help control resistance and promote drug development. Pharmacokinetic/pharmacodynamic research models offer promising approaches to define the determinants of resistance selection and drug doses that optimize efficacy and reduce resistance selection. Internationally, variations exist in how regulators use drug scheduling, subsidy restrictions, central directives, educational guidelines, amendments to prescribing information, and indication review. Recent consultations and collaborations between regulators, academics, and industry are welcome. Efforts to coordinate regulatory measures would benefit from greater levels of international dialogue. PMID:16494740

  4. Dissemination of bacterial fluoroquinolone resistance in two multidrug-resistant enterobacteriaceae.

    PubMed

    Jung, Carina M

    2014-01-01

    Bacterial resistance to antimicrobials has become one of the greatest challenges for clinical microbiologists and healthcare practitioners worldwide. Acquisition of resistance genes has proven to be difficult to characterize and is largely uncontrollable in the environment. Here we sought to characterize conjugal horizontal gene transfer of plasmid-encoded fluoroquinolone resistance genes from two strains of Enterobacteriaceae, one clinical and one from a municipal wastewater treatment plant environment. Conjugation was dissimilar between the two strains. Escherichia coli strain LR09, containing a plasmid with the aac(6')-Ib-cr fluoroquinolone resistance gene, did not conjugate with any of the 15 strains tested, while Enterobacter aerogenes strain YS11 conjugated with two strains of E. coli. The resultant transconjugants were also dissimilar in their stability and potential persistence. The observations presented herein exemplify the difficulties in understanding and controlling the spread of antimicrobial resistance. Thus, it may be prudent to address drug disposal and destruction, incorporating a life-cycle assessment plan 'from cradle to grave', treating antimicrobials as chemical or environmental contaminants. PMID:24862457

  5. 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

  6. Emerging pathogens: Dynamics, mutation and drug resistance

    SciTech Connect

    Perelson, A.S.; Goldstein, B.; Korber, B.T.

    1997-10-01

    This is the final report of a one-year, Laboratory Directed Research and Development (LDRD) project at Los Alamos National Laboratory (LANL). The objectives of this project were to develop models of the spread of pathogens, such as HIV-1 and influenza, in humans, and then to use the models to address the possibility of designing appropriate drug therapies that may limit the ability of the pathogen to escape treatment by mutating into a drug resistant form. We have developed a model of drug-resistance to amantidine and rimantadine, the two major antiviral drugs used to treat influenza, and have used the model to suggest treatment strategies during an epidemic.

  7. [Research development of HIV drug resistance].

    PubMed

    Zou, Wen; Liu, Ying; Wang, Jian; Gao, Guo-Jian; Dong, Ji-Peng; Xian, Qing-Fei

    2013-08-01

    Highly active antiretroviral combination therapy significantly reduced the mortality, but in the high-speed copying, high genetic variation and drug selection pressure under the effect of the increasingly serious problem of drug resistance greatly weakened the role of HAART inhibit viral replication and reduce antiviral treatment. This paper reports the latest trends in HIV drug-resistance in order to develop anti-HIV drugs in clinical programs, research and development of new guidance anti-HIV-1 strategy to bring guidance. PMID:24228557

  8. Clinical and economic outcomes in respiratory tract infections: The impact of bacterial resistance.

    PubMed

    Rapp, Robert P

    2002-09-01

    Drug acquisition cost is an important component in the analysis of economic and clinical outcomes in the treatment of respiratory tract infections (RTIs). However, bacterial resistance has emerged as a crucial variable that must also be considered. Drug-resistant infections result in more expensive drug therapy, longer hospital stays, and increased mortality. The high prevalence of community-acquired pneumonia (CAP), as well as the continuing growth in resistant pathogens, make RTIs an appropriate model for studying methods of cost-containment without sacrificing clinical outcome. The University of Kentucky Medical Center has developed a uniform CAP treatment pathway to minimize costs and maximize outcomes. First-line therapy in this model is doxycycline monotherapy, high-dose amoxicillin plus azithromycin, or levofloxacin monotherapy. One major future concern in selecting antibacterial agents for CAP is the spread of macrolide- and fluoroquinolone-resistant Streptococcus pneumoniae. PMID:19667590

  9. Bacterial resistance to antimicrobials in urinary isolates.

    PubMed

    Muratani, Tetsuro; Matsumoto, Tetsuro

    2004-09-01

    Escherichia coli accounted for about 80% of organisms in uncomplicated urinary tract infections (UTIs), followed by Staphylococcus spp. especially Staphylococcus saprophyticus, and Proteus mirabilis. Against E. coli isolates from patients with uncomplicated UTI, faropenem was the most effective. Up to 1999, fluoroquinolone-resistant isolates were not observed in patients with uncomplicated UTI, but in 2001 fluoroquinolone-resistant E. coli isolates emerged and accounted for about 8%. Various types of organisms were isolated in patients with complicated UTI. Enterococcus faecalis, E. coli, and Pseudomonas aeruginosa were the three most frequent organisms isolated. These three organisms accounted for 44.6%. Amongst oral agents, faropenem showed the lowest rate of resistance against E. coli followed by cephems. The rates of highly fluoroquinolone-resistant and cefpodoxime-resistant E. coli isolates increased rapidly from 1998 to 2001. Fluoroquinolone-resistant P. aeruginosa isolates accounted for about 40% in 2001. Against this species, amikacin was the most effective antimicrobials among all agents tested. About 17% of Pseudomonas were resistant to carbapenem. Eight milligram per litre of ampicillin inhibited all E. faecalis isolates; about 60% of Enterococcus faecium were resistant to ampicillin. The rates of levofloxacin-resistant isolates of E. faecalis and E. faecium were 38 and 97% respectively. UTIs caused by vancomycin resistant enterococci (VRE) are rare in Japan. PMID:15364302

  10. Identifying representative drug resistant mutants of HIV

    PubMed Central

    2015-01-01

    Background Drug resistance is one of the most important causes for failure of anti-AIDS treatment. During therapy, multiple mutations accumulate in the HIV genome, eventually rendering the drugs ineffective in blocking replication of the mutant virus. The huge number of possible mutants precludes experimental analysis to explore the molecular mechanisms of resistance and develop improved antiviral drugs. Results In order to solve this problem, we have developed a new algorithm to reveal the most representative mutants from the whole drug resistant mutant database based on our newly proposed unified protein sequence and 3D structure encoding method. Mean shift clustering and multiple regression analysis were applied on genotype-resistance data for mutants of HIV protease and reverse transcriptase. This approach successfully chooses less than 100 mutants with the highest resistance to each drug out of about 10K in the whole database. When considering high level resistance to multiple drugs, the numbers reduce to one or two representative mutants. Conclusion This approach for predicting the most representative mutants for each drug has major importance for experimental verification since the results provide a small number of representative sequences, which will be amenable for in vitro testing and characterization of the expressed mutant proteins. PMID:26678327

  11. Multidrug-resistant bacterial infection in solid organ transplant recipients.

    PubMed

    Cervera, Carlos; Linares, Laura; Bou, Germán; Moreno, Asunción

    2012-03-01

    The most frequent complication from infection after solid organ transplantation is bacterial infection. This complication is more frequent in organ transplantation involving the abdominal cavity, such as liver or pancreas transplantation, and less frequent in heart transplant recipients. The sources, clinical characteristics, antibiotic resistance and clinical outcomes vary according to the time of onset after transplantation. Most bacterial infections during the first month post-transplantation are hospital acquired, and there is usually a high incidence of multidrug-resistant bacterial infections. The higher incidence of complications from bacterial infection in the first month post-transplantation may be associated with high morbidity. Of special interest due to their frequency are infections by S. aureus, enterococci, Gram-negative enteric and non-fermentative bacilli. Opportunistic bacterial infections may occur at any time on the posttransplant timeline, but are more frequent between months two and six, the period in which immunosuppression is higher. The most frequent bacterial species causing opportunistic infections in organ transplant recipients are Listeria monocytogenes and Nocardia spp. After month six, posttransplantation solid organ transplant patients usually develop conventional community-acquired bacterial infections, especially urinary tract infections by E. coli and S. pneumoniae pneumonia. In this article we review the clinical characteristics, epidemiology, diagnosis and prognosis of bacterial infections in solid organ transplant patients. PMID:22542034

  12. NOTE: Dielectrophoretic assay of bacterial resistance to antibiotics

    NASA Astrophysics Data System (ADS)

    Johari, Juliana; Hübner, Yvonne; Hull, Judith C.; Dale, Jeremy W.; Hughes, Michael P.

    2003-07-01

    The dielectrophoretic collection spectra of antibiotic-sensitive and antibiotic-resistant strains of Staphylococcus epidermidis have been determined. These indicate that in the absence of antibiotic treatment there is a strong similarity between the dielectric properties of sensitive and resistant strains, and that there is a significant difference between the sensitive strains before and after treatment with the antibiotic streptomycin after 24 h exposure. This method offers possibilities for the assessment of bacterial resistance to antibiotics.

  13. Mechanisms of echinocandin antifungal drug resistance.

    PubMed

    Perlin, David S

    2015-09-01

    Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall-active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which is frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promotes the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin-resistance mechanism, along with cellular and clinical factors promoting resistance, will facilitate more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  14. Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

    SciTech Connect

    Wallace, Bret D.; Wang, Hongwei; Lane, Kimberly T.; Scott, John E.; Orans, Jillian; Koo, Ja Seol; Venkatesh, Madhukumar; Jobin, Christian; Yeh, Li-An; Mani, Sridhar; Redinbo, Matthew R.

    2011-08-12

    The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial {beta}-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial {beta}-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial {beta}-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.

  15. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance

    PubMed Central

    Obolski, Uri; Stein, Gideon Y.; Hadany, Lilach

    2015-01-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used—mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists. PMID:26110266

  16. Expression of cytokeratin confers multiple drug resistance

    SciTech Connect

    Bauman, P.A.; Dalton, W.S.; Anderson, J.M.; Cress, A.E. )

    1994-06-07

    The cytokeratin network is an extensive filamentous structure in the cytoplasm whose biological function(s) is unknown. Based upon previous data showing the modification of cytokeratin by mitoxantrone, the authors investigated the ability of cytokeratin networks to influence the survival response of cells to chemotherapeutic agents. They have compared the survival of mouse L fibroblasts lacking cytokeratins with that of L cells transfected with cytokeratins 8 and 18 in the presence of chemotherapeutic drugs. The expression of cytokeratins 8 and 18 conferred a multiple drug resistance phenotype on cells exposed to mitoxantrone, doxorubicin, methotrexate, melphalan, Colcemid, and vincristine. The degree of drug resistance was 5-454 times that of parental cells, depending upon the agent used. Drug resistance could not be attributed to altered growth characteristics, altered drug accumulation, or an altered drug efflux in the transfected cells. Cytokeratin does not confer resistance to ionizing radiation, which damages DNA independently on intracellular transport mechanisms. These data suggest a role for cytokeratin networks in conferring a drug resistance phenotype.

  17. Antibiotic Adjuvants: Diverse Strategies for Controlling Drug-Resistant Pathogens

    PubMed Central

    Gill, Erin E; Franco, Octavio L; Hancock, Robert E W

    2015-01-01

    The growing number of bacterial pathogens that are resistant to numerous antibiotics is a cause for concern around the globe. There have been no new broad-spectrum antibiotics developed in the last 40 years, and the drugs we have currently are quickly becoming ineffective. In this article, we explore a range of therapeutic strategies that could be employed in conjunction with antibiotics and may help to prolong the life span of these life-saving drugs. Discussed topics include antiresistance drugs, which are administered to potentiate the effects of current antimicrobials in bacteria where they are no longer (or never were) effective; antivirulence drugs, which are directed against bacterial virulence factors; host-directed therapies, which modulate the host's immune system to facilitate infection clearance; and alternative treatments, which include such therapies as oral rehydration for diarrhea, phage therapy, and probiotics. All of these avenues show promise for the treatment of bacterial infections and should be further investigated to explore their full potential in the face of a postantibiotic era. PMID:25393203

  18. Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens.

    PubMed

    Gill, Erin E; Franco, Octavio L; Hancock, Robert E W

    2015-01-01

    The growing number of bacterial pathogens that are resistant to numerous antibiotics is a cause for concern around the globe. There have been no new broad-spectrum antibiotics developed in the last 40 years, and the drugs we have currently are quickly becoming ineffective. In this article, we explore a range of therapeutic strategies that could be employed in conjunction with antibiotics and may help to prolong the life span of these life-saving drugs. Discussed topics include antiresistance drugs, which are administered to potentiate the effects of current antimicrobials in bacteria where they are no longer (or never were) effective; antivirulence drugs, which are directed against bacterial virulence factors; host-directed therapies, which modulate the host's immune system to facilitate infection clearance; and alternative treatments, which include such therapies as oral rehydration for diarrhea, phage therapy, and probiotics. All of these avenues show promise for the treatment of bacterial infections and should be further investigated to explore their full potential in the face of a postantibiotic era. PMID:25393203

  19. Bacterial resistance to disinfectants: present knowledge and future problems.

    PubMed

    Russell, A D

    1999-12-01

    Bacterial resistance to antibiotics is a long-established, widely-studied problem. Increasingly, attention is being directed to the responses of various types of microbes to biocides (antiseptics, disinfectants and preservatives). Different groups of bacteria vary in their susceptibility to biocides, with bacterial spores being the most resistant, followed by mycobacteria, then Gram-negative organisms, with cocci generally being the most sensitive. There are wide divergencies within this general classification. Thus, (i) spores of Bacillus subtilis are less susceptible to biocides than those of Clostridium difficile: (ii) Mycobacterium chelonae strains may show high resistance to glutaraldehyde and M. avium intracellulare is generally less sensitive than M. tuberculosis; (iii) Gram-negative bacteria such as Pseudomonas aeruginosa, Providencia spp and Proteus spp may be difficult to inactivate; (iv) enterococci are less sensitive than staphylococci to biocides and antibiotic-resistant strains of Staphylococcus aureus might show low-level biocide resistance. The mechanisms involved in biocide resistance to biocides are becoming better understood. Intrinsic resistance (intrinsic insusceptibility) is found with bacterial spores, mycobacteria and Gram-negative bacteria. This resistance might, in some instances, be associated with constitutive degradative enzymes but in reality is more closely linked to cellular impermeability. The coats(s) and, to some extent, the cortex in spores, the arabinogalactan and possibly other components of the mycobacterial cell wall and the outer membrane of Gram-negative bacteria limit the concentration of active biocide that can reach the target site(s) in these bacterial cells. A special situation is found with bacteria present in biofilms, which can be considered as being an intrinsic resistance mechanism resulting from physiological (phenotypic) adaptation of cells. Acquired resistance to biocides may arise by cellular mutation or by the acquisition of genetic elements. Plasmid/transposon-mediated resistance to inorganic and organic mercury compounds by hydrolases and reductases has been extensively studied. Plasmid-mediated resistance to some other biocides in Gram-negative bacteria and in staphylococci has been described, but its significance remains uncertain. As to the future, there is a need to establish conclusively whether there is a clear-cut linkage between antibiotic and biocide resistance in non-sporulating bacteria and whether biocides can select for antibiotic resistance. Additionally, the responses to biocides of new and emerging pathogens must be assessed. At the same time, continuing research is necessary to establish further the underlying mechanisms of resistance and to provide more efficient means of bacterial inactivation. PMID:10658759

  20. Malaria Epidemic and Drug Resistance, Djibouti

    PubMed Central

    Pradines, Bruno; Bogreau, H.; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-01-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations. PMID:15752455

  1. Legal issues associated with antimicrobial drug resistance.

    PubMed Central

    Fidler, D. P.

    1998-01-01

    An effective public health strategy against the development of antimicrobial drug resistance needs to be informed by legal as well as scientific analysis. This article describes some legal issues arising from current efforts against antimicrobial resistance and underscores the interdependence between law and public health in these efforts. PMID:9621187

  2. A network-based approach for resistance transmission in bacterial populations.

    PubMed

    Gehring, Ronette; Schumm, Phillip; Youssef, Mina; Scoglio, Caterina

    2010-01-01

    Horizontal transfer of mobile genetic elements (conjugation) is an important mechanism whereby resistance is spread through bacterial populations. The aim of our work is to develop a mathematical model that quantitatively describes this process, and to use this model to optimize antimicrobial dosage regimens to minimize resistance development. The bacterial population is conceptualized as a compartmental mathematical model to describe changes in susceptible, resistant, and transconjugant bacteria over time. This model is combined with a compartmental pharmacokinetic model to explore the effect of different plasma drug concentration profiles. An agent-based simulation tool is used to account for resistance transfer occurring when two bacteria are adjacent or in close proximity. In addition, a non-linear programming optimal control problem is introduced to minimize bacterial populations as well as the drug dose. Simulation and optimization results suggest that the rapid death of susceptible individuals in the population is pivotal in minimizing the number of transconjugants in a population. This supports the use of potent antimicrobials that rapidly kill susceptible individuals and development of dosage regimens that maintain effective antimicrobial drug concentrations for as long as needed to kill off the susceptible population. Suggestions are made for experiments to test the hypotheses generated by these simulations. PMID:19747924

  3. Bacterial histone-like proteins: roles in stress resistance.

    PubMed

    Wang, Ge; Maier, Robert J

    2015-11-01

    Histone-like proteins (HLPs) are small and basic bacterial proteins that are associated with a nucleoid and play roles in maintaining DNA architecture and regulating DNA transactions such as replication, recombination/repair and transcription. The studies on HLPs from a variety of bacterial species in recent years are summarized in this mini-review. A recent study reported a novel DNA-binding protein (HP119) in Helicobacter pylori that shows some HLP features. It plays a large role in aiding bacterial stress resistance. We provide herein additional evidence that HP119 is a nucleoid-associated protein, and present some perspectives for future study. PMID:25677732

  4. Nitroheterocyclic drug resistance mechanisms in Trypanosoma brucei

    PubMed Central

    Wyllie, Susan; Foth, Bernardo J.; Kelner, Anna; Sokolova, Antoaneta Y.; Berriman, Matthew; Fairlamb, Alan H.

    2016-01-01

    Objectives The objective of this study was to identify the mechanisms of resistance to nifurtimox and fexinidazole in African trypanosomes. Methods Bloodstream-form Trypanosoma brucei were selected for resistance to nifurtimox and fexinidazole by stepwise exposure to increasing drug concentrations. Clones were subjected to WGS to identify putative resistance genes. Transgenic parasites modulating expression of genes of interest were generated and drug susceptibility phenotypes determined. Results Nifurtimox-resistant (NfxR) and fexinidazole-resistant (FxR) parasites shared reciprocal cross-resistance suggestive of a common mechanism of action. Previously, a type I nitroreductase (NTR) has been implicated in nitro drug activation. WGS of resistant clones revealed that NfxR parasites had lost >100 kb from one copy of chromosome 7, rendering them hemizygous for NTR as well as over 30 other genes. FxR parasites retained both copies of NTR, but lost >70 kb downstream of one NTR allele, decreasing NTR transcription by half. A single knockout line of NTR displayed 1.6- and 1.9-fold resistance to nifurtimox and fexinidazole, respectively. Since NfxR and FxR parasites are ∼6- and 20-fold resistant to nifurtimox and fexinidazole, respectively, additional factors must be involved. Overexpression and knockout studies ruled out a role for a putative oxidoreductase (Tb927.7.7410) and a hypothetical gene (Tb927.1.1050), previously identified in a genome-scale RNAi screen. Conclusions NTR was confirmed as a key resistance determinant, either by loss of one gene copy or loss of gene expression. Further work is required to identify which of the many dozens of SNPs identified in the drug-resistant cell lines contribute to the overall resistance phenotype. PMID:26581221

  5. [Efficacy of chemotherapy of pulmonary tuberculosis drug-resistant m.tuberculosis].

    PubMed

    Khomenko, A G; Chukanov, V I; Korneev, A A

    1996-01-01

    M. tuberculosis examined in 717 patients with pulmonary tuberculosis appeared resistant to chemotherapy in 67.2% of cases. Whereas chronic patients developed drug resistance (DR) as secondary DR in 90.2% of cases, new cases with DR (50.1% of the examinees) seemed to be infected with drug-resistant M. tuberculosis. 2-stage chemotherapy with 4-5 drugs terminates bacterial discharge within first 3 months of treatment in the majority of the patients, especially if early correction of chemotherapy is used by the results of early determination M. tuberculosis drug sensitivity. PMID:9019768

  6. Drug Resistance in Glioblastoma: A Mini Review

    PubMed Central

    Haar, Catherine P.; Hebbar, Preetha; Wallace, Gerald C.; Das, Arabinda; Vandergrift, William A.; Smith, Joshua A.; Giglio, Pierre; Patel, Sunil J.; Ray, Swapan K.; Banik, Naren L.

    2015-01-01

    Glioblastoma multiforme (GBM) is recognized as the most common and lethal form of central nervous system cancer. Currently used surgical techniques, chemotherapeutic agents, and radiotherapy strategies have done very little in extending the life expectancies of patients diagnosed with GBM. The difficulty in treating this malignant disease lies both in its inherent complexity and numerous mechanisms of drug resistance. In this review, we summarize several of the primary mechanisms of drug resistance. We reviewed available published literature in the English language regarding drug resistance in glioblastoma. The reasons for drug resistance in glioblastoma include drug efflux, hypoxic areas of tumor cells, cancer stem cells, DNA damage repair, and miRNAs. Many potential therapies target these mechanisms, including a series of investigated alternative and plant-derived agents. Future research and clinical trials in glioblastoma patients should pursue combination of therapies to help combat drug resistance. The emerging new data on the potential of plant-derived therapeutics should also be closely considered and further investigated. PMID:22228201

  7. 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 Multi-Drug Resistant Acinetobacter baumanii have been isolated from different sites. The other Gram negative isolates included Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Klebsiella oxytoca, Serratia marcescens and Stenotrophomonas maltophilia. A significant rise in R and MDR but there is rise in R and MDR Acinetobacter baumanii Strains has been interceded other isolates. It is important to adopt proper and sustainable policies and guideline regarding antibiotics prescription and used. We should also check our infection control practices in our hospital or healthcare settings. We should start antibiotics stewardship in our hospital in order to reducing or overcoming antibiotics Resistant (R) and Multi-Drug Resistant (MDR) strains prevalence. PMID:26004714

  8. Enhanced Resistance to Bacterial Infection in Protegrin-1 Transgenic Mice▿

    PubMed Central

    Cheung, Queenie C. K.; Turner, Patricia V.; Song, Cheng; Wu, De; Cai, Hugh Y.; MacInnes, Janet I.; Li, Julang

    2008-01-01

    Antibiotic-resistant bacteria have become a public health concern. It was suggested that one source of resistant pathogens may be food-producing animals. Alternative approaches are therefore needed to enhance the resistance of farm animals to bacterial infection. Protegrin-1 (PG-1) is a neutrophil-derived antimicrobial peptide that possesses activity against a wide range of bacteria and enveloped viruses. Here we report on the production of transgenic mice that ectopically expressed PG-1 and compare their susceptibilities to Actinobacillus suis infection with those of their wild-type (WT) littermates. Of the 126 mice that were challenged with A. suis, 87% of the transgenic mice survived, whereas 31% of their WT littermates survived. The PG-1 transgenic mice had significantly lower bacterial loads in their lungs and reduced numbers of pulmonary pathological lesions. The antimicrobial function of PG-1 was confirmed in vitro by using fibroblast cells isolated from the transgenic mice but not the WT mice. Moreover, differential blood cell counts in bronchoalveolar lavage fluid indicated greater number of neutrophils in PG-1 transgenic mice than in their WT littermates after bacterial challenge. Our data suggest that the ectopic expression of PG-1 in mice confers enhanced resistance to bacterial infection, laying the foundation for the development of livestock with improved resistance to infection. PMID:18316527

  9. Resistance of bacterial spores to ultraviolet light

    SciTech Connect

    Setlow, P.

    1988-01-01

    Dormant spores of gram-positive bacteria, such as the various Bacillus species, usually are more resistant to killing by ultraviolet light than are growing cells. During the first minutes of spore germination, the spore's UV resistance rises significantly before dropping to the decreased value of the vegetative cell. For all strains of all species that have been tested, the spores are considerably more UV-resistant than their corresponding growing cells. Since the killing of cells or spores by UV-radiation is due to the presence of UV-induced photoproducts in DNA, there are two major factors that might be expected to influence UV resistance. (1) the UV photochemistry of the DNA in vivo, i.e., the type of photoproducts formed in DNA by UV radiation, the quantum efficiency of their formation, and their lethality; and (2) the efficiency of the repair or removal of these photoproducts. The DNA in the dormant spores has a different UV photochemistry than does the DNA in the growing cell, while the young germinated spore's DNA may exhibit a third type of UV photochemistry. There is at least one repair system which is specific for UV photoproducts produced in the dormant spore, as well as repair systems that act on UV photoproducts formed in other stages of growth.

  10. Recent trends in resistance to cell envelope-active antibacterial agents among key bacterial pathogens.

    PubMed

    Master, Ronald N; Deane, Jennifer; Opiela, Carol; Sahm, Daniel F

    2013-01-01

    Cell envelope-active agents, particularly β-lactams, play a pivotal role in the treatment of bacterial infections and the extent to which their activity is affected by the emergence of multidrug-resistant organisms is of concern. We analyzed the Surveillance Network (TSN) database to evaluate resistant trends for key cell envelope-active drugs among ESKAPE pathogens. Analysis demonstrated that the activity of these drugs has been notably influenced by the emergence of multidrug resistance; this was especially evident for the β-lactam drugs. For example, Acinetobacter baumannii resistance to imipenem increased from 23.9% to 34.3%, and resistance to piperacillin-tazobactam increased from 37.0% to 49.7% between 2007 and 2011. During the same time period Klebsiella pneumoniae resistance to imipenem increased from 0.8% to 3.8%. As β-lactams are a cornerstone of anti-infective therapy, it is important to closely monitor the activity of the agents being used today and to aggressively pursue new strategies that can augment current drugs and thwart ever-emerging β-lactam resistance mechanisms that are continuously encountered. PMID:23346857

  11. Drug-resistant tuberculosis: emerging treatment options.

    PubMed

    Adhvaryu, Meghna; Vakharia, Bhasker

    2011-01-01

    Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug-drug interactions in patients coinfected with human immunodeficiency virus (HIV), inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drugsusceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO) has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and markers for adequacy of treatment and an integrative approach to fulfill WHO goals. However, regulatory control over the drug market, as well as public-private partnership to use health program facilities to track patients and ensure completion of adequate therapy will be necessary to exploit fully the potential of the newer regimens to eliminate tuberculosis. PMID:22287857

  12. Strategies to overcome the action of aminoglycoside-modifying enzymes for treating resistant bacterial infections.

    PubMed

    Labby, Kristin J; Garneau-Tsodikova, Sylvie

    2013-07-01

    Shortly after the discovery of the first antibiotics, bacterial resistance began to emerge. Many mechanisms give rise to resistance; the most prevalent mechanism of resistance to the aminoglycoside (AG) family of antibiotics is the action of aminoglycoside-modifying enzymes (AMEs). Since the identification of these modifying enzymes, many efforts have been put forth to prevent their damaging alterations of AGs. These diverse strategies are discussed within this review, including: creating new AGs that are unaffected by AMEs; developing inhibitors of AMEs to be co-delivered with AGs; or regulating AME expression. Modern high-throughput methods as well as drug combinations and repurposing are highlighted as recent drug-discovery efforts towards fighting the increasing antibiotic resistance crisis. PMID:23859208

  13. Aedesin: Structure and Antimicrobial Activity against Multidrug Resistant Bacterial Strains

    PubMed Central

    Padilla, André; Hamel, Rodolphe; Luplertlop, Natthanej; Chauffour, Aurélie; Vittecoq, Marion; Hoh, François; Thomas, Frédéric; Sougakoff, Wladimir; Lionne, Corinne; Yssel, Hans; Missé, Dorothée

    2014-01-01

    Multidrug resistance, which is acquired by both Gram-positive and Gram-negative bacteria, causes infections that are associated with significant morbidity and mortality in many clinical settings around the world. Because of the rapidly increasing incidence of pathogens that have become resistant to all or nearly all available antibiotics, there is a need for a new generation of antimicrobials with a broad therapeutic range for specific applications against infections. Aedesin is a cecropin-like anti-microbial peptide that was recently isolated from dengue virus-infected salivary glands of the Aedes aegypti mosquito. In the present study, we have refined the analysis of its structural characteristics and have determined its antimicrobial effects against a large panel of multidrug resistant bacterial strains, directly isolated from infected patients. Based the results from nuclear magnetic resonance spectroscopy analysis, Aedesin has a helix-bend-helix structure typical for a member of the family of α-helix anti-microbial peptides. Aedesin efficiently killed Gram-negative bacterial strains that display the most worrisome resistance mechanisms encountered in the clinic, including resistance to carbapenems, aminoglycosides, cephalosporins, 4th generation fluoroquinolones, folate inhibitors and monobactams. In contrast, Gram-positive strains were insensitive to the lytic effects of the peptide. The anti-bacterial activity of Aedesin was found to be salt-resistant, indicating that it is active under physiological conditions encountered in body fluids characterized by ionic salt concentrations. In conclusion, because of its strong lytic activity against multidrug resistant Gram-negative bacterial strains displaying all types of clinically relevant resistance mechanisms known today, Aedesin might be an interesting candidate for the development of alternative treatment for infections caused by these types of bacteria. PMID:25162372

  14. Drug targeting of leptin resistance.

    PubMed

    Santoro, Anna; Mattace Raso, Giuseppina; Meli, Rosaria

    2015-11-01

    Leptin regulates glucose, lipid and energy homeostasis as well as feeding behavior, serving as a bridge between peripheral metabolically active tissues and the central nervous system (CNS). Indeed, this adipocyte-derived hormone, whose circulating levels mirror fat mass, not only exerts its anti-obesity effects mainly modulating the activity of specific hypothalamic neurons expressing the long form of the leptin receptor (Ob-Rb), but it also shows pleiotropic functions due to the activation of Ob-Rb in peripheral tissues. Nevertheless, several mechanisms have been suggested to mediate leptin resistance, including obesity-associated hyperleptinemia, impairment of leptin access to CNS and the reduction in Ob-Rb signal transduction effectiveness, among others. During the onset and progression of obesity, the dampening of leptin sensitivity often occurs, preventing the efficacy of leptin replacement therapy from overcoming obesity and/or its comorbidities. This review focuses on obesity-associated leptin resistance and the mechanisms underpinning this condition, to highlight the relevance of leptin sensitivity restoration as a useful therapeutic strategy to treat common obesity and its complications. Interestingly, although promising strategies to counteract leptin resistance have been proposed, these pharmacological approaches have shown limited efficacy or even relevant adverse effects in preclinical and clinical studies. Therefore, the numerous findings from this review clearly indicate a lack of a single and efficacious treatment for leptin resistance, highlighting the necessity to find new therapeutic tools to improve leptin sensitivity, especially in patients with most severe disease profiles. PMID:26071010

  15. The Pharmacology of HIV Drug Resistance

    PubMed Central

    Zdanowicz, Martin M.

    2006-01-01

    Drug resistance to human immunodeficiency virus (HIV) is a major factor in the failure of antiretroviral therapy.1 In order for practitioners to provide effective pharmaceutical care to their HIV patients, it is essential that they understand the mechanisms of HIV drug resistance as well as the various factors that can contribute to its emergence. This article is based on didactic content from the infectious disease section of the Integrated Sequence II Course in the PharmD program at South University. In the course, students are first given an overview that includes key structural components of HIV and a discussion of the HIV life cycle. A detailed presentation on the pharmacology of the various classes of antiretroviral agents follows. The clinical impact and prevalence of HIV drug resistance is then discussed along with factors that might contribute to it. Mechanisms of drug resistance for each class of antiretroviral agents are presented in detail followed by a discussion of the basis and clinical utility of HIV drug resistance testing. Finally, new targets for HIV pharmacotherapy are presented along with an overview of new antiretroviral agents that are being developed. Content taught in lecture is reinforced by relevant case studies that students work on in small groups during the recitation period. PMID:17149429

  16. Phylogenetic Sequence Variations in Bacterial rRNA Affect Species-Specific Susceptibility to Drugs Targeting Protein Synthesis▿‡

    PubMed Central

    Akshay, Subramanian; Bertea, Mihai; Hobbie, Sven N.; Oettinghaus, Björn; Shcherbakov, Dimitri; Böttger, Erik C.; Akbergenov, Rashid

    2011-01-01

    Antibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences in Mycobacterium smegmatis ribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket. PMID:21730122

  17. Antiplaque biocides and bacterial resistance: a review.

    PubMed

    Sreenivasan, Prem; Gaffar, Abdul

    2002-11-01

    Modern dentistry emphasizes the importance of dental plaque control to improve oral health. The use of oral care formulations with antiplaque biocides plays a crucial role in patient-directed approaches for plaque control. The antiplaque efficacies of these formulations have been extensively studied in many long-term clinical studies designed in accordance with well-accepted guidelines. The results from these studies conclusively demonstrate that long-term use of oral care formulations with well-known antiplaque biocides such as chlorhexidine and triclosan reduce supragingival plaque and gingivitis. This review summarizes microbiological results from clinical studies conducted with oral care formulations containing antiplaque biocides. Results from a number of long-term clinical studies conducted under real-life use conditions indicate no adverse alterations in the bacteria found in dental plaque or emergent microbial resistance. Additionally, microbial sampling of dental plaque subsequent to extended use of antiplaque biocides reveals no increase in resistant microflora. Large numbers of common oral bacteria isolated from patients using chlorhexidine indicate no increase in microbial resistance to chlorhexidine or to commonly used antibiotics. The effects of antiplaque biocides containing oral care formulations on dental plaque that exists naturally as a biofilm are examined. These formulations contain biocide, surfactants, polymers and other components that are effective against the biofilm. In summary, the results of studies on the real-life use of oral care formulations with antiplaque biocides show no emergence of resistant microflora or alterations of the oral microbiota, while such formulations have been found to provide the benefits of reducing plaque and gingivitis. PMID:12472989

  18. Protein Oxidation: Key to Bacterial Desiccation Resistance?

    SciTech Connect

    Fredrickson, Jim K.; Li, Shu-Mei W.; Gaidamakova, E.; Matrosova, V.; Zhai, M.; Sulloway, Heather M.; Scholten, Johannes C.; Brown,, Mindy G.; Balkwill, David L.; Daly, Michael J.

    2008-04-01

    For extremely ionizing radiation resistant bacteria, survival has been attributed to protection of proteins from oxidative damage during irradiation, with the result that repair systems survive and function with far greater efficiency during recovery than in sensitive bacteria. Here we examined the relationship between survival of dry-climate soil bacteria and the level of cellular protein oxidation induced by desiccation. Bacteria were isolated from surface soils of the shrub-steppe of the U.S. Department of Energys Hanford Site in Washington state. A total of 63 isolates were used for phylogenetic analysis. The majority of isolates were closely related to members of the genus Deinococcus, with Chelatococcus, Methylobacterium and Bosea also among the genera identified. Desiccation-resistant isolates accumulated high intracellular manganese and low iron concentrations compared to sensitive bacteria. In vivo, proteins of desiccation-resistant bacteria were protected from oxidative modifications that introduce carbonyl groups in sensitive bacteria during drying. We present the case that survival of bacteria that inhabit dry-climate soils are highly dependent on mechanisms which limit protein oxidation during dehydration.

  19. Genetics and breeding of bacterial leaf spot resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial leaf spot (BLS) caused by the pathogen Xanthomonas campestris pv. vitians (Xcv) is a globally important disease of whole head and baby leaf lettuce that reduces crop yield and quality. Host resistance is the most feasible method to reduce disease losses. Screening Lactuca accessions has id...

  20. Antifungals: Mechanism of Action and Drug Resistance.

    PubMed

    Prasad, Rajendra; Shah, Abdul Haseeb; Rawal, Manpreet Kaur

    2016-01-01

    There are currently few antifungals in use which show efficacy against fungal diseases. These antifungals mostly target specific components of fungal plasma membrane or its biosynthetic pathways. However, more recent class of antifungals in use is echinocandins which target the fungal cell wall components. The availability of mostly fungistatic antifungals in clinical use, often led to the development of tolerance to these very drugs by the pathogenic fungal species. Thus, the development of clinical multidrug resistance (MDR) leads to higher tolerance to drugs and its emergence is helped by multiple mechanisms. MDR is indeed a multifactorial phenomenon wherein a resistant organism possesses several mechanisms which contribute to display reduced susceptibility to not only single drug in use but also show collateral resistance to several drugs. Considering the limited availability of antifungals in use and the emergence of MDR in fungal infections, there is a continuous need for the development of novel broad spectrum antifungal drugs with better efficacy. Here, we briefly present an overview of the current understanding of the antifungal drugs in use, their mechanism of action and the emerging possible novel antifungal drugs with great promise. PMID:26721281

  1. Drug-resistant tuberculosis: emerging treatment options

    PubMed Central

    Adhvaryu, Meghna; Vakharia, Bhasker

    2011-01-01

    Multidrug-resistant tuberculosis has emerged worldwide, with an increasing incidence due to failure of implementation of apparently effective first-line antituberculous therapy as well as primary infection with drug-resistant strains. Failure of current therapy is attributed to a long duration of treatment leading to nonadherence and irregular therapy, lack of patient education about the disease, poverty, irregular supply by care providers, drug–drug interactions in patients coinfected with human immunodeficiency virus (HIV), inadequate regulations causing market overlap and irresponsible drug usage in the private sector, and lack of research, with no addition of new drugs in the last four decades. Present standards of care for the treatment of drugsusceptible tuberculosis, multidrug-resistant tuberculosis, tuberculosis-HIV coinfection, and latent tuberculosis infection are all unsatisfactory. Since 2000, the World Health Organization (WHO) has focused on drug development for tuberculosis, as well as research in all relevant aspects to discover new regimens by 2015 and to eliminate tuberculosis as a public health concern by 2050. As a result, some 20 promising compounds from 14 groups of drugs have been discovered. Twelve candidates from eight classes are currently being evaluated in clinical trials. Ongoing research should prioritize identification of novel targets and newer application of existing drugs, discovery of multitargeted drugs from natural compounds, strengthening host factors by immunopotentiation with herbal immunomodulators, as well as protective vaccines before and after exposure, consideration of surgical measures when indicated, development of tools for rapid diagnosis, early identification of resistant strains, and markers for adequacy of treatment and an integrative approach to fulfill WHO goals. However, regulatory control over the drug market, as well as public-private partnership to use health program facilities to track patients and ensure completion of adequate therapy will be necessary to exploit fully the potential of the newer regimens to eliminate tuberculosis. PMID:22287857

  2. [Investigation of extensive drug resistance in multidrug resistance tuberculosis isolates].

    PubMed

    Bektöre, Bayhan; Haznedaroğlu, Tunçer; Baylan, Orhan; Ozyurt, Mustafa; Ozkütük, Nuri; Satana, Dilek; Cavuşoğlu, Cengiz; Seber, Engin

    2013-01-01

    Increasing number of drug resistant tuberculosis (TB) cases, observed in recent years, is an important public health problem. Extensively drug resistant TB (XDR-TB) is the development of resistance against any fluoroquinolones and at least one of the injectable second line anti-TB drugs in addition to resistance against isoniazide and rifampicin which are the first line anti-TB drugs [definition of multidrug resistant TB (MDR-TB)]. Anti-TB therapy failed with first-line anti-TB drugs due to MDR-TB cases is being planned according to second-line anti-TB drug susceptibility test results if available and if not, standart treatment protocols are used. Although it is recommended that individual anti-TB therapy should be designed according to the isolate's susceptibility test results, standart therapeutic protocols are always needed since second-line anti-TB drug susceptibility testing generally could not be performed in developing countries like Turkey. For this reason, nationwide and regional surveillance studies to determine the resistance patterns are always needed to make decisions about the standard therapy algorithms. In this study, it was aimed to investigate the presence of extensive drug resistance among 81 MDR-TB isolates obtained from various health care facilities from Istanbul, Izmir and Manisa and to determine the XDR-TB incidence in Marmara and Aegean regions. Furthermore, we aimed to provide epidemiological data to clinicians to support their choice of second-line anti-TB drugs for MDR-TB infections. Susceptibility testing of isolates for the first and the second-line anti-TB drugs were performed by using modified Middlebrook 7H9 broth in fluorometric BACTEC MGIT 960 system (Becton Dickinson, USA). Eighty-one MDR-TB isolates included in this study were isolated from 43 (53.1%) patients residing in Istanbul, 26 (32.1%) in Izmir and 12 (14.8%) in Manisa provinces. We could not find any isolate consistent with XDR-TB definition in this study. Second-line drug resistance rates of MDR-TB isolates to amikacin and kanamycin were 1.2%, ofloxacin and levofloxacin were 2.5%, capreomycin was 14.8%, ethionamide was 37% whereas linezolid resistance was not detected. Statistically significant correlation was detected between resistance rates of these antibiotic pairs; levofloxacin-ofloxacin (p< 0.01), amikacin-kanamycin (p= 0.01) and streptomycin-ethionamide (p= 0.04). In our study, extensive drug resistance was not encountered in any MDR-TB isolates while high resistance rates was observed against ethionamide and capreomycin. It can be concluded that parenteral aminoglycosides amikasin and kanamycin, fluoroquinolones and linezolid seemed to be reliable anti-TB agents in MDR-TB treatment, however, further larger scale studies are needed. PMID:23390903

  3. Test for bacterial resistance build-up against plasma treatment

    NASA Astrophysics Data System (ADS)

    Zimmermann, J. L.; Shimizu, T.; Schmidt, H.-U.; Li, Y.-F.; Morfill, G. E.; Isbary, G.

    2012-07-01

    It is well known that the evolution of resistance of microorganisms to a range of different antibiotics presents a major problem in the control of infectious diseases. Accordingly, new bactericidal ‘agents’ are in great demand. Using a cold atmospheric pressure (CAP) plasma dispenser operated with ambient air, a more than five orders of magnitude inactivation or reduction of Methicillin-resistant Staphylococcus aureus (MRSA; resistant against a large number of the tested antibiotics) was obtained in less than 10 s. This makes CAP the most promising candidate for combating nosocomial (hospital-induced) infections. To test for the occurrence and development of bacterial resistance against such plasmas, experiments with Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Enterococcus mundtii) were performed. The aim was to determine quantitative limits for primary (naturally) or secondary (acquired) resistance against the plasma treatment. Our results show that E. coli and E. mundtii possess no primary resistance against the plasma treatment. By generating four generations of bacteria for every strain, where the survivors of the plasma treatment were used for the production of the next generation, a lower limit to secondary resistance was obtained. Our results indicate that CAP technology could contribute to the control of infections in hospitals, in outpatient care and in disaster situations, providing a new, fast and efficient broad-band disinfection technology that is not constrained by bacterial resistance mechanisms.

  4. Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance

    NASA Astrophysics Data System (ADS)

    Artemova, Tatiana; Gerardin, Ylaine; Hsin-Jung Li, Sophia; Gore, Jeff

    2011-03-01

    Since the discovery of penicillin, antibiotics have been our primary weapon against bacterial infections. Unfortunately, bacteria can gain resistance to penicillin by acquiring the gene that encodes beta-lactamase, which inactivates the antibiotic. However, mutations in this gene are necessary to degrade the modern antibiotic cefotaxime. Understanding the conditions that favor the spread of these mutations is a challenge. Here we show that bacterial growth in beta-lactam antibiotics is cooperative and that the nature of this growth determines the conditions in which resistance evolves. Quantitative analysis of the growth dynamics predicts a peak in selection at very low antibiotic concentrations; competition between strains confirms this prediction. We also find significant selection at higher antibiotic concentrations, close to the minimum inhibitory concentrations of the strains. Our results argue that an understanding of the evolutionary forces that lead to antibiotic resistance requires a quantitative understanding of the evolution of cooperation in bacteria.

  5. Resistance to antibiotics targeted to the bacterial cell wall.

    PubMed

    Nikolaidis, I; Favini-Stabile, S; Dessen, A

    2014-03-01

    Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed. PMID:24375653

  6. Resistance to antibiotics targeted to the bacterial cell wall

    PubMed Central

    Nikolaidis, I; Favini-Stabile, S; Dessen, A

    2014-01-01

    Peptidoglycan is the main component of the bacterial cell wall. It is a complex, three-dimensional mesh that surrounds the entire cell and is composed of strands of alternating glycan units crosslinked by short peptides. Its biosynthetic machinery has been, for the past five decades, a preferred target for the discovery of antibacterials. Synthesis of the peptidoglycan occurs sequentially within three cellular compartments (cytoplasm, membrane, and periplasm), and inhibitors of proteins that catalyze each stage have been identified, although not all are applicable for clinical use. A number of these antimicrobials, however, have been rendered inactive by resistance mechanisms. The employment of structural biology techniques has been instrumental in the understanding of such processes, as well as the development of strategies to overcome them. This review provides an overview of resistance mechanisms developed toward antibiotics that target bacterial cell wall precursors and its biosynthetic machinery. Strategies toward the development of novel inhibitors that could overcome resistance are also discussed. PMID:24375653

  7. Virologic Tools for HCV Drug Resistance Testing

    PubMed Central

    Fourati, Slim; Pawlotsky, Jean-Michel

    2015-01-01

    Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors. Due to the high genetic variability of HCV, the outcome of DAA-based therapies may be altered by the selection of amino-acid substitutions located within the targeted proteins, which affect viral susceptibility to the administered compounds. At the drug developmental stage, preclinical and clinical characterization of HCV resistance to new drugs in development is mandatory. In the clinical setting, accurate diagnostic tools have become available to monitor drug resistance in patients who receive treatment with DAAs. In this review, we describe tools available to investigate drug resistance in preclinical studies, clinical trials and clinical practice. PMID:26690198

  8. [Effect of Three Typical Disinfection Byproducts on Bacterial Antibiotic Resistance].

    PubMed

    Lü, Lu; Zhang, Meng-lu; Wang, Chun-ming; Lin, Hui-rong; Yu, Xin

    2015-07-01

    The effect of typical disinfection byproducts (DBPs) on bacterial antibiotic resistance was investigated in this study. chlorodibromomethane (CDBM), iodoacetic acid (IAA) and chloral hydrate (CH) were selected, which belong to trihalomethanes (THMs), haloacetic acids (HAAs) and aldehydes, respectively. After exposure to the selected DBPs, the resistance change of the tested strains to antibiotics was determined. As a result, all of the three DBPs induced Pseudomonas aeruginosa PAO1 to gain increased resistance to the five antibiotics tested, and the DBPs ranked as IAA > CH > CDBM according to their enhancement effects. Multidrug resistance could also be enhanced by treatment with IAA. The same result was observed in Escherichia coli K12, suggesting that the effect of DBPs on antibiotic resistance was a common phenomenon. The mechanism was probably that DBPs stimulated oxidative stress, which induced mutagenesis. And the antibiotic resistance mutation frequency could be increased along with mutagenesis. This study revealed that the acquisition of bacterial antibiotic resistance might be related to DBPs in drinking water systems. Besides the genotoxicological risks, the epidemiological risks of DBPs should not be overlooked. PMID:26489321

  9. The drinking water treatment process as a potential source of affecting the bacterial antibiotic resistance.

    PubMed

    Bai, Xiaohui; Ma, Xiaolin; Xu, Fengming; Li, Jing; Zhang, Hang; Xiao, Xiang

    2015-11-15

    Two waterworks, with source water derived from the Huangpu or Yangtze River in Shanghai, were investigated, and the effluents were plate-screened for antibiotic-resistant bacteria (ARB) using five antibiotics: ampicillin (AMP), kanamycin (KAN), rifampicin (RFP), chloramphenicol (CM) and streptomycin (STR). The influence of water treatment procedures on the bacterial antibiotic resistance rate and the changes that bacteria underwent when exposed to the five antibiotics at concentration levels ranging from 1 to 100 μg/mL were studied. Multi-drug resistance was also analyzed using drug sensitivity tests. The results indicated that bacteria derived from water treatment plant effluent that used the Huangpu River rather than the Yangtze River as source water exhibited higher antibiotic resistance rates against AMP, STR, RFP and CM but lower antibiotic resistance rates against KAN. When the antibiotic concentration levels ranged from 1 to 10 μg/mL, the antibiotic resistance rates of the bacteria in the water increased as water treatment progressed. Biological activated carbon (BAC) filtration played a key role in increasing the antibiotic resistance rate of bacteria. Chloramine disinfection can enhance antibiotic resistance. Among the isolated ARB, 75% were resistant to multiple antibiotics. Ozone oxidation, BAC filtration and chloramine disinfection can greatly affect the relative abundance of bacteria in the community. PMID:26150304

  10. Drug Transporters and Multiple Drug Resistance in Pediatric Solid Tumors.

    PubMed

    Fruci, Doriana; Cho, William C S; Nobili, Valerio; Locatelli, Franco; Alisi, Anna

    2016-01-01

    Solid tumors account for approximately 30% of all childhood cancers. Although chemotherapy has largely contributed to strongly improve the outcome of children with cancer, multidrug resistance (MDR) remains a major mechanism limiting the overall survival of patients. An increased efflux rate of the anti-neoplastic drugs from cancer cells by action of members of the ATP-binding cassette (ABC) transporters is one of the most important mechanisms of MDR. These drug transporters play a pivotal role in preserving the balance between sensitivity and resistance to anti-neoplastic drug in specific tumor cells. The functional activity of ABC transporters have been extensively studied in adults, but barely investigated in pediatric solid malignancies. Here, we provide evidence from the current literature about MDR and ABC transporters in the most common types of pediatric solid tumors, including neuroblastoma, rhabdomyosarcoma, retinoblastoma, hepatoblastoma and Wilms' tumor. PMID:26694726

  11. Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants.

    PubMed

    Bragg, Robert; Jansen, Arina; Coetzee, Marisa; van der Westhuizen, Wouter; Boucher, Charlotte

    2014-01-01

    Control of bacterial diseases has, for many years, been dependent on the use of antibiotics. Due to the high levels of efficacy of antibiotics in the past other disease control options have, to a large extent, been neglected. Mankind is now facing an increasing problem with antibiotic resistance. In an effort to retain some antibiotics for human use, there are moves afoot to limit or even ban the use of antibiotics in animal production. The use of antibiotics as growth promoters have been banned in the European Union and the USA. The potential ban on the use of antibiotics to treat diseases in production animals creates a dilemma for man-suffer significant problem with bacterial infection or suffer from a severe shortage of food! There are other options for the control of bacterial diseases. These include vaccine development, bacteriophage therapy, and improved biosecurity. Vaccine development against bacterial pathogens, particularly opportunistic pathogens, is often very challenging, as in many cases the molecular basis of the virulence is not always clearly understood. This is particularly true for Escherichia coli. Biosecurity (disinfection) has been a highly neglected area in disease control. With the ever-increasing problems with antibiotic resistance-the focus should return to improvements in biosecurity. As with antibiotics, bacteria also have mechanisms for resistance to disinfectants. To ensure that we do not replace one set of problems (increasing antibiotic resistance) with another (increasing resistance to disinfectants) we need to fully understand the modes of action of disinfectants and how the bacteria develop resistance to these disinfectants. Molecular studies have been undertaken to relate the presence of QAC resistance genes in bacteria to their levels of sensitivity to different generations of QAC-based products. The mode of action of QAC on bacteria has been studied using NanoSAM technology, where it was revealed that the QAC causes disruption of the bacterial cell wall and leaking of the cytoplasm out of the cells. Our main focus is on the control of bacterial and viral diseases in the poultry industry in a post-antibiotic era, but the principles remain similar for disease control in any veterinary field as well as in human medicine. PMID:24595606

  12. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens

    PubMed Central

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

    2015-01-01

    Without a doubt, our current antimicrobials are losing the battle in the fight against newly-emerged multidrug-resistant pathogens. There is a pressing, unmet need for novel antimicrobials and novel approaches to develop them; however, it is becoming increasingly difficult and costly to develop new antimicrobials. One strategy to reduce the time and cost associated with antimicrobial innovation is drug repurposing, which is to find new applications outside the scope of the original medical indication of the drug. Ebselen, an organoselenium clinical molecule, possesses potent antimicrobial activity against clinical multidrug-resistant Gram-positive pathogens, including Staphylococcus, Streptococcus, and Enterococcus, but not against Gram-negative pathogens. Moreover, the activity of ebselen against Gram-positive pathogens exceeded those activities determined for vancomycin and linezolid, drugs of choice for treatment of Enterococcus and Staphylococcus infections. The minimum inhibitory concentrations of ebselen at which 90% of clinical isolates of Enterococcus and Staphylococcus were inhibited (MIC90) were found to be 0.5 and 0.25 mg/L, respectively. Ebselen showed significant clearance of intracellular methicillin-resistant S. aureus (MRSA) in comparison to vancomycin and linezolid. We demonstrated that ebselen inhibits the bacterial translation process without affecting mitochondrial biogenesis. Additionally, ebselen was found to exhibit excellent activity in vivo in a Caenorhabditis elegans MRSA-infected whole animal model. Finally, ebselen showed synergistic activities with conventional antimicrobials against MRSA. Taken together, our results demonstrate that ebselen, with its potent antimicrobial activity and safety profiles, can be potentially used to treat multidrug resistant Gram-positive bacterial infections alone or in combination with other antibiotics and should be further clinically evaluated. PMID:26222252

  13. PARAMETERS OF TREATED STAINLESS STEEL SURFACES IMPORTANT FOR RESISTANCE TO BACTERIAL CONTAMINATION

    EPA Science Inventory

    Use of materials that are resistant to bacterial contamination could enhance food safety during processing. Common finishing treatments of stainless steel surfaces used for components of poultry processing equipment were tested for resistance to bacterial attachment. Surface char...

  14. Essential Oils, A New Horizon in Combating Bacterial Antibiotic Resistance

    PubMed Central

    Yap, Polly Soo Xi; Yiap, Beow Chin; Ping, Hu Cai; Lim, Swee Hua Erin

    2014-01-01

    For many years, the battle between humans and the multitudes of infection and disease causing pathogens continues. Emerging at the battlefield as some of the most significant challenges to human health are bacterial resistance and its rapid rise. These have become a major concern in global public health invigorating the need for new antimicrobial compounds. A rational approach to deal with antibiotic resistance problems requires detailed knowledge of the different biological and non-biological factors that affect the rate and extent of resistance development. Combination therapy combining conventional antibiotics and essential oils is currently blooming and represents a potential area for future investigations. This new generation of phytopharmaceuticals may shed light on the development of new pharmacological regimes in combating antibiotic resistance. This review consolidated and described the observed synergistic outcome between essential oils and antibiotics, and highlighted the possibilities of essential oils as the potential resistance modifying agent. PMID:24627729

  15. Host-Directed Antimicrobial Drugs with Broad-Spectrum Efficacy against Intracellular Bacterial Pathogens

    PubMed Central

    Czyż, Daniel M.; Potluri, Lakshmi-Prasad; Jain-Gupta, Neeta; Riley, Sean P.; Martinez, Juan J.; Steck, Theodore L.; Crosson, Sean; Gabay, Joëlle E.

    2014-01-01

    ABSTRACT We sought a new approach to treating infections by intracellular bacteria, namely, by altering host cell functions that support their growth. We screened a library of 640 Food and Drug Administration (FDA)-approved compounds for agents that render THP-1 cells resistant to infection by four intracellular pathogens. We identified numerous drugs that are not antibiotics but were highly effective in inhibiting intracellular bacterial growth with limited toxicity to host cells. These compounds are likely to target three kinds of host functions: (i) G protein-coupled receptors, (ii) intracellular calcium signals, and (iii) membrane cholesterol distribution. The compounds that targeted G protein receptor signaling and calcium fluxes broadly inhibited Coxiella burnetii, Legionella pneumophila, Brucella abortus, and Rickettsia conorii, while those directed against cholesterol traffic strongly attenuated the intracellular growth of C. burnetii and L. pneumophila. These pathways probably support intracellular pathogen growth so that drugs that perturb them may be therapeutic candidates. Combining host- and pathogen-directed treatments is a strategy to decrease the emergence of drug-resistant intracellular bacterial pathogens. PMID:25073644

  16. Molecular basis of bacterial resistance to chloramphenicol and florfenicol.

    PubMed

    Schwarz, Stefan; Kehrenberg, Corinna; Doublet, Benoît; Cloeckaert, Axel

    2004-11-01

    Chloramphenicol (Cm) and its fluorinated derivative florfenicol (Ff) represent highly potent inhibitors of bacterial protein biosynthesis. As a consequence of the use of Cm in human and veterinary medicine, bacterial pathogens of various species and genera have developed and/or acquired Cm resistance. Ff is solely used in veterinary medicine and has been introduced into clinical use in the mid-1990s. Of the Cm resistance genes known to date, only a small number also mediates resistance to Ff. In this review, we present an overview of the different mechanisms responsible for resistance to Cm and Ff with particular focus on the two different types of chloramphenicol acetyltransferases (CATs), specific exporters and multidrug transporters. Phylogenetic trees of the different CAT proteins and exporter proteins were constructed on the basis of a multisequence alignment. Moreover, information is provided on the mobile genetic elements carrying Cm or Cm/Ff resistance genes to provide a basis for the understanding of the distribution and the spread of Cm resistance--even in the absence of a selective pressure imposed by the use of Cm or Ff. PMID:15539072

  17. Countering amyloid polymorphism and drug resistance with minimal drug cocktails

    PubMed Central

    2010-01-01

    Several fatal, progressive neurodegenerative diseases, including various prion and prion-like disorders, are connected with the misfolding of specific proteins. These proteins misfold into toxic oligomeric species and a spectrum of distinct self-templating amyloid structures, termed strains. Hence, small molecules that prevent or reverse these protein-misfolding events might have therapeutic utility. Yet it is unclear whether a single small molecule can antagonize the complete repertoire of misfolded forms encompassing diverse amyloid polymorphs and soluble oligomers. We have begun to investigate this issue using the yeast prion protein Sup35 as an experimental paradigm. We have discovered that a polyphenol, (−)epigallocatechin-3-gallate (EGCG), effectively inhibited the formation of infectious amyloid forms (prions) of Sup35 and even remodeled preassembled prions. Surprisingly, EGCG selectively modulated specific prion strains and even selected for EGCG-resistant prion strains with novel structural and biological characteristics. Thus, treatment with a single small molecule antagonist of amyloidogenesis can select for novel, drug-resistant amyloid polymorphs. Importantly, combining EGCG with another small molecule, 4,5-bis-(4-methoxyanilino)phthalimide, synergistically antagonized and remodeled a wide array of Sup35 prion strains without producing any drug-resistant prions. We suggest that minimal drug cocktails, small collections of drugs that collectively antagonize all amyloid polymorphs, should be identified to besiege various neurodegenerative disorders. PMID:20935457

  18. Heavy metals in liquid pig manure in light of bacterial antimicrobial resistance

    SciTech Connect

    Hoelzel, Christina S.; Mueller, Christa; Harms, Katrin S.; Mikolajewski, Sabine; Schaefer, Stefanie; Schwaiger, Karin; Bauer, Johann

    2012-02-15

    Heavy metals are regularly found in liquid pig manure, and might interact with bacterial antimicrobial resistance. Concentrations of heavy metals were determined by atomic spectroscopic methods in 305 pig manure samples and were connected to the phenotypic resistance of Escherichia coli (n=613) against 29 antimicrobial drugs. Concentrations of heavy metals (/kg dry matter) were 0.08-5.30 mg cadmium, 1.1-32.0 mg chrome, 22.4-3387.6 mg copper, <2.0-26.7 mg lead, <0.01-0.11 mg mercury, 3.1-97.3 mg nickel and 93.0-8239.0 mg zinc. Associated with the detection of copper and zinc, resistance rates against {beta}-lactams were significantly elevated. By contrast, the presence of mercury was significantly associated with low antimicrobial resistance rates of Escherichia coli against {beta}-lactams, aminoglycosides and other antibiotics. Effects of subinhibitory concentrations of mercury on bacterial resistance against penicillins, cephalosporins, aminoglycosides and doxycycline were also demonstrated in a laboratory trial. Antimicrobial resistance in the porcine microflora might be increased by copper and zinc. By contrast, the occurrence of mercury in the environment might, due to co-toxicity, act counter-selective against antimicrobial resistant strains.

  19. Additional Drug Resistance in Mycobacterium tuberculosis Isolates From Resected Cavities Among Patients With Multidrug-Resistant or Extensively Drug-Resistant Pulmonary Tuberculosis

    PubMed Central

    Rabin, Alexander S.; Nikolaishvili, Ketino; Kalandadze, Iagor; Gogishvili, Shota; Blumberg, Henry M.; Vashakidze, Sergo

    2012-01-01

    The pathogenesis of increasing drug resistance among patients with multidrug-resistant or extensively drug-resistant tuberculosis undergoing treatment is poorly understood. Increasing drug resistance found among Mycobacterium tuberculosis recovered from cavitary isolates compared with paired sputum isolates suggests pulmonary cavities may play a role in the development of worsening tuberculosis drug resistance. PMID:22198790

  20. Marine bacterial communities are resistant to elevated carbon dioxide levels.

    PubMed

    Oliver, Anna E; Newbold, Lindsay K; Whiteley, Andrew S; van der Gast, Christopher J

    2014-12-01

    It is well established that the release of anthropogenic-derived CO2 into the atmosphere will be mainly absorbed by the oceans, with a concomitant drop in pH, a process termed ocean acidification. As such, there is considerable interest in how changes in increased CO2 and lower pH will affect marine biota, such as bacteria, which play central roles in oceanic biogeochemical processes. Set within an ecological framework, we investigated the direct effects of elevated CO2, contrasted with ambient conditions on the resistance and resilience of marine bacterial communities in a replicated temporal seawater mesocosm experiment. The results of the study strongly indicate that marine bacterial communities are highly resistant to the elevated CO2 and lower pH conditions imposed, as demonstrated from measures of turnover using taxa–time relationships and distance–decay relationships. In addition, no significant differences in community abundance, structure or composition were observed. Our results suggest that there are no direct effects on marine bacterial communities and that the bacterial fraction of microbial plankton holds enough flexibility and evolutionary capacity to withstand predicted future changes from elevated CO2 and subsequent ocean acidification. PMID:25756110

  1. Bacterial Transcription as a Target for Antibacterial Drug Development.

    PubMed

    Ma, Cong; Yang, Xiao; Lewis, Peter J

    2016-03-01

    Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

  2. The Culturable Soil Antibiotic Resistome: A Community of Multi-Drug Resistant Bacteria

    PubMed Central

    Walsh, Fiona; Duffy, Brion

    2013-01-01

    Understanding the soil bacterial resistome is essential to understanding the evolution and development of antibiotic resistance, and its spread between species and biomes. We have identified and characterized multi-drug resistance (MDR) mechanisms in the culturable soil antibiotic resistome and linked the resistance profiles to bacterial species. We isolated 412 antibiotic resistant bacteria from agricultural, urban and pristine soils. All isolates were multi-drug resistant, of which greater than 80% were resistant to 16–23 antibiotics, comprising almost all classes of antibiotic. The mobile resistance genes investigated, (ESBL, blaNDM-1, and plasmid mediated quinolone resistance (PMQR) resistance genes) were not responsible for the respective resistance phenotypes nor were they present in the extracted soil DNA. Efflux was demonstrated to play an important role in MDR and many resistance phenotypes. Clinically relevant Burkholderia species are intrinsically resistant to ciprofloxacin but the soil Burkholderia species were not intrinsically resistant to ciprofloxacin. Using a phenotypic enzyme assay we identified the antibiotic specific inactivation of trimethoprim in 21 bacteria from different soils. The results of this study identified the importance of the efflux mechanism in the soil resistome and variations between the intrinsic resistance profiles of clinical and soil bacteria of the same family. PMID:23776501

  3. Population Dynamics of Patients with Bacterial Resistance in Hospital Environment

    PubMed Central

    Qu, Leilei; Pan, Qiuhui; Gao, Xubin; He, Mingfeng

    2016-01-01

    During the past decades, the increase of antibiotic resistance has become a major concern worldwide. The researchers found that superbugs with new type of resistance genes (NDM-1) have two aspects of transmission characteristics; the first is that the antibiotic resistance genes can horizontally transfer among bacteria, and the other is that the superbugs can spread between humans through direct contact. Based on these two transmission mechanisms, we study the dynamics of population in hospital environment where superbugs exist. In this paper, we build three mathematic models to illustrate the dynamics of patients with bacterial resistance in hospital environment. The models are analyzed using stability theory of differential equations. Positive equilibrium points of the system are investigated and their stability analysis is carried out. Moreover, the numerical simulation of the proposed model is also performed which supports the theoretical findings. PMID:26904150

  4. Population Dynamics of Patients with Bacterial Resistance in Hospital Environment.

    PubMed

    Qu, Leilei; Pan, Qiuhui; Gao, Xubin; He, Mingfeng

    2016-01-01

    During the past decades, the increase of antibiotic resistance has become a major concern worldwide. The researchers found that superbugs with new type of resistance genes (NDM-1) have two aspects of transmission characteristics; the first is that the antibiotic resistance genes can horizontally transfer among bacteria, and the other is that the superbugs can spread between humans through direct contact. Based on these two transmission mechanisms, we study the dynamics of population in hospital environment where superbugs exist. In this paper, we build three mathematic models to illustrate the dynamics of patients with bacterial resistance in hospital environment. The models are analyzed using stability theory of differential equations. Positive equilibrium points of the system are investigated and their stability analysis is carried out. Moreover, the numerical simulation of the proposed model is also performed which supports the theoretical findings. PMID:26904150

  5. Membrane permeabilization of colistin toward pan-drug resistant Gram-negative isolates.

    PubMed

    Mohamed, Yasmine Fathy; Abou-Shleib, Hamida Moustafa; Khalil, Amal Mohamed; El-Guink, Nadia Mohamed; El-Nakeeb, Moustafa Ahmed

    2016-01-01

    Pan-drug resistant Gram-negative bacteria, being resistant to most available antibiotics, represent a huge threat to the medical community. Colistin is considered the last therapeutic option for patients in hospital settings. Thus, we were concerned in this study to demonstrate the membrane permeabilizing activity of colistin focusing on investigating its efficiency toward those pan-drug resistant isolates which represent a critical situation. We determined the killing dynamics of colistin against pan-drug resistant isolates. The permeability alteration was confirmed by different techniques as: leakage, electron microscopy and construction of an artificial membrane model; liposomes. Moreover, selectivity of colistin against microbial cells was also elucidated. Colistin was proved to be rapid bactericidal against pan-drug resistant isolates. It interacts with the outer bacterial membrane leading to deformation of its outline, pore formation, leakage of internal contents, cell lysis and finally death. Furthermore, variations in membrane composition of eukaryotic and microbial cells provide a key for colistin selectivity toward bacterial cells. Colistin selectively alters membrane permeability of pan-drug resistant isolates which leads to cell lysis. Colistin was proved to be an efficient last line treatment for pan-drug resistant infections which are hard to treat. PMID:26991296

  6. Screening Rice Cultivars for Resistance to Bacterial Leaf Blight.

    PubMed

    Fred, Agaba Kayihura; Kiswara, Gilang; Yi, Gihwan; Kim, Kyung-Min

    2016-05-28

    Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious threats to rice production. In this study, screening of rice for resistance to BLB was carried out at two different times and locations; that is, in a greenhouse during winter and in an open field during summer. The pathogenicity of Xoo race K1 was tested on 32 Korean rice cultivars. Inoculation was conducted at the maximum tillering stage, and the lesion length was measured after 14 days of inoculation. Five cultivars, Hanareum, Namcheon, Samgdeok, Samgang, and Yangjo, were found to be resistant in both the greenhouse and open-field screenings. Expression of the plant defense-related genes JAmyb, OsNPR1, OsPR1a, OsWRKY45, and OsPR10b was observed in resistant and susceptible cultivars by qRT-PCR. Among the five genes tested, only OsPR10b showed coherent expression with the phenotypes. Screening of resistance to Xoo in rice was more accurate when conducted in open fields in the summer cultivation period than in greenhouses in winter. The expression of plant defenserelated genes after bacterial inoculation could give another perspective in elucidating defense mechanisms by using both resistant and susceptible individuals. PMID:26869604

  7. Absence of bacterial resistance following repeat exposure to photodynamic therapy

    NASA Astrophysics Data System (ADS)

    Pedigo, Lisa A.; Gibbs, Aaron J.; Scott, Robert J.; Street, Cale N.

    2009-06-01

    The prevalence of antibiotic resistant bacteria necessitates exploration of alternative approaches to treat hospital and community acquired infections. The aim of this study was to determine whether bacterial pathogens develop resistance to antimicrobial photodynamic therapy (aPDT) during repeated sub-lethal challenge. Antibiotic sensitive and resistant strains of S. aureus and antibiotic sensitive E. coli were subjected to repeat PDT treatments using a methylene blue photosensitizer formulation and 670 nm illumination from a non-thermal diode laser. Parameters were adjusted such that kills were <100% so that surviving colonies could be passaged for subsequent exposures. With each repeat, kills were compared to those using non-exposed cultures of the same strain. Oxacillin resistance was induced in S. aureus using a disc diffusion method. For each experiment, "virgin" and "repeat" cultures were exposed to methylene blue at 0.01% w/v and illuminated with an energy dose of 20.6 J/cm2. No significant difference in killing of E. coli (repeat vs. virgin culture) was observed through 11 repeat exposures. Similar results were seen using MSSA and MRSA, wherein kill rate did not significantly differ from control over 25 repeat exposures. In contrast, complete oxacillin resistance could be generated in S. aureus over a limited number of exposures. PDT is effective in the eradication of pathogens including antibiotic resistance strains. Furthermore, repeated sub-lethal exposure does not induce resistance to subsequent PDT treatments. The absence of resistance formation represents a significant advantage of PDT over traditional antibiotics.

  8. Challenges of drug-resistant malaria

    PubMed Central

    Sinha, Shweta; Medhi, Bikash; Sehgal, Rakesh

    2014-01-01

    Over the past six decades, the drug resistance of Plasmodium falciparum has become an issue of utmost concern. Despite the remarkable progress that has been made in recent years in reducing the mortality rate to about 30% with the scaling-up of vector control, introduction of artemisinin-based combination therapies and other malaria control strategies, the confirmation of artemisinin resistance on the Cambodia–Thailand border threatened all the previous success. This review addresses the global scenario of antimalarial resistance and factors associated with it, with the main emphasis on futuristic approaches like nanotechnology and stem cell therapy that may impede resistant malaria, along with novel medications which are preparing to enter the global antimalarial market. These novel studies are likely to escalate over the coming years and will hopefully help to reduce the burden of malaria. PMID:25402734

  9. Understanding Cancer Drug Resistance by Developing and Studying Resistant Cell Line Models.

    PubMed

    Xavier, Cristina P R; Pesic, Milica; Vasconcelos, M Helena

    2016-01-01

    Despite the enormous number of anticancer drugs presently available in the clinic, treatment failure due to drug resistance is very frequent. The identification of mechanisms of resistance to different drugs is necessary, in order to identify ways to prevent and circumvent such resistance. Indeed, the identification of novel therapeutic targets to overcome cancer drug resistance remains one of the major challenges in drug discovery and development. The methods employed to identify drug resistance mechanisms and novel therapeutic targets depend greatly on the establishment of cancer drug resistant cell lines. The establishment of such drug resistant cell lines is laborious and time-consuming and various different approaches have been described. This manuscript reviews the methodologies that have been used to create cancer drug resistant cell lines and to identify their mechanisms of resistance. In addition, this review highlights the most frequent drug resistance mechanisms found in cancer cells. PMID:26563882

  10. Understanding the metabolic basis of drug resistance

    PubMed Central

    Martinez-Outschoorn, Ubaldo E; Lin, Zhao; Ko, Ying-Hui; Goldberg, Allison F; Flomenberg, Neal; Wang, Chenguang; Pavlides, Stephanos; Pestell, Richard G; Howell, Anthony

    2011-01-01

    Previously, we identified a form of epithelial-stromal metabolic coupling, in which cancer cells induce aerobic glycolysis in adjacent stromal fibroblasts, via oxidative stress, driving autophagy and mitophagy. In turn, these cancer-associated fibroblasts provide recycled nutrients to epithelial cancer cells, “fueling” oxidative mitochondrial metabolism and anabolic growth. An additional consequence is that these glycolytic fibroblasts protect cancer cells against apoptosis, by providing a steady nutrient stream to mitochondria in cancer cells. Here, we investigated whether these interactions might be the basis of tamoxifen-resistance in ER(+) breast cancer cells. We show that MCF7 cells alone are Tamoxifen-sensitive, but become resistant when co-cultured with hTERT-immortalized human fibroblasts. Next, we searched for a drug combination (Tamoxifen + Dasatinib) that could over-come fibroblast-induced Tamoxifen-resistance. Importantly, we show that this drug combination acutely induces the Warburg effect (aerobic glycolysis) in MCF7 cancer cells, abruptly cutting off their ability to use their fuel supply, effectively killing these cancer cells. Thus, we believe that the Warburg effect in tumor cells is not the “root cause” of cancer, but rather it may provide the necessary clues to preventing chemoresistance in cancer cells. Finally, we observed that this drug combination (Tamoxifen + Dasatinib) also had a generalized anti-oxidant effect, on both co-cultured fibroblasts and cancer cells alike, potentially reducing tumor-stroma co-evolution. Our results are consistent with the idea that chemo-resistance may be both a metabolic and stromal phenomenon that can be overcome by targeting mitochondrial function in epithelial cancer cells. Thus, simultaneously targeting both (1) the tumor stroma and (2) the epithelial cancer cells, with combination therapies, may be the most successful approach to anti-cancer therapy. This general strategy of combination therapy for overcoming drug resistance could be applicable to many different types of cancer. PMID:21768775

  11. Evolutionary consequences of drug resistance: shared principles across diverse targets and organisms.

    PubMed

    Hughes, Diarmaid; Andersson, Dan I

    2015-08-01

    Drug therapy has a crucial role in the treatment of viral, bacterial, fungal and protozoan infections, as well as the control of human cancer. The success of therapy is being threatened by the increasing prevalence of resistance. We examine and compare mechanisms of drug resistance in these diverse biological systems (using HIV and Plasmodium falciparum as examples of viral and protozoan pathogens, respectively) and discuss how factors — such as mutation rates, fitness effects of resistance, epistasis and clonal interference — influence the evolutionary trajectories of drug-resistant clones. We describe commonalities and differences related to resistance development that could guide strategies to improve therapeutic effectiveness and the development of a new generation of drugs. PMID:26149714

  12. The prevalence of bacterial resistance in clinical, food, water and some environmental samples in Southwest Nigeria.

    PubMed

    Lateef, A; Oloke, J K; Gueguimkana, E B

    2005-01-01

    The resistance pattern and mechanisms of bacterial isolates obtained from clinical origin, soil, industrial effluent, orange juice products and drinking water were studied using commonly used antibiotics. The microbial load of the water samples, industrial effluent and orange juice products were 1.0 x 10(1)-2.25 x 10(6), 2.15 x 10(5), and 3.5 x 10(4)-2.15 x 10(5) cfu mL(-1), respectively. The faecal coliform test revealed that only two out of twenty orange juice products had MPN of 2 and 20, the MPN of water ranged from 1-> or = 1800, while the effluent had MPN of > or = 1800. The bacterial isolates that were isolated include E. coli, S. aureus, P. vulgaris, S. marcescens, S. pyogenes, B. cereus, B. subtilis, Micrococcus sp., Klebsiella sp., P. aeruginosa, and Enterobacter sp. Also, clinical and soil isolates of P. aeruginosa were used in the study. Among the eight antibiotics tested for resistance on five strains of each bacterium, seven different resistance patterns were observed among the bacterial isolates obtained from water, effluent and orange juice products. Among the clinical and soil isolates of P. aeruginosa, four multiple-drug resistance patterns were obtained. Thirty strains of E. coli and S. aureus were tested for beta-lactamase production and fourteen strains, seven each of E. coli and S. aureus that had high Minimum Inhibitory Concentration values (MIC) for both Amoxycillin and Cloxacillin were positive. PMID:15727300

  13. Antifungal drug resistance of oral fungi.

    PubMed

    Niimi, Masakazu; Firth, Norman A; Cannon, Richard D

    2010-02-01

    Fungi comprise a minor component of the oral microbiota but give rise to oral disease in a significant proportion of the population. The most common form of oral fungal disease is oral candidiasis, which has a number of presentations. The mainstay for the treatment of oral candidiasis is the use of polyenes, such as nystatin and amphotericin B, and azoles including miconazole, fluconazole, and itraconazole. Resistance of fungi to polyenes is rare, but some Candida species, such as Candida glabrata and C. krusei, are innately less susceptible to azoles, and C. albicans can acquire azole resistance. The main mechanism of high-level fungal azole resistance, measured in vitro, is energy-dependent drug efflux. Most fungi in the oral cavity, however, are present in multispecies biofilms that typically demonstrate an antifungal resistance phenotype. This resistance is the result of multiple factors including the expression of efflux pumps in the fungal cell membrane, biofilm matrix permeability, and a stress response in the fungal cell. Removal of dental biofilms, or treatments to prevent biofilm development in combination with antifungal drugs, may enable better treatment and prevention of oral fungal disease. PMID:20155503

  14. Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies

    PubMed Central

    Armstrong, Cameron M; Gao, Allen C

    2015-01-01

    Several mechanisms facilitate the progression of hormone-sensitive prostate cancer to castration-resistant prostate cancer (CRPC). At present, the approved chemotherapies for CRPC include systemic drugs (docetaxel and cabazitaxel) and agents that target androgen signaling, including enzalutamide and abiraterone. While up to 30% of patients have primary resistance to these treatments, each of these drugs confers a significant survival benefit for many. Over time, however, all patients inevitably develop resistance to treatment and their disease will continue to progress. Several key mechanisms have been identified that give rise to drug resistance. Expression of constitutively active variants of the androgen receptor, such as AR-V7, intracrine androgens and overexpression of androgen synthesis enzymes like AKR1C3, and increased drug efflux through ABCB1 are just some of the many discovered mechanisms of drug resistance. Treatment strategies are being developed to target these pathways and reintroduce drug sensitivity. Niclosamide has been discovered to reduce AR-V7 activity and synergized to enzalutamide. Indomethacin has been explored to inhibit AKR1C3 activity and showed to be able to reverse resistance to enzalutamide. ABCB1 transport activity can be mitigated by the phytochemical apigenin and by antiandrogens such as bicalutamide, with each improving cellular response to chemotherapeutics. By better understanding the mechanisms by which drug resistance develops improved treatment strategies will be made possible. Herein, we review the existing knowledge of CRPC therapies and resistance mechanisms as well as methods that have been identified which may improve drug sensitivity. PMID:26309896

  15. Structural Studies of Bacterial Enzymes and their Relation to Antibiotic Resistance Mechanisms - Final Paper

    SciTech Connect

    Maltz, Lauren

    2015-08-27

    By using protein crystallography and X-ray diffraction, structures of bacterial enzymes were solved to gain a better understanding of how enzymatic modification acts as an antibacterial resistance mechanism. Aminoglycoside phosphotransferases (APHs) are one of three aminoglycoside modifying enzymes that confer resistance to the aminoglycoside antibiotics via enzymatic modification, rendering many drugs obsolete. Specifically, the APH(2”) family vary in their substrate specificities and also in their preference for the phosphate donor (ADP versus GDP). By solving the structures of members of the APH(2”) family of enzymes, we can see how domain movements are important to their substrate specificity. Our structure of the ternary complex of APH(2”)-IIIa with GDP and kanamycin, when compared to the known structures of APH(2”)-IVa, reveals that there are real physical differences between these two enzymes, a structural finding that explains why the two enzymes differ in their preferences for certain aminoglycosides. Another important group of bacterial resistance enzymes are the Class D β- lactamases. Oxacillinase carbapenemases (OXAs) are part of this enzyme class and have begun to confer resistance to ‘last resort’ drugs, most notably carbapenems. Our structure of OXA-143 shows that the conformational flexibility of a conserved hydrophobic residue in the active site (Val130) serves to control the entry of a transient water molecule responsible for a key step in the enzyme’s mechanism. Our results provide insight into the structural mechanisms of these two different enzymes

  16. Drug Resistant Fetal Arrhythmia in Obstetric Cholestasis

    PubMed Central

    Altug, Nahide; Kirbas, Ayse; Daglar, Korkut; Biberoglu, Ebru; Uygur, Dilek; Danisman, Nuri

    2015-01-01

    Obstetric cholestasis (OC) is a pregnancy specific liver disease characterized by increased levels of bile acid (BA) and pruritus. Raised maternal BA levels could be associated with intrauterine death, fetal distress, and preterm labor and also alter the rate and rhythm of cardiomyocyte contraction and may cause fetal arrhythmic events. We report a case of drug resistant fetal supraventricular tachycardia and concomitant OC. Conclusion. If there are maternal OC and concomitant fetal arrhythmia, possibility of the resistance to antiarrhythmic treatment should be kept in mind. PMID:25821617

  17. Chemical Communication of Antibiotic Resistance by a Highly Resistant Subpopulation of Bacterial Cells

    PubMed Central

    El-Halfawy, Omar M.; Valvano, Miguel A.

    2013-01-01

    The overall antibiotic resistance of a bacterial population results from the combination of a wide range of susceptibilities displayed by subsets of bacterial cells. Bacterial heteroresistance to antibiotics has been documented for several opportunistic Gram-negative bacteria, but the mechanism of heteroresistance is unclear. We use Burkholderia cenocepacia as a model opportunistic bacterium to investigate the implications of heterogeneity in the response to the antimicrobial peptide polymyxin B (PmB) and also other bactericidal antibiotics. Here, we report that B. cenocepacia is heteroresistant to PmB. Population analysis profiling also identified B. cenocepacia subpopulations arising from a seemingly homogenous culture that are resistant to higher levels of polymyxin B than the rest of the cells in the culture, and can protect the more sensitive cells from killing, as well as sensitive bacteria from other species, such as Pseudomonas aeruginosa and Escherichia coli. Communication of resistance depended on upregulation of putrescine synthesis and YceI, a widely conserved low-molecular weight secreted protein. Deletion of genes for the synthesis of putrescine and YceI abrogate protection, while pharmacologic inhibition of putrescine synthesis reduced resistance to polymyxin B. Polyamines and YceI were also required for heteroresistance of B. cenocepacia to various bactericidal antibiotics. We propose that putrescine and YceI resemble "danger" infochemicals whose increased production by a bacterial subpopulation, becoming more resistant to bactericidal antibiotics, communicates higher level of resistance to more sensitive members of the population of the same or different species. PMID:23844246

  18. Clinical relevance of HCV antiviral drug resistance.

    PubMed

    Welsch, C; Zeuzem, S

    2012-10-01

    The approval of direct-acting antiviral agents (DAAs) against the hepatitis C virus (HCV) NS3 protease revolutionized antiviral therapy in chronic hepatitis C. They mark the beginning of an era with drugs designed to inhibit specific viral proteins involved in the virus life cycle rather than the nonspecific antiviral activity of interferon. Upcoming generations of antivirals are expected that lead to viral eradication in most patients who undergo treatment with hope held for years that HCV can be cured without interferon. Antiviral drug resistance plays a key role in DAA-treatment failure. Knowledge on molecular escape mechanisms of resistant variants, their time to wild-type reversal and potential persistence is of upmost importance to design treatment strategies for patients with previous DAA-treatment failure. PMID:23006585

  19. Bacterial cheating limits the evolution of antibiotic resistance

    NASA Astrophysics Data System (ADS)

    Chao, Hui Xiao; Datta, Manoshi; Yurtsev, Eugene; Gore, Jeff

    2011-03-01

    The widespread use of antibiotics has led to the evolution of resistance in bacteria. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removing the antibiotic. The cooperative nature of this growth suggests that a cheater strain--which does not contribute to breaking down the antibiotic--may be able to take advantage of cells cooperatively inactivating the antibiotic. Here we experimentally find that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We observe stable coexistence between the two strains and find that a simple model successfully explains the behavior as a function of antibiotic concentration and cell density. We anticipate that our results will provide insight into the evolutionary origin of phenotypic diversity and cooperative behaviors found in nature.

  20. Current Perspectives on HIV-1 Antiretroviral Drug Resistance

    PubMed Central

    Iyidogan, Pinar; Anderson, Karen S.

    2014-01-01

    Current advancements in antiretroviral therapy (ART) have turned HIV-1 infection into a chronic and manageable disease. However, treatment is only effective until HIV-1 develops resistance against the administered drugs. The most recent antiretroviral drugs have become superior at delaying the evolution of acquired drug resistance. In this review, the viral fitness and its correlation to HIV-1 mutation rates and drug resistance are discussed while emphasizing the concept of lethal mutagenesis as an alternative therapy. The development of resistance to the different classes of approved drugs and the importance of monitoring antiretroviral drug resistance are also summarized briefly. PMID:25341668

  1. DDTRP: Database of Drug Targets for Resistant Pathogens

    PubMed Central

    Sundaramurthi, Jagadish Chandrabose; Ramanandan, Prabhakaran; Brindha, Sridharan; Subhasree, Chelladurai Ramarathnam; Prasad, Abhimanyu; Kumaraswami, Vasanthapuram; Hanna, Luke Elizabeth

    2011-01-01

    Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called ‘Database of Drug Targets for Resistant Pathogens’ (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP. PMID:21938213

  2. 77 FR 61417 - Guidance for Industry on Acute Bacterial Sinusitis: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-09

    ...The Food and Drug Administration (FDA) is announcing the availability of a guidance for industry entitled ``Acute Bacterial Sinusitis: Developing Drugs for Treatment.'' This guidance addresses FDA's current thinking regarding the overall development program and clinical trial designs for drugs to support an indication for the treatment of acute bacterial sinusitis (ABS). This guidance......

  3. Overcoming drug resistance in multi-drug resistant cancers and microorganisms

    PubMed Central

    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 large size and are often released only on contact with the perceived competitor. Thus, multi-domain proteins are missed during traditional methods of looking for growth zone inhibition of susceptible bacteria as demonstrated by antibiotics, but may represent the weapons of the future in the fights against both drug-resistant cancers and pathogens such as P. aeruginosa. PMID:22750915

  4. QTLs for Resistance to Major Rice Diseases Exacerbated by Global Warming: Brown Spot, Bacterial Seedling Rot, and Bacterial Grain Rot.

    PubMed

    Mizobuchi, Ritsuko; Fukuoka, Shuichi; Tsushima, Seiya; Yano, Masahiro; Sato, Hiroyuki

    2016-12-01

    In rice (Oryza sativa L.), damage from diseases such as brown spot, caused by Bipolaris oryzae, and bacterial seedling rot and bacterial grain rot, caused by Burkholderia glumae, has increased under global warming because the optimal temperature ranges for growth of these pathogens are relatively high (around 30 °C). Therefore, the need for cultivars carrying genes for resistance to these diseases is increasing to ensure sustainable rice production. In contrast to the situation for other important rice diseases such as blast and bacterial blight, no genes for complete resistance to brown spot, bacterial seedling rot or bacterial grain rot have yet been discovered. Thus, rice breeders have to use partial resistance, which is largely influenced by environmental conditions. Recent progress in molecular genetics and improvement of evaluation methods for disease resistance have facilitated detection of quantitative trait loci (QTLs) associated with resistance. In this review, we summarize the results of worldwide screening for cultivars with resistance to brown spot, bacterial seedling rot and bacterial grain rot and we discuss the identification of QTLs conferring resistance to these diseases in order to provide useful information for rice breeding programs. PMID:27178300

  5. Community HIV-1 Drug Resistance is Associated with Transmitted Drug Resistance

    PubMed Central

    Tilghman, M.W.; Pérez-Santiago, J.; Osorio, G.; Little, S.J.; Richman, D.D.; Mathews, W.C.; Haubrich, R.H.; Smith, D.M.

    2014-01-01

    Objective Since community viral load (CVL) measurements are associated with incidence of new HIV-1 infections in a population, we hypothesized that similarly measured community drug resistance (CDR) could predict prevalence of transmitted drug resistance (TDR). Methods Between 2001 and 2011, the prevalence of HIV-1 drug resistance for patients with established infection receiving HIV care (i.e. CDR) and TDR in recently infected patients was determined in San Diego. At each position in HIV-1 reverse transcriptase (RT) and protease (pro), drug resistance was evaluated both as the overall prevalence of resistance associated mutations and by weighting each resistance position to concurrent viral load of the patient and its proportion to the total viral load of the clinic (CVL). The weighting was the proportion of the CVL associated with patients identified with resistance at each residue. Spearman ranked correlation coefficients were used to determine associations between CDR and TDR. Results We analyzed 1,088 resistance tests from 971 clinic patients and baseline resistance tests for 542 recently infected patients. CDR at positions 30, 46, and 88 in pro was associated with TDR between 2001 and 2011. When CDR was weighted by viral load of patients, CDR was associated with TDR at position 103 in RT. Each of these associations was corroborated at least once using shorter measurement intervals. Conclusions Despite evaluation of a limited percentage of chronically infected patients in San Diego, CDR correlated with TDR at key resistance positions and therefore may be a useful tool to predict the prevalence of TDR. PMID:24417811

  6. Biophysics of Cell Membrane Lipids in Cancer Drug Resistance: Implications for Drug Transport and Drug Delivery with Nanoparticles

    PubMed Central

    Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

    2013-01-01

    In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcoming drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. PMID:24055719

  7. Alkylaminoquinolines inhibit the bacterial antibiotic efflux pump in multidrug-resistant clinical isolates.

    PubMed Central

    Malla, Monique; Mahamoud, Abdallah; Chevalier, Jacqueline; Alibert-Franco, Sandrine; Brouant, Pierre; Barbe, Jacques; Pags, Jean-Marie

    2003-01-01

    Over the last decade, MDR (multidrug resistance) has increased worldwide in microbial pathogens by efflux mechanisms, leading to treatment failures in human infections. Several Gram-negative bacteria efflux pumps have been described. These proteinaceous channels are capable of expelling structurally different drugs across the envelope and conferring antibiotic resistance in various bacterial pathogens. Combating antibiotic resistance is an urgency and the blocking of efflux pumps is an attractive response to the emergence of MDR phenotypes in infectious bacteria. In the present study, various alkylaminoquinolines were tested as potential inhibitors of drug transporters. We showed that alkylaminoquinolines are capable of restoring susceptibilities to structurally unrelated antibiotics in clinical isolates of MDR Gram-negative bacteria. Antibiotic efflux studies indicated that 7-nitro-8-methyl-4-[2'-(piperidino)ethyl]aminoquinoline acts as an inhibitor of the AcrAB-TolC efflux pump and restores a high level of intracellular drug concentration. Inhibitory activity of this alkylaminoquinoline is observed on clinical isolates showing different resistance phenotypes. PMID:12959639

  8. Exploiting Nanotechnology to Overcome Tumor Drug Resistance: Challenges and Opportunities

    PubMed Central

    Kirtane, Ameya; Kalscheuer, Stephen; Panyam, Jayanth

    2013-01-01

    Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. PMID:24036273

  9. Exploiting nanotechnology to overcome tumor drug resistance: Challenges and opportunities.

    PubMed

    Kirtane, Ameya R; Kalscheuer, Stephen M; Panyam, Jayanth

    2013-11-01

    Tumor cells develop resistance to chemotherapeutic drugs through multiple mechanisms. Overexpression of efflux transporters is an important source of drug resistance. Efflux transporters such as P-glycoprotein reduce intracellular drug accumulation and compromise drug efficacy. Various nanoparticle-based approaches have been investigated to overcome efflux-mediated resistance. These include the use of formulation excipients that inhibit transporter activity and co-delivery of the anticancer drug with a specific inhibitor of transporter function or expression. However, the effectiveness of nanoparticles can be diminished by poor transport in the tumor tissue. Hence, adjunct therapies that improve the intratumoral distribution of nanoparticles may be vital to the successful application of nanotechnology to overcome tumor drug resistance. This review discusses the mechanisms of tumor drug resistance and highlights the opportunities and challenges in the use of nanoparticles to improve the efficacy of anticancer drugs against resistant tumors. PMID:24036273

  10. Bacterial stress responses as determinants of antimicrobial resistance.

    PubMed

    Poole, Keith

    2012-09-01

    Bacteria encounter a myriad of stresses in their natural environments, including, for pathogens, their hosts. These stresses elicit a variety of specific and highly regulated adaptive responses that not only protect bacteria from the offending stress, but also manifest changes in the cell that impact innate antimicrobial susceptibility. Thus exposure to nutrient starvation/limitation (nutrient stress), reactive oxygen and nitrogen species (oxidative/nitrosative stress), membrane damage (envelope stress), elevated temperature (heat stress) and ribosome disruption (ribosomal stress) all impact bacterial susceptibility to a variety of antimicrobials through their initiation of stress responses that positively impact recruitment of resistance determinants or promote physiological changes that compromise antimicrobial activity. As de facto determinants of antimicrobial, even multidrug, resistance, stress responses may be worthy of consideration as therapeutic targets. PMID:22618862

  11. Bacterial spore structures and their protective role in biocide resistance.

    PubMed

    Leggett, M J; McDonnell, G; Denyer, S P; Setlow, P; Maillard, J-Y

    2012-09-01

    The structure and chemical composition of bacterial spores differ considerably from those of vegetative cells. These differences largely account for the unique resistance properties of the spore to environmental stresses, including disinfectants and sterilants, resulting in the emergence of spore-forming bacteria such as Clostridium difficile as major hospital pathogens. Although there has been considerable work investigating the mechanisms of action of many sporicidal biocides against Bacillus subtilis spores, there is far less information available for other species and particularly for various Clostridia. This paucity of information represents a major gap in our knowledge given the importance of Clostridia as human pathogens. This review considers the main spore structures, highlighting their relevance to spore resistance properties and detailing their chemical composition, with a particular emphasis on the differences between various spore formers. Such information will be vital for the rational design and development of novel sporicidal chemistries with enhanced activity in the future. PMID:22574673

  12. Newer systems for bacterial resistances to toxic heavy metals.

    PubMed Central

    Silver, S; Ji, G

    1994-01-01

    Bacterial plasmids contain specific genes for resistances to toxic heavy metal ions including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, and Zn2+. Recent progress with plasmid copper-resistance systems in Escherichia coli and Pseudomonas syringae show a system of four gene products, an inner membrane protein (PcoD), an outer membrane protein (PcoB), and two periplasmic Cu(2+)-binding proteins (PcoA and PcoC). Synthesis of this system is governed by two regulatory proteins (the membrane sensor PcoS and the soluble responder PcoR, probably a DNA-binding protein), homologous to other bacterial two-component regulatory systems. Chromosomally encoded Cu2+ P-type ATPases have recently been recognized in Enterococcus hirae and these are closely homologous to the bacterial cadmium efflux ATPase and the human copper-deficiency disease Menkes gene product. The Cd(2+)-efflux ATPase of gram-positive bacteria is a large P-type ATPase, homologous to the muscle Ca2+ ATPase and the Na+/K+ ATPases of animals. The arsenic-resistance system of gram-negative bacteria functions as an oxyanion efflux ATPase for arsenite and presumably antimonite. However, the structure of the arsenic ATPase is fundamentally different from that of P-type ATPases. The absence of the arsA gene (for the ATPase subunit) in gram-positive bacteria raises questions of energy-coupling for arsenite efflux. The ArsC protein product of the arsenic-resistance operons of both gram-positive and gram-negative bacteria is an intracellular enzyme that reduces arsenate [As(V)] to arsenite [As(III)], the substrate for the transport pump. Newly studied cation efflux systems for Cd2+, Zn2+, and Co2+ (Czc) or Co2+ and Ni2+ resistance (Cnr) lack ATPase motifs in their predicted polypeptide sequences. Therefore, not all plasmid-resistance systems that function through toxic ion efflux are ATPases. The first well-defined bacterial metallothionein was found in the cyanobacterium Synechococcus. Bacterial metallothionein is encoded by the smtA gene and contains 56 amino acids, including nine cysteine residues (fewer than animal metallothioneins). The synthesis of Synechococcus metallothionein is regulated by a repressor protein, the product of the adjacent but separately transcribed smtB gene. Regulation of metallothionein synthesis occurs at different levels; quickly by derepression of repressor activity, or over a longer time by deletion of the repressor gene at fixed positions and by amplification of the metallothionein DNA region leading to multiple copies of the gene. PMID:7843081

  13. Trypanocidal drugs: mechanisms, resistance and new targets.

    PubMed

    Wilkinson, Shane R; Kelly, John M

    2009-01-01

    The protozoan parasites Trypanosoma brucei and Trypanosoma cruzi are the causative agents of African trypanosomiasis and Chagas disease, respectively. These are debilitating infections that exert a considerable health burden on some of the poorest people on the planet. Treatment of trypanosome infections is dependent on a small number of drugs that have limited efficacy and can cause severe side effects. Here, we review the properties of these drugs and describe new findings on their modes of action and the mechanisms by which resistance can arise. We further outline how a greater understanding of parasite biology is being exploited in the search for novel chemotherapeutic agents. This effort is being facilitated by new research networks that involve academic and biotechnology/pharmaceutical organisations, supported by public-private partnerships, and are bringing a new dynamism and purpose to the search for trypanocidal agents. PMID:19863838

  14. Sterilization Resistance of Bacterial Spores Explained with Water Chemistry.

    PubMed

    Friedline, Anthony W; Zachariah, Malcolm M; Middaugh, Amy N; Garimella, Ravindranath; Vaishampayan, Parag A; Rice, Charles V

    2015-11-01

    Bacterial spores can survive for long periods without nutrients and in harsh environmental conditions. This survival is influenced by the structure of the spore, the presence of protective compounds, and water retention. These compounds, and the physical state of water in particular, allow some species of bacterial spores to survive sterilization schemes with hydrogen peroxide and UV light. The chemical nature of the spore core and its water has been a subject of some contention and the chemical environment of the water impacts resistance paradigms. Either the spore has a glassy core, where water is immobilized along with other core components, or the core is gel-like with mobile water diffusion. These properties affect the movement of peroxide and radical species, and hence resistance. Deuterium solid-state NMR experiments are useful for examining the nature of the water inside the spore. Previous work in our lab with spores of Bacillus subtilis indicate that, for spores, the core water is in a more immobilized state than expected for the gel-like core theory, suggesting a glassy core environment. Here, we report deuterium solid-state NMR observations of the water within UV- and peroxide-resistant spores from Bacillus pumilus SAFR-032. Variable-temperature NMR experiments indicate no change in the line shape after heating to 50 °C, but an overall decrease in signal after heating to 100 °C. These results show glass-like core dynamics within B. pumilus SAFR-032 that may be the potential source of its known UV-resistance properties. The observed NMR traits can be attributed to the presence of an exosporium containing additional labile deuterons that can aid in the deactivation of sterilizing agents. PMID:26435315

  15. [Prostate cancer stem cell and drug resistance].

    PubMed

    Kosaka, Takeo; Oya, Mototsugu

    2016-01-01

    Cancer tissues are comprised of cell population including a variety of cells, such as stem cell-like cancer cells, upon which a hierarchical society is constructed. This hypothesis has been applied not only to leukemia, in which the hypothesis was first experimentally confirmed, but also to solid cancers. Recent topics shed light on the modified heterogeneity by various treatments which evolve disease progression. In prostate cancer, the identification of cancer stem cells using surface markers and the relationship with prostate origin are of current interest. This article reviews studies related to the development of prostate cancer and introduce recent progress of our project, focusing on cancer stemness and drug resistance. PMID:26793878

  16. A Locked Nucleic Acid (LNA)-Based Real-Time PCR Assay for the Rapid Detection of Multiple Bacterial Antibiotic Resistance Genes Directly from Positive Blood Culture

    PubMed Central

    Zhu, Lingxiang; Shen, Dingxia; Zhou, Qiming; Li, Zexia; Fang, Xiangdong; Li, Quan-Zhen

    2015-01-01

    Bacterial strains resistant to various antibiotic drugs are frequently encountered in clinical infections, and the rapid identification of drug-resistant strains is highly essential for clinical treatment. We developed a locked nucleic acid (LNA)-based quantitative real-time PCR (LNA-qPCR) method for the rapid detection of 13 antibiotic resistance genes and successfully used it to distinguish drug-resistant bacterial strains from positive blood culture samples. A sequence-specific primer-probe set was designed, and the specificity of the assays was assessed using 27 ATCC bacterial strains and 77 negative blood culture samples. No cross-reaction was identified among bacterial strains and in negative samples, indicating 100% specificity. The sensitivity of the assays was determined by spiking each bacterial strain into negative blood samples, and the detection limit was 1–10 colony forming units (CFU) per reaction. The LNA-qPCR assays were first applied to 72 clinical bacterial isolates for the identification of known drug resistance genes, and the results were verified by the direct sequencing of PCR products. Finally, the LNA-qPCR assays were used for the detection in 47 positive blood culture samples, 19 of which (40.4%) were positive for antibiotic resistance genes, showing 91.5% consistency with phenotypic susceptibility results. In conclusion, LNA-qPCR is a reliable method for the rapid detection of bacterial antibiotic resistance genes and can be used as a supplement to phenotypic susceptibility testing for the early detection of antimicrobial resistance to allow the selection of appropriate antimicrobial treatment and to prevent the spread of resistant isolates. PMID:25775001

  17. Inhibitors of bacterial transcription are compounds for potent antimicrobial drugs.

    PubMed

    Turecka, Katarzyna; Waleron, Krzysztof

    2013-01-01

    The increasing resistance of microorganisms against antibiotics available on the pharmaceutical market is now a global problem. There is an incessant necessity to search for new, effective treatments against resistant strains of microorganisms, for new potent classes of antibiotics with novel modes of action targeted at important components of microbial cells. Such a critical, essential system for cell functioning is a RNA polymerase (RNAP), an enzyme that catalyses one of the stages of gene expression: transcription. RNAP is a proven target for a number of antibiotics, and it still remains an attractive drug target for new potent antimicrobial compounds. In this review several examples of inhibitors for transcription and RNAP are presented. PMID:24809716

  18. Emergence of antibiotic resistance from multinucleated bacterial filaments

    PubMed Central

    Bos, Julia; Zhang, Qiucen; Vyawahare, Saurabh; Rogers, Elizabeth; Rosenberg, Susan M.; Austin, Robert H.

    2015-01-01

    Bacteria can rapidly evolve resistance to antibiotics via the SOS response, a state of high-activity DNA repair and mutagenesis. We explore here the first steps of this evolution in the bacterium Escherichia coli. Induction of the SOS response by the genotoxic antibiotic ciprofloxacin changes the E. coli rod shape into multichromosome-containing filaments. We show that at subminimal inhibitory concentrations of ciprofloxacin the bacterial filament divides asymmetrically repeatedly at the tip. Chromosome-containing buds are made that, if resistant, propagate nonfilamenting progeny with enhanced resistance to ciprofloxacin as the parent filament dies. We propose that the multinucleated filament creates an environmental niche where evolution can proceed via generation of improved mutant chromosomes due to the mutagenic SOS response and possible recombination of the new alleles between chromosomes. Our data provide a better understanding of the processes underlying the origin of resistance at the single-cell level and suggest an analogous role to the eukaryotic aneuploidy condition in cancer. PMID:25492931

  19. Drug resistance in Indian visceral leishmaniasis.

    PubMed

    Sundar, S

    2001-11-01

    Throughout the world, pentavalent antimonial compounds (Sb(v)) have been the mainstay of antileishmanial therapy for more than 50 years. Sb(v) has been highly effective in the treatment of Indian visceral leishmaniasis (VL: kala-azar) at a low dose (10 mg/kg) for short durations (6-10 days). But in the early 1980s reports of its ineffectiveness emerged, and the dose of Sb(v) was eventually raised to 20 mg/kg for 30-40 days. This regimen cures most patients with VL except in India, where the proportion of patients unresponsive to Sb(v) has steadily increased. In hyperendemic districts of north Bihar, 50-65% patients fail treatment with Sb(v). Important reasons are rampant use of subtherapeutic doses, incomplete duration of treatment and substandard drugs. In vitro experiments have established emergence of Sb(v) resistant strains of Leishmania donovani, as isolates from unresponsive patients require 3-5 times more Sb(v) to reach similarly effectiveness against the parasite as in Sb(v) responders. Anthroponotic transmission in India has been an important factor in rapid increase in the Sb(v) refractoriness. Pentamidine was the first drug to be used and cured 99% of these refractory patients, but over time even with double the amount of initial doses, it cures only 69-78% patients now and its use has largely been abandoned in India. Despite several disadvantages, amphotericin B is the only drug available for use in these areas and should be used as first-line drug instead of Sb(v). The new oral antileishmanial drug miltefosine is likely to be the first-line drug in future. Unfortunately, development of newer antileishmanial drugs is rare; two promising drugs, aminosidine and sitamaquine, may be developed for use in the treatment of VL. Lipid associated amphotericin B has an excellent safety and efficacy profile, but remains out of reach for most patients because of its high cost. PMID:11703838

  20. Lysosomes as mediators of drug resistance in cancer.

    PubMed

    Zhitomirsky, Benny; Assaraf, Yehuda G

    2016-01-01

    Drug resistance remains a leading cause of chemotherapeutic treatment failure and cancer-related mortality. While some mechanisms of anticancer drug resistance have been well characterized, multiple mechanisms remain elusive. In this respect, passive ion trapping-based lysosomal sequestration of multiple hydrophobic weak-base chemotherapeutic agents was found to reduce the accessibility of these drugs to their target sites, resulting in a markedly reduced cytotoxic effect and drug resistance. Recently we have demonstrated that lysosomal sequestration of hydrophobic weak base drugs triggers TFEB-mediated lysosomal biogenesis resulting in an enlarged lysosomal compartment, capable of enhanced drug sequestration. This study further showed that cancer cells with an increased number of drug-accumulating lysosomes are more resistant to lysosome-sequestered drugs, suggesting a model of drug-induced lysosome-mediated chemoresistance. In addition to passive drug sequestration of hydrophobic weak base chemotherapeutics, other mechanisms of lysosome-mediated drug resistance have also been reported; these include active lysosomal drug sequestration mediated by ATP-driven transporters from the ABC superfamily, and a role for lysosomal copper transporters in cancer resistance to platinum-based chemotherapeutics. Furthermore, lysosomal exocytosis was suggested as a mechanism to facilitate the clearance of chemotherapeutics which highly accumulated in lysosomes, thus providing an additional line of resistance, supplementing the organelle entrapment of chemotherapeutics away from their target sites. Along with these mechanisms of lysosome-mediated drug resistance, several approaches were recently developed for the overcoming of drug resistance or exploiting lysosomal drug sequestration, including lysosomal photodestruction and drug-induced lysosomal membrane permeabilization. In this review we explore the current literature addressing the role of lysosomes in mediating cancer drug resistance as well as novel modalities to overcome this chemoresistance. PMID:26830313

  1. Adaptive and Mutational Resistance: Role of Porins and Efflux Pumps in Drug Resistance

    PubMed Central

    Fernández, Lucía

    2012-01-01

    Summary: The substantial use of antibiotics in the clinic, combined with a dearth of new antibiotic classes, has led to a gradual increase in the resistance of bacterial pathogens to these compounds. Among the various mechanisms by which bacteria endure the action of antibiotics, those affecting influx and efflux are of particular importance, as they limit the interaction of the drug with its intracellular targets and, consequently, its deleterious effects on the cell. This review evaluates the impact of porins and efflux pumps on two major types of resistance, namely, mutational and adaptive types of resistance, both of which are regarded as key phenomena in the global rise of antibiotic resistance among pathogenic microorganisms. In particular, we explain how adaptive and mutational events can dramatically influence the outcome of antibiotic therapy by altering the mechanisms of influx and efflux of antibiotics. The identification of porins and pumps as major resistance markers has opened new possibilities for the development of novel therapeutic strategies directed specifically against these mechanisms. PMID:23034325

  2. Identification of drug-resistant subpopulations in canine hemangiosarcoma.

    PubMed

    Khammanivong, A; Gorden, B H; Frantz, A M; Graef, A J; Dickerson, E B

    2014-08-11

    Canine hemangiosarcoma is a rapidly progressive disease that is poorly responsive to conventional chemotherapy. Despite numerous attempts to advance treatment options and improve outcomes, drug resistance remains a hurdle to successful therapy. To address this problem, we used recently characterized progenitor cell populations derived from canine hemangiosarcoma cell lines and grown as non-adherent spheres to identify potential drug resistance mechanisms as well as drug-resistant cell populations. Cells from sphere-forming cultures displayed enhanced resistance to chemotherapy drugs, expansion of dye-excluding side populations and altered ATP-binding cassette (ABC) transporter expression. Invasion studies demonstrated variability between cell lines as well as between sphere and monolayer cell populations. Collectively, our results suggest that sphere cell populations contain distinct subpopulations of drug-resistant cells that utilize multiple mechanisms to evade cytotoxic drugs. Our approach represents a new tool for the study of drug resistance in hemangiosarcoma, which could alter approaches for treating this disease. PMID:25112808

  3. Inhibition of adherence of multi-drug resistant E. coli by proanthocyanidin.

    PubMed

    Gupta, Ashish; Dwivedi, Mayank; Mahdi, Abbas Ali; Nagana Gowda, G A; Khetrapal, Chunni Lal; Bhandari, Mahendra

    2012-04-01

    Proanthocyanidin is commonly used for inhibiting urinary tract infection (UTI) of sensitive strains of Escherichia coli. The aim of this study was to investigate the effect of proanthocyanidin on adherence of uropathogenic multi-drug resistant E. coli to uroepithelial cells, which has not yet been investigated so far. Extracts of the purified proanthocyanidin were prepared from dried cranberry juice. Purity and structural assignment of proanthocyanidin was assessed using high performance liquid chromatography and (13)C nuclear magnetic resonance spectroscopy, respectively. Subsequently, its affect on multi-drug resistant bacteria as well as quantification of anti-adherence bioactivity on human vaginal and bladder epithelial cells was appraised. Inhibition of adherence to an extent of about 70% with multi-drug resistant E. coli strains was observed on uroepithelial cell. The anti-adherence bioactivity of the proanthocyanidin was detected at concentrations of 10-50 g/ml with significant bacteriuria. Probable proanthocyanidin through A-type linkages either combines to P-fimbriae of bacterial cells or modifies the structural entity of P-fimbriae and inhibits bacterial adherence to uroepithelial cells. The proanthocyanidin exhibited anti-adherence property with multi-drug resistant strains of uropathogenic P-fimbriated E. coli with in vitro study. Hence proanthocyanidin may be considered as an inhibitory agent for multi-drug resistant strains of E. coli adherence to uroepithelial cells. PMID:21688109

  4. The Bacterial Protein Azurin Enhances Sensitivity of Oral Squamous Carcinoma Cells to Anticancer Drugs

    PubMed Central

    Choi, Jeong-Hae; Lee, Moo-Hyung; Cho, Yun-Jung; Park, Bong-Soo

    2011-01-01

    Purpose Surgical therapy is the primary treatment for oral cancer, but it can cause facial distortion. Therefore, if anticancer drugs are effective against oral cancer, they may be used preferentially. However, oral squamous carcinoma cells (OSCCs) are resistant to these drugs, so finding a way to enhance the sensitivity of these cells to anticancer drugs is important. The bacterial protein azurin is known to selectively enter cancer cells and induce apoptosis. In this study, we show the anticancer effect of azurin in OSCC. Materials and Methods OSCC cell line (YD-9) was subjected to azurin treatment. Cell viability, morphology and protein expression levels were monitored after treatment of azurin. Cells were also subjected to combination treatment of azurin with either 5-fluorouracil or etopside. Results Azurin-treated cells showed decreased cell viability accompanied by apoptotic phenotypes including morphological change, DNA breakage, and increases in p53 and cyclin B1 protein levels. Combination treatment of azurin with other anti-tumor agents caused an increase in sensitivity to anticancer drugs in azurin-treated YD-9 cells. Conclusion Azurin has a strong synergistic anticancer effect on oral cancer cells when it is used along with anticancer drugs. PMID:21786442

  5. Young Women's Experiences of Resisting Invitations to Use Illicit Drugs

    ERIC Educational Resources Information Center

    Koehn, Corinne V.; O'Neill, Linda K.

    2011-01-01

    Ten young women were interviewed regarding their experiences of resisting invitations to use illicit drugs. Hermeneutic phenomenology was used to gather and analyze information. One key theme was the motivations that inspired women to refuse drug offers. Young women resisted drug invitations because of their desires to be authentic, protect their…

  6. Rural Adolescent Perceptions of Alcohol and Other Drug Resistance.

    ERIC Educational Resources Information Center

    Jenkins, Jeanne E.

    2001-01-01

    Used questionnaires and focus groups to examine 361 rural high schoolers' perceptions of drug resistance difficulties when offered beer, marijuana, and hard drugs. Found that drug nonusers had the widest range of explanations for resistance difficulty. Peer pressure was cited most frequently by nonusers, and seldom by heavy users. Frequent users…

  7. Evaluation of Idaho's DARE "Drug Abuse Resistance Education" Projects.

    ERIC Educational Resources Information Center

    Silva, Roberta K.

    The DARE (Drug Abuse Resistance Education) program teaches students decision-making skills, shows them how to resist peer pressure to experiment with drugs and alcohol, and provides positive alternatives to drug use. This report looks at one state's DARE programs. Included are an overview of the implementation process, a program appraisal with…

  8. Emergence of HIV-1 drug resistance during antiretroviral treatment.

    PubMed

    Rong, Libin; Feng, Zhilan; Perelson, Alan S

    2007-08-01

    Treating HIV-infected patients with a combination of several antiretroviral drugs usually contributes to a substantial decline in viral load and an increase in CD4(+) T cells. However, continuing viral replication in the presence of drug therapy can lead to the emergence of drug-resistant virus variants, which subsequently results in incomplete viral suppression and a greater risk of disease progression. In this paper, we use a simple mathematical model to study the mechanism of the emergence of drug resistance during therapy. The model includes two viral strains: wild-type and drug-resistant. The wild-type strain can mutate and become drug-resistant during the process of reverse transcription. The reproductive ratio [Symbol: see text](0) for each strain is obtained and stability results of the steady states are given. We show that drug-resistant virus is more likely to arise when, in the presence of antiretroviral treatment, the reproductive ratios of both strains are close. The wild-type virus can be suppressed even when the reproductive ratio of this strain is greater than 1. A pharmacokinetic model including blood and cell compartments is employed to estimate the drug efficacies of both the wild-type and the drug-resistant strains. We investigate how time-varying drug efficacy (due to the drug dosing schedule and suboptimal adherence) affects the antiviral response, particularly the emergence of drug resistance. Simulation results suggest that perfect adherence to regimen protocol will well suppress the viral load of the wild-type strain while drug-resistant variants develop slowly. However, intermediate levels of adherence may result in the dominance of the drug-resistant virus several months after the initiation of therapy. When more doses of drugs are missed, the failure of suppression of the wild-type virus will be observed, accompanied by a relatively slow increase in the drug-resistant viral load. PMID:17450401

  9. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    NASA Astrophysics Data System (ADS)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  10. Antitubercular and antibacterial activity of quinonoid natural products against multi-drug resistant clinical isolates.

    PubMed

    Dey, Diganta; Ray, Ratnamala; Hazra, Banasri

    2014-07-01

    Multi-drug resistant Mycobacterium tuberculosis and other bacterial pathogens represent a major threat to human health. In view of the critical need to augment the current drug regime, we have investigated therapeutic potential of five quinonoids, viz. emodin, diospyrin, plumbagin, menadione and thymoquinone, derived from natural products. The antimicrobial activity of quinonoids was evaluated against a broad panel of multi-drug and extensively drug-resistant tuberculosis (M/XDR-TB) strains, rapid growing mycobacteria and other bacterial isolates, some of which were producers of β-lactamase, Extended-spectrum β-lactamase (ESBL), AmpC β-lactamase, metallo-beta-lactamase (MBL) enzymes, as well as their drug-sensitive ATCC counterparts. All the tested quinones exhibited antimycobacterial and broad spectrum antibacterial activity, particularly against M. tuberculosis (lowest MIC 0.25 µg/mL) and Gram-positive bacteria (lowest MIC <4 µg/mL) of clinical origin. The order of antitubercular activity of the tested quinonoids was plumbagin > emodin ~ menadione ~ thymoquinone > diospyrin, whereas their antibacterial efficacy was plumbagin > menadione ~ thymoquinone > diospyrin > emodin. Furthermore, this is the first evaluation performed on these quinonoids against a broad panel of drug-resistant and drug-sensitive clinical isolates, to the best of our knowledge. PMID:24318724

  11. Heat stable antimicrobial activity of Burkholderia gladioli OR1 against clinical drug resistant isolates

    PubMed Central

    Bharti, Pratibha; Anand, Vivek; Chander, Jagdish; Singh, Inder Pal; Singh, Tej Vir; Tewari, Rupinder

    2012-01-01

    Background & objectives: Drug resistant microbes are a serious challenge to human health. During the search for novel antibiotics/inhibitors from the agricultural soil, a bacterial colony was found to inhibit the growth of clinical isolates including Staphylococcus (resistant to amikacin, ciprofloxacin, clindamycin, clinafloxacin, erythromycin, gentamicin and methicillin) and Candida (resistant to fluconazole and itraconazole). The culture was identified as Burkholderia gladioli and produced at least five different antimicrobial compounds which were highly stable at high temperature (121°C) and in the broad pH range (3.0-11.0). We report here the antimicrobial activity of B. gladioli against drug resistant bacterial pathogens. Methods: The bacterial culture was identified using morphological, biochemical and 16S rRNA gene sequencing techniques. The antimicrobial activity of the identified organism against a range of microbial pathogens was checked by Kirby-Bauer's disc diffusion method. The antimicrobial compounds in the cell free supernatant were chloroform-extracted and separated by thin layer chromatography (TLC). Results: B. gladioli OR1 exhibited broad spectrum antimicrobial activity against drug resistant clinical isolates belonging to various genera of bacteria (Staphylococcus, Enterobacter, Enterococcus, Acinetobacter and Citrobacter) and a fungus (Candida). Based on TLC profile and bioautography studies, the chloroform extract of B. gladioli OR1 consisted of at least three anti-staphylococcal and two anti-Candida metabolites. The antimicrobial activity was heat stable (121°C/20 min) as well as pH stable (3.0-11.0). Interpretation & conclusions: The bacterial soil isolate, B. gladioli OR1 possessed the ability to kill various drug resistant bacteria and a fungus. This organism produced many antimicrobial metabolites which might have the potential to be used as antibiotics in future. PMID:22771597

  12. Clinical treatment of pandrug-resistant bacterial infection consulted by clinical pharmacist

    PubMed Central

    Zhi-Wen, Yang; Yan-Li, Zhang; Man, Yuan; Wei-Jun, Fang

    2015-01-01

    Objective Pandrug-resistant (PDR) bacterial infections are associated with considerable prolongation of hospitalization and mortality in clinical practice. Method This case-series study was conducted during a 3-year period from 2011 to 2013. A total of 30 PDR patients consulted by clinical pharmacist were recorded to evaluate the anti-infection treatment. Results All isolates of PDR bacteria from patients were identified as pan-drug resistant acine-tobacter baumannii (63.3%), pan-drug resistant klebsiella pneumonia (20.0%), and pandrug-resistant pseudomonas aeruginosa (16.7%). Of the 30 patients, 96.7% therapeutic regimens supposed by clinical pharmacists were applied to treat the infectious patients up to 82.8% clinical cure rates. 30 patients completed the prescribed treatment, of which 19 underwent monotherapy that the clinical cure rate was 78.9%, and 10 underwent combination therapy that the clinical cure rate was 90.0%. In the following therapy, doxycycline, cefoperazone shubatan and amikacin have the certain effect on anti-infection therapy. Combination therapy combined with doxycycline was better treatment option for PDR infectious patients. Conclusion In a word, it appears to be effective for the successful therapy of PDR infections upon tetracyclines administration.

  13. The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers.

    PubMed

    Leng, Mengtian; Hu, Shaodong; Lu, Aijing; Cai, Mengtan; Luo, Xianglin

    2016-04-01

    Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL-PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4)∼10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs. PMID:26615398

  14. Bacteriocin from Bacillus subtilis as a novel drug against diabetic foot ulcer bacterial pathogens

    PubMed Central

    Joseph, Baby; Dhas, Berlina; Hena, Vimalin; Raj, Justin

    2013-01-01

    Objective To isolate and identify Bacillus subtilis (B. subtilis) from soil and to characterize and partially purify the bacteriocin. To evaluate the antimicrobial activity against four diabetic foot ulcer bacterial pathogens. Methods Genotypic identification was done based on Bergey's manual of systemic bacteriology. Antimicrobial susceptibility test was done by Kirby-Bauer disc diffusion method. Colonies were identified by colony morphology and biochemical characterization and also compared with MTCC 121 strain. Further identification was done by 16S rRNA sequencing. Inhibitory activities of partially purified bacteriocin on all the DFU isolates were done by agar well diffusion method. The strain was identified to produce bacteriocin by stab overlay assay. Bacteriocin was extracted by organic solvent extraction using chloroform, further purified by HPLC and physical, and chemical characterization was performed. Results The four isolates showed high level of resistance to amoxyclav and sensitivity to ciprofloxacin. HPLC purification revealed that the extracts are bacteriocin. The phylogenetic tree analysis results showed that the isolate was 99% related to B. subtilis BSF01. The results reveled activity to all the four isolates and high level of activity was seen in case of Klebsiella sp. Conclusions Partially purified bacteriocin was found to have antimicrobial activity against the four diabetic foot ulcer bacterial pathogens, which can thus be applied as a better drug molecule on further studies. The strain B. subtilis are found to be safe for use and these antimicrobial peptides can be used as an antimicrobial in humans to treat DFU bacterial pathogens. PMID:24093784

  15. Antimalarial drug resistance in Africa: key lessons for the future

    PubMed Central

    Takala-Harrison, Shannon; Laufer, Miriam K.

    2015-01-01

    Drug-resistant parasites repeatedly arise as a result of widespread use of antimalarial drugs and have contributed significantly to the failure to control and eradicate malaria throughout the world. In this review, we describe the spread of resistance to chloroquine and sulfadoxinepyrimethamine, two old drugs that are no longer used owing to high rates of resistance, and examine the effect of the removal of drug pressure on the survival of resistant parasites. Artemisinin-resistant malaria is now emerging in Southeast Asia in a unique and unexpected pattern. We will review the most recent genomic and clinical data to help predict the behavior of resistance to new antimalarial medications and inform strategies to prevent the spread of drug-resistant malaria in Africa in the future. PMID:25891142

  16. Structure and function of efflux pumps that confer resistance to drugs.

    PubMed Central

    Borges-Walmsley, M Ines; McKeegan, Kenneth S; Walmsley, Adrian R

    2003-01-01

    Resistance to therapeutic drugs encompasses a diverse range of biological systems, which all have a human impact. From the relative simplicity of bacterial cells, fungi and protozoa to the complexity of human cancer cells, resistance has become problematic. Stated in its simplest terms, drug resistance decreases the chance of providing successful treatment against a plethora of diseases. Worryingly, it is a problem that is increasing, and consequently there is a pressing need to develop new and effective classes of drugs. This has provided a powerful stimulus in promoting research on drug resistance and, ultimately, it is hoped that this research will provide novel approaches that will allow the deliberate circumvention of well understood resistance mechanisms. A major mechanism of resistance in both microbes and cancer cells is the membrane protein-catalysed extrusion of drugs from the cell. Resistant cells exploit proton-driven antiporters and/or ATP-driven ABC (ATP-binding cassette) transporters to extrude cytotoxic drugs that usually enter the cell by passive diffusion. Although some of these drug efflux pumps transport specific substrates, many are transporters of multiple substrates. These multidrug pumps can often transport a variety of structurally unrelated hydrophobic compounds, ranging from dyes to lipids. If we are to nullify the effects of efflux-mediated drug resistance, we must first of all understand how these efflux pumps can accommodate a diverse range of compounds and, secondly, how conformational changes in these proteins are coupled to substrate translocation. These are key questions that must be addressed. In this review we report on the advances that have been made in understanding the structure and function of drug efflux pumps. PMID:13678421

  17. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides.

    PubMed

    Almutairi, Mashal M; Park, Sung Ryeol; Rose, Simon; Hansen, Douglas A; Vázquez-Laslop, Nora; Douthwaite, Stephen; Sherman, David H; Mankin, Alexander S

    2015-10-20

    Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism. PMID:26438831

  18. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides

    PubMed Central

    Almutairi, Mashal M.; Park, Sung Ryeol; Rose, Simon; Hansen, Douglas A.; Vázquez-Laslop, Nora; Douthwaite, Stephen; Sherman, David H.; Mankin, Alexander S.

    2015-01-01

    Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism. PMID:26438831

  19. Advantage and limitations of nitrofurantoin in multi-drug resistant Indian scenario.

    PubMed

    Shakti, Laishram; Veeraraghavan, Balaji

    2015-01-01

    Infections caused by antibiotic resistant pathogens are of significant concern and are associated with higher mortality and morbidity. Nitrofurantoin is a broad-spectrum bactericidal antibiotic and is effectively used to treat urinary tract infections (UTIs) caused by E. coli, Klebsiella sp., Enterobacter sp., Enterococcus sp. and Staphylococcus aureus. It interfere with the synthesis of cell wall, bacterial proteins and DNA of both Gram positive and Gram negative pathogens. Nitrofurantoin has been used successfully for treatment and prophylaxis of acute lower urinary tract infections. With the emergence of antibiotic resistance, nitrofurantoin has become the choice of agent for treating UTIs caused by multi-drug resistant pathogens. PMID:26470951

  20. HIV-1 Protease: Structural Perspectives on Drug Resistance

    PubMed Central

    Weber, Irene T.; Agniswamy, Johnson

    2009-01-01

    Antiviral inhibitors of HIV-1 protease are a notable success of structure-based drug design and have dramatically improved AIDS therapy. Analysis of the structures and activities of drug resistant protease variants has revealed novel molecular mechanisms of drug resistance and guided the design of tight-binding inhibitors for resistant variants. The plethora of structures reveals distinct molecular mechanisms associated with resistance: mutations that alter the protease interactions with inhibitors or substrates; mutations that alter dimer stability; and distal mutations that transmit changes to the active site. These insights will inform the continuing design of novel antiviral inhibitors targeting resistant strains of HIV. PMID:21994585

  1. Mutational Pathway Determines Whether Drug Gradients Accelerate Evolution of Drug-Resistant Cells

    NASA Astrophysics Data System (ADS)

    Greulich, Philip; Waclaw, Bartłomiej; Allen, Rosalind J.

    2012-08-01

    Drug gradients are believed to play an important role in the evolution of bacteria resistant to antibiotics and tumors resistant to anticancer drugs. We use a statistical physics model to study the evolution of a population of malignant cells exposed to drug gradients, where drug resistance emerges via a mutational pathway involving multiple mutations. We show that a nonuniform drug distribution has the potential to accelerate the emergence of resistance when the mutational pathway involves a long sequence of mutants with increasing resistance, but if the pathway is short or crosses a fitness valley, the evolution of resistance may actually be slowed down by drug gradients. These predictions can be verified experimentally, and may help to improve strategies for combating the emergence of resistance.

  2. The non-medical use of antibiotics and the risk of causing microbial drug-resistance*

    PubMed Central

    Manten, A.

    1963-01-01

    One of the hazards involved in the use of antibiotics in animal feeds is that it may lead to the development of bacterial drug-resistance. An analysis of the phenomenon shows that this possibility largely depends on the size of the bacterial populations involved and on the possibility of selective multiplication of the resistant mutants that may be present. Additional factors involved in the development of resistance are the type of drug applied and the time during which the bacteria are in contact with it. Animal experiments and general practical experience show that resistance, especially in E. coli, Salm. typhimurium and Staph. aureus, may considerably increase as higher doses are added to the feed. Therefore, the lowest effective level for growth promotion (5-20 p.p.m. of penicillin or tetracycline) is to be preferred over higher levels. As to the practice of food preservation by means of antibiotics, a dangerous situation may arise if two factors combine: emergence of bacterial resistance in Salmonella and perhaps other pathogenic bacteria in the animal as a result of the addition of a certain antibiotic to feeds, and subsequent use of the same substance for preservation of the meat. PMID:14058230

  3. 78 FR 63220 - Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Acute Bacterial Skin and Skin... guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... drugs to treat acute bacterial skin and skin structure infections (ABSSSI). This guidance finalizes...

  4. Genetic analysis of drug resistance in Neisseria gonorrhoeae: identification and linkage relationships of loci controlling drug resistance.

    PubMed

    Maier, T W; Zubrzycki, L; Coyle, M B

    1975-05-01

    The genetic basis of multiple drug resistance of Neisseria gonorrhoeae was investigated by the technique of transformation. Six different genetic loci were characterized by the type and amount of antibiotic resistance they controlled, and also by the degree of linkage to other resistance markers. A streptomycin resistance locus is linked to separate loci determining resistance to tetracycline, chloramphenicol, and erythromycin. A multiple resistance locus was identified. This genetic locus determines resistance to a variety of antibacterial agents. Lastly, a locus determining resistance to the penicillins was found which is unlinked to any other resistance locus. PMID:807159

  5. Genetic Analysis of Drug Resistance in Neisseria gonorrhoeae: Identification and Linkage Relationships of Loci Controlling Drug Resistance

    PubMed Central

    Maier, Thomas W.; Zubrzycki, Leonard; Coyle, Marie B.

    1975-01-01

    The genetic basis of multiple drug resistance of Neisseria gonorrhoeae was investigated by the technique of transformation. Six different genetic loci were characterized by the type and amount of antibiotic resistance they controlled, and also by the degree of linkage to other resistance markers. A streptomycin resistance locus is linked to separate loci determining resistance to tetracycline, chloramphenicol, and erythromycin. A multiple resistance locus was identified. This genetic locus determines resistance to a variety of antibacterial agents. Lastly, a locus determining resistance to the penicillins was found which is unlinked to any other resistance locus. PMID:807159

  6. Acid-Responsive Therapeutic Polymer for Prolonging Nanoparticle Circulation Lifetime and Destroying Drug-Resistant Tumors.

    PubMed

    Piao, Ji-Gang; Gao, Feng; Yang, Lihua

    2016-01-13

    How to destroy drug-resistant tumor cells remains an ongoing challenge for cancer treatment. We herein report on a therapeutic nanoparticle, aHLP-PDA, which has an acid-activated hemolytic polymer (aHLP) grafted onto photothermal polydopamine (PDA) nanosphere via boronate ester bond, in efforts to ablate drug-resistant tumors. Upon exposure to oxidative stress and/or near-infrared laser irradiation, aHLP-PDA nanoparticle responsively releases aHLP, likely via responsive cleavage of boronate ester bond, and thus responsively exhibits acid-facilitated mammalian-membrane-disruptive activity. In vitro cell studies with drug-resistant and/or thermo-tolerant cancer cells show that the aHLP-PDA nanoparticle demonstrates preferential cytotoxicity at acidic pH over physiological pH. When administered intravenously, the aHLP-PDA nanoparticle exhibits significantly prolonged blood circulation lifetime and enhanced tumor uptake compared to bare PDA nanosphere, likely owing to aHLP's stealth effects conferred by its zwitterionic nature at blood pH. As a result, the aHLP-PDA nanoparticle effectively ablates drug-resistant tumors, leading to 100% mouse survival even on the 32nd day after suspension of photothermal treatment, as demonstrated with the mouse model. This work suggests that a combination of nanotechnology with lessons learned in bacterial antibiotic resistance may offer a feasible and effective strategy for treating drug-resistant cancers often found in relapsing patients. PMID:26654626

  7. GWAMAR: Genome-wide assessment of mutations associated with drug resistance in bacteria

    PubMed Central

    2014-01-01

    Background Development of drug resistance in bacteria causes antibiotic therapies to be less effective and more costly. Moreover, our understanding of the process remains incomplete. One promising approach to improve our understanding of how resistance is being acquired is to use whole-genome comparative approaches for detection of drug resistance-associated mutations. Results We present GWAMAR, a tool we have developed for detecting of drug resistance-associated mutations in bacteria through comparative analysis of whole-genome sequences. The pipeline of GWAMAR comprises several steps. First, for a set of closely related bacterial genomes, it employs eCAMBer to identify homologous gene families. Second, based on multiple alignments of the gene families, it identifies mutations among the strains of interest. Third, it calculates several statistics to identify which mutations are the most associated with drug resistance. Conclusions Based on our analysis of two large datasets retrieved from publicly available data for M. tuberculosis, we identified a set of novel putative drug resistance-associated mutations. As a part of this work, we present also an application of our tool to detect putative compensatory mutations. PMID:25559874

  8. Novel antimicrobial agents against multi-drug-resistant gram-positive bacteria: an overview.

    PubMed

    Giannakaki, Venetia; Miyakis, Spiros

    2012-12-01

    Antimicrobial resistance threatens to compromise the treatment of bacterial infectious diseases. Strains resistant to most (if not all) antibiotics available have emerged. Gram-positive such representatives include strains of Methicillinresistant Staphylococcus aureus (MRSA), Vancomycin-resistant Enterococci (VRE) and highly-resistant to penicillin Streptococcus pneumoniae. Although the phenomenon of antimicrobial drug resistance is expanding, limited number of new antibiotics has been successfully developed in the last few decades. Several novel antimicrobial agents, however, are currently in diverse phases of development and undergoing clinical trials. This review will summarize the main candidates for novel antibacterial agents active against Gram-positive multi-resistant pathogens along with the discussion of some patents relevant to the topic. PMID:23016758

  9. Investigating specific bacterial resistance to AMPs by using a magainin I-resistant Escherichia coli model.

    PubMed

    de Almeida, Keyla C; Lima, Thais B; Motta, Dielle O; Silva, Osmar N; Magalhães, Beatriz S; Dias, Simoni C; Franco, Octávio L

    2014-10-01

    Antimicrobial peptides (AMPs) are multifunctional compounds that may show antimicrobial and immunomodulatory activities. With the rapid increase in the incidence of multidrug-resistant bacteria, there is an enormous interest in AMPs as templates for the production of new antibiotics. However, there are concerns that the therapeutic administration of AMPs can select resistant strains. In order to distinguish between resistant and non-resistant strains and verify resistance specificity to AMPs, in this study a magainin I-resistant Escherichia coli model was used. First, the identity of all strains was confirmed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF)-MS, VITEK 2 and MicroScan, and the susceptible and magainin-resistant strains were successfully differentiated by MALDI-TOF-MS analysis. Furthermore, cross-resistances to a broad spectrum of antibiotics were evaluated, showing that all E. coli strains are susceptible to the drugs tested, suggesting that the resistance seems to be specific to AMPs. Finally, the specific resistance to magainin I compared with other AMPs was checked by microdilution. This experiment showed that the magainin MICs were 62 and 104 μM for susceptible and resistant strains, respectively. The other AMPs MICs were 3.4 μM to proline-arginine-rich 39-amino-acid peptide, 43 μM to porcine myeloid antimicrobial 23-amino-acid peptide-23 and 1.2 μM to cecropin P1 for all strains, demonstrating any additional resistance to peptides here evaluated, confirming that the resistance seems to be essentially specific to magainin I. In summary, the data reported here reinforce the proposal that magainin I seems not to be merely a membrane disruptor, probably showing additional molecular targets in pathogenic bacteria. PMID:24802209

  10. Rainbow Trout (Oncorhynchus mykiss) resistance to columnaris disease is heritable and favorably correlated with bacterial cold water disease resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Columnaris disease (CD) is an emerging disease affecting rainbow trout aquaculture. Objectives were to estimate heritability of CD resistance in a line (ARS-Fp-R) selected 4 generations for improved bacterial cold water disease (BCWD) resistance; estimate genetic correlations among CD resistance, BC...

  11. Molecular structure and dynamics in bacterial mercury resistance

    SciTech Connect

    Johs, Alexander; Shi, Liang; Miller, Susan M; Summers, Anne O; Liang, Liyuan

    2008-01-01

    Bacteria participate significantly in mercury transformation in natural and industrial environments. Previous studies have shown that bacterial mercury resistance is mediated by the mer operon, typically located on transposons or plasmids. It encodes specific genes that facilitate uptake of mercury species, cleavage of organomercurials, and reduction of Hg(II) to Hg(0). Expression of mer operon genes is regulated by MerR, a metal-responsive regulator protein on the level of transcription. In vitro studies have shown that MerR forms a non-transcribing pre-initiation complex with RNA polymerase and the promoter DNA. Binding of Hg(II) induces conformational changes in MerR and other components of the complex resulting in the transcription of mer operon genes. As part of ongoing investigations on allosteric conformational changes induced by Hg(II) in dimeric MerR, and the implications on the binding of RNA polymerase to the promoter of the mer operon, we applied small angle scattering to study the regulatory mechanism of MerR in the presence and absence of Hg(II). Our results show that in the presence of Hg(II) the MerR dimer undergoes a significant reorientation from a compact state to a conformation revealing two distinct domains. Bacterial reduction of Hg(II) can also occur at concentrations too low to induce mer operon functions. Dissimilatory metal reducing bacteria, such as Shewanella and Geobacter are able to reduce Hg(II) in the presence of mineral oxides. This process has been linked to the activity of outer membrane multiheme cytochromes. We isolated and purified a decaheme outer membrane cytochrome OmcA from Shewanella oneidensis MR-1 and characterized its envelope shape in solution by small angle x-ray scattering. Structural features were identified and compared to homology models. These results show that OmcA is an elongated macromolecule consisting of separate modules, which may be connected by flexible linkers.

  12. In Search of Alternative Antibiotic Drugs: Quorum-Quenching Activity in Sponges and their Bacterial Isolates

    PubMed Central

    Saurav, Kumar; Bar-Shalom, Rinat; Haber, Markus; Burgsdorf, Ilia; Oliviero, Giorgia; Costantino, Valeria; Morgenstern, David; Steindler, Laura

    2016-01-01

    Owing to the extensive development of drug resistance in pathogens against the available antibiotic arsenal, antimicrobial resistance is now an emerging major threat to public healthcare. Anti-virulence drugs are a new type of therapeutic agent aiming at virulence factors rather than killing the pathogen, thus providing less selective pressure for evolution of resistance. One promising example of this therapeutic concept targets bacterial quorum sensing (QS), because QS controls many virulence factors responsible for bacterial infections. Marine sponges and their associated bacteria are considered a still untapped source for unique chemical leads with a wide range of biological activities. In the present study, we screened extracts of 14 sponge species collected from the Red and Mediterranean Sea for their quorum-quenching (QQ) potential. Half of the species showed QQ activity in at least 2 out of 3 replicates. Six out of the 14 species were selected for bacteria isolation, to test for QQ activity also in isolates, which, once cultured, represent an unlimited source of compounds. We show that ≈20% of the isolates showed QQ activity based on a Chromobacterium violaceum CV026 screen, and that the presence or absence of QQ activity in a sponge extract did not correlate with the abundance of isolates with the same activity from the same sponge species. This can be explained by the unknown source of QQ compounds in sponge-holobionts (host or symbionts), and further by the possible non-symbiotic nature of bacteria isolated from sponges. The potential symbiotic nature of the isolates showing QQ activity was tested according to the distribution and abundance of taxonomically close bacterial Operational Taxonomic Units (OTUs) in a dataset including 97 sponge species and 178 environmental samples (i.e., seawater, freshwater, and marine sediments). Most isolates were found not to be enriched in sponges and may simply have been trapped in the filtration channels of the sponge at the time of collection. Our results highlight potential for QQ-bioactive lead molecules for anti-virulence therapy both from sponges and the bacteria isolated thereof, independently on the symbiotic nature of the latter. PMID:27092109

  13. In Search of Alternative Antibiotic Drugs: Quorum-Quenching Activity in Sponges and their Bacterial Isolates.

    PubMed

    Saurav, Kumar; Bar-Shalom, Rinat; Haber, Markus; Burgsdorf, Ilia; Oliviero, Giorgia; Costantino, Valeria; Morgenstern, David; Steindler, Laura

    2016-01-01

    Owing to the extensive development of drug resistance in pathogens against the available antibiotic arsenal, antimicrobial resistance is now an emerging major threat to public healthcare. Anti-virulence drugs are a new type of therapeutic agent aiming at virulence factors rather than killing the pathogen, thus providing less selective pressure for evolution of resistance. One promising example of this therapeutic concept targets bacterial quorum sensing (QS), because QS controls many virulence factors responsible for bacterial infections. Marine sponges and their associated bacteria are considered a still untapped source for unique chemical leads with a wide range of biological activities. In the present study, we screened extracts of 14 sponge species collected from the Red and Mediterranean Sea for their quorum-quenching (QQ) potential. Half of the species showed QQ activity in at least 2 out of 3 replicates. Six out of the 14 species were selected for bacteria isolation, to test for QQ activity also in isolates, which, once cultured, represent an unlimited source of compounds. We show that ≈20% of the isolates showed QQ activity based on a Chromobacterium violaceum CV026 screen, and that the presence or absence of QQ activity in a sponge extract did not correlate with the abundance of isolates with the same activity from the same sponge species. This can be explained by the unknown source of QQ compounds in sponge-holobionts (host or symbionts), and further by the possible non-symbiotic nature of bacteria isolated from sponges. The potential symbiotic nature of the isolates showing QQ activity was tested according to the distribution and abundance of taxonomically close bacterial Operational Taxonomic Units (OTUs) in a dataset including 97 sponge species and 178 environmental samples (i.e., seawater, freshwater, and marine sediments). Most isolates were found not to be enriched in sponges and may simply have been trapped in the filtration channels of the sponge at the time of collection. Our results highlight potential for QQ-bioactive lead molecules for anti-virulence therapy both from sponges and the bacteria isolated thereof, independently on the symbiotic nature of the latter. PMID:27092109

  14. Drug Resistance Mechanisms in Bacteria Causing Sexually Transmitted Diseases and Associated with Vaginosis

    PubMed Central

    Shaskolskiy, Boris; Dementieva, Ekaterina; Leinsoo, Arvo; Runina, Anastassia; Vorobyev, Denis; Plakhova, Xenia; Kubanov, Alexey; Deryabin, Dmitrii; Gryadunov, Dmitry

    2016-01-01

    Here, we review sexually transmitted diseases (STDs) caused by pathogenic bacteria and vaginal infections which result from an overgrowth of opportunistic bacterial microflora. First, we describe the STDs, the corresponding pathogens and the antimicrobials used for their treatment. In addition to the well-known diseases caused by single pathogens (i.e., syphilis, gonococcal infections, and chlamydiosis), we consider polymicrobial reproductive tract infections (especially those that are difficult to effectively clinically manage). Then, we summarize the biochemical mechanisms that lead to antimicrobial resistance and the most recent data on the emergence of drug resistance in STD pathogens and bacteria associated with vaginosis. A large amount of research performed in the last 10–15 years has shed light on the enormous diversity of mechanisms of resistance developed by bacteria. A detailed understanding of the mechanisms of antimicrobials action and the emergence of resistance is necessary to modify existing drugs and to develop new ones directed against new targets.

  15. The Drug Resistance Strategies Project as Translational Research

    ERIC Educational Resources Information Center

    Hecht, Michael L.; Miller-Day, Michelle

    2007-01-01

    This paper tells the story of the multi-layered translational process of the Drug Resistance Strategies Project. The Drug Resistance Strategies Project provides an exemplar of translational scholarship, translating adolescent narratives about their substance use experiences into an efficacious, substance abuse prevention middle school curriculum.

  16. Prediction of resistance development against drug combinations by collateral responses to component drugs.

    PubMed

    Munck, Christian; Gumpert, Heidi K; Wallin, Annika I Nilsson; Wang, Harris H; Sommer, Morten O A

    2014-11-12

    Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution. PMID:25391482

  17. Prediction of resistance development against drug combinations by collateral responses to component drugs

    PubMed Central

    Munck, Christian; Gumpert, Heidi K.; Nilsson Wallin, Annika I.; Wang, Harris H.; Sommer, Morten O. A.

    2015-01-01

    Resistance arises quickly during chemotherapeutic selection and is particularly problematic during long-term treatment regimens such as those for tuberculosis, HIV infections, or cancer. Although drug combination therapy reduces the evolution of drug resistance, drug pairs vary in their ability to do so. Thus, predictive models are needed to rationally design resistance-limiting therapeutic regimens. Using adaptive evolution, we studied the resistance response of the common pathogen Escherichia coli to 5 different single antibiotics and all 10 different antibiotic drug pairs. By analyzing the genomes of all evolved E. coli lineages, we identified the mutational events that drive the differences in drug resistance levels and found that the degree of resistance development against drug combinations can be understood in terms of collateral sensitivity and resistance that occurred during adaptation to the component drugs. Then, using engineered E. coli strains, we confirmed that drug resistance mutations that imposed collateral sensitivity were suppressed in a drug pair growth environment. These results provide a framework for rationally selecting drug combinations that limit resistance evolution. PMID:25391482

  18. Understanding bacterial resistance to antimicrobial peptides: From the surface to deep inside.

    PubMed

    Maria-Neto, Simone; de Almeida, Keyla Caroline; Macedo, Maria Ligia Rodrigues; Franco, Octávio Luiz

    2015-11-01

    Resistant bacterial infections are a major health problem in many parts of the world. The major commercial antibiotic classes often fail to combat common bacteria. Although antimicrobial peptides are able to control bacterial infections by interfering with microbial metabolism and physiological processes in several ways, a large number of cases of resistance to antibiotic peptide classes have also been reported. To gain a better understanding of the resistance process various technologies have been applied. Here we discuss multiple strategies by which bacteria could develop enhanced antimicrobial peptide resistance, focusing on sub-cellular regions from the surface to deep inside, evaluating bacterial membranes, cell walls and cytoplasmic metabolism. Moreover, some high-throughput methods for antimicrobial resistance detection and discrimination are also examined. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID:25724815

  19. [Combination therapy as a strategy to prevent antimalarial drug resistance].

    PubMed

    Orjuela, Pamela; González, Iveth; Osorio, Lyda

    2004-12-01

    Resistance of Plasmodium falciparum to antimalarials is considered one of the factors responsible for the impairment of the malaria treatment and control worldwide. Resistance emerges as a result of selection and then disemination of spontaneous mutant parasites with reduced drug susceptibility. Combination therapy is considered as the main strategy to control antimalarial drug resistance. Currently, combination therapies that include artemisinin derivatives are highly recommended. Combination therapy has been used in Colombia for more than 20 years; however, its impact on preventing the dissemination of drug resistance is unknown. This paper reviews the theoretical bases and clinical studies that support the use of combination therapy. PMID:15678806

  20. Managing Drug Resistance in Cancer: Role of Cancer Informatics.

    PubMed

    Gautam, Ankur; Chaudhary, Kumardeep; Kumar, Rahul; Gupta, Sudheer; Singh, Harinder; Raghava, Gajendra P S

    2016-01-01

    Understanding and managing cancer drug resistance is the main goal of the modern oncology programs worldwide. One of the major factors contributing to drug resistance in cancer cells is the acquired mutations in drug targets. Advances in sequencing technologies and high-throughput screening assays have generated huge information related to pharmaco-profiling of anticancer drugs and revealed the mutational spectrum of different cancers. Systematic meta-analysis of this complex data is very essential to make useful conclusions in order to manage cancer drug resistance. Bioinformatics can play a significant role to interpret this complex data into useful conclusions. In this chapter, the use of bioinformatics platforms, particularly CancerDR, in understanding the cancer drug resistance is described. PMID:26910081

  1. Dominant drug targets suppress the emergence of antiviral resistance.

    PubMed

    Tanner, Elizabeth J; Liu, Hong-mei; Oberste, M Steven; Pallansch, Mark; Collett, Marc S; Kirkegaard, Karla

    2014-01-01

    The emergence of drug resistance can defeat the successful treatment of pathogens that display high mutation rates, as exemplified by RNA viruses. Here we detail a new paradigm in which a single compound directed against a 'dominant drug target' suppresses the emergence of naturally occurring drug-resistant variants in mice and cultured cells. All new drug-resistant viruses arise during intracellular replication and initially express their phenotypes in the presence of drug-susceptible genomes. For the targets of most anti-viral compounds, the presence of these drug-susceptible viral genomes does not prevent the selection of drug resistance. Here we show that, for an inhibitor of the function of oligomeric capsid proteins of poliovirus, the expression of drug-susceptible genomes causes chimeric oligomers to form, thus rendering the drug-susceptible genomes dominant. The use of dominant drug targets should suppress drug resistance whenever multiple genomes arise in the same cell and express products in a common milieu. PMID:25365453

  2. Mechanisms and insights into drug resistance in cancer.

    PubMed

    Zahreddine, Hiba; Borden, Katherine L B

    2013-01-01

    Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies. PMID:23504227

  3. 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

  4. 2015 Update of the Drug Resistance Mutations in HIV-1.

    PubMed

    Wensing, Annemarie M; Calvez, Vincent; Günthard, Huldrych F; Johnson, Victoria A; Paredes, Roger; Pillay, Deenan; Shafer, Robert W; Richman, Douglas D

    2015-01-01

    The 2015 edition of the IAS-USA drug resistance mutations list updates the figures last published in July 2014. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The figures are designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs and, therefore, in making clinical decisions regarding antiretroviral therapy. PMID:26713503

  5. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance.

    PubMed

    Chevereau, Guillaume; Dravecká, Marta; Batur, Tugce; Guvenek, Aysegul; Ayhan, Dilay Hazal; Toprak, Erdal; Bollenbach, Tobias

    2015-11-01

    The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the "morbidostat", a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations-an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. PMID:26581035

  6. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance

    PubMed Central

    Chevereau, Guillaume; Dravecká, Marta; Batur, Tugce; Guvenek, Aysegul; Ayhan, Dilay Hazal; Toprak, Erdal; Bollenbach, Tobias

    2015-01-01

    The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall, we identified novel quantitative characteristics of the evolutionary landscape that provide the conceptual foundation for predicting the dynamics of drug resistance evolution. PMID:26581035

  7. Molecular mechanisms of drug resistance and its reversal in cancer.

    PubMed

    Kartal-Yandim, Melis; Adan-Gokbulut, Aysun; Baran, Yusuf

    2016-08-01

    Chemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance. PMID:25757878

  8. Cancer stem cells and drug resistance: the potential of nanomedicine

    PubMed Central

    Vinogradov, Serguei; Wei, Xin

    2012-01-01

    Properties of the small group of cancer cells called tumor-initiating or cancer stem cells (CSCs) involved in drug resistance, metastasis and relapse of cancers can significantly affect tumor therapy. Importantly, tumor drug resistance seems to be closely related to many intrinsic or acquired properties of CSCs, such as quiescence, specific morphology, DNA repair ability and overexpression of antiapoptotic proteins, drug efflux transporters and detoxifying enzymes. The specific microenvironment (niche) and hypoxic stability provide additional protection against anticancer therapy for CSCs. Thus, CSC-focused therapy is destined to form the core of any effective anticancer strategy. Nanomedicine has great potential in the development of CSC-targeting drugs, controlled drug delivery and release, and the design of novel gene-specific drugs and diagnostic modalities. This review is focused on tumor drug resistance-related properties of CSCs and describes current nanomedicine approaches, which could form the basis of novel combination therapies for eliminating metastatic and CSCs. PMID:22471722

  9. Efflux-Mediated Drug Resistance in Bacteria: an Update

    PubMed Central

    Li, Xian-Zhi; Nikaido, Hiroshi

    2010-01-01

    Drug efflux pumps play a key role in drug resistance and also serve other functions in bacteria. There has been a growing list of multidrug and drug-specific efflux pumps characterized from bacteria of human, animal, plant and environmental origins. These pumps are mostly encoded on the chromosome although they can also be plasmid-encoded. A previous article (Li X-Z and Nikaido H, Drugs, 2004; 64[2]: 159–204) had provided a comprehensive review regarding efflux-mediated drug resistance in bacteria. In the past five years, significant progress has been achieved in further understanding of drug resistance-related efflux transporters and this review focuses on the latest studies in this field since 2003. This has been demonstrated in multiple aspects that include but are not limited to: further molecular and biochemical characterization of the known drug efflux pumps and identification of novel drug efflux pumps; structural elucidation of the transport mechanisms of drug transporters; regulatory mechanisms of drug efflux pumps; determining the role of the drug efflux pumps in other functions such as stress responses, virulence and cell communication; and development of efflux pump inhibitors. Overall, the multifaceted implications of drug efflux transporters warrant novel strategies to combat multidrug resistance in bacteria. PMID:19678712

  10. Primary drug resistance to anti-tuberculosis drugs in major towns of Amhara region, Ethiopia.

    PubMed

    Yimer, Solomon Abebe; Agonafir, Mulualem; Derese, Yohannes; Sani, Yusuf; Bjune, Gunnar A; Holm-Hansen, Carol

    2012-06-01

    Drug resistance is a major obstacle to effective TB control program performance. In this study, we assessed the prevalence of primary drug resistance in Mycobacterium tuberculosis (Mtb) isolates in Amhara Region, Ethiopia. A total of 112 Mtb isolates from cases with newly diagnosed pulmonary TB were subjected to drug susceptibility testing (DST) in a cross-sectional study. Isolates were tested for sensitivity to isoniazid, rifampicin, ethambutol, and streptomycin using the MGIT 960 protocol. A total of 93 Mtb isolates yielded valid DST results and 28 (30.1%) were resistant to one or more of first line anti-TB drugs. One isolate (1.0%) was multi-drug resistant (MDR), five (5.4%) were classified as poly-resistant and 22 showed single drug resistance to either streptomycin (n = 19) or isoniazid (n = 3). Isolates from HIV-positive patients were more likely to be resistant to at least one of the four anti-TB drugs compared with HIV-negative individuals (odds ratio 2.76, 95% confidence interval 1.06-7.22; p = 0.03). The study showed a high prevalence of primary drug resistance. Even though the prevalence of MDR was low, conditions that can contribute to the development of MDR are increasing. Therefore, regular monitoring of drug resistance and enhanced implementation of TB/HIV collaborative activities in the study region are imperative. PMID:22583363

  11. Overcome Cancer Cell Drug Resistance Using Natural Products

    PubMed Central

    Wang, Pu; Yang, Hua Li; Yang, Ying Juan; Wang, Lan; Lee, Shao Chin

    2015-01-01

    Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1) in vitro studies using cell line models; (2) serum pharmacology; (3) in vivo studies using animal models; and (4) clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance. PMID:26421052

  12. On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy

    PubMed Central

    Mattila, Sari; Ruotsalainen, Pilvi; Jalasvuori, Matti

    2015-01-01

    Bacteriophages are bacterial viruses, capable of killing even multi-drug resistant bacterial cells. For this reason, therapeutic use of phages is considered as a possible alternative to conventional antibiotics. However, phages are very host specific in comparison to wide-spectrum antibiotics and thus preparation of phage-cocktails beforehand against pathogens can be difficult. In this study, we evaluate whether it may be possible to isolate phages on-demand from environmental reservoir. We attempted to enrich infectious bacteriophages from sewage against nosocomial drug-resistant bacterial strains of different medically important species in order to evaluate the probability of discovering novel therapeutic phages. Stability and host-range were determined for the acquired phages. Our results suggest that on-demand isolation of phages is possible against Pseudomonas aeruginosa, Salmonella and extended spectrum beta-lactamase Escherichia coli and Klebsiella pneumoniae. The probability of finding suitable phages was less than 40% against vancomycin resistant Enterococcus and Acinetobacter baumannii strains. Furthermore, isolation of new phages against methicillin resistant Staphylococcus aureus strains was found to be very difficult. PMID:26617601

  13. On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy.

    PubMed

    Mattila, Sari; Ruotsalainen, Pilvi; Jalasvuori, Matti

    2015-01-01

    Bacteriophages are bacterial viruses, capable of killing even multi-drug resistant bacterial cells. For this reason, therapeutic use of phages is considered as a possible alternative to conventional antibiotics. However, phages are very host specific in comparison to wide-spectrum antibiotics and thus preparation of phage-cocktails beforehand against pathogens can be difficult. In this study, we evaluate whether it may be possible to isolate phages on-demand from environmental reservoir. We attempted to enrich infectious bacteriophages from sewage against nosocomial drug-resistant bacterial strains of different medically important species in order to evaluate the probability of discovering novel therapeutic phages. Stability and host-range were determined for the acquired phages. Our results suggest that on-demand isolation of phages is possible against Pseudomonas aeruginosa, Salmonella and extended spectrum beta-lactamase Escherichia coli and Klebsiella pneumoniae. The probability of finding suitable phages was less than 40% against vancomycin resistant Enterococcus and Acinetobacter baumannii strains. Furthermore, isolation of new phages against methicillin resistant Staphylococcus aureus strains was found to be very difficult. PMID:26617601

  14. Shigella Antimicrobial Drug Resistance Mechanisms, 2004–2014

    PubMed Central

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert

    2016-01-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004–2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis. PMID:27191035

  15. Shigella Antimicrobial Drug Resistance Mechanisms, 2004-2014.

    PubMed

    Nüesch-Inderbinen, Magdalena; Heini, Nicole; Zurfluh, Katrin; Althaus, Denise; Hächler, Herbert; Stephan, Roger

    2016-06-01

    To determine antimicrobial drug resistance mechanisms of Shigella spp., we analyzed 344 isolates collected in Switzerland during 2004-2014. Overall, 78.5% of isolates were multidrug resistant; 10.5% were ciprofloxacin resistant; and 2% harbored mph(A), a plasmid-mediated gene that confers reduced susceptibility to azithromycin, a last-resort antimicrobial agent for shigellosis. PMID:27191035

  16. Mycobacterium tuberculosis resistance to antituberculosis drugs in Mozambique*, **

    PubMed Central

    Pires, Germano Manuel; Folgosa, Elena; Nquobile, Ndlovu; Gitta, Sheba; Cadir, Nureisha

    2014-01-01

    OBJECTIVE: To determine the drug resistance profile of Mycobacterium tuberculosis in Mozambique. METHODS: We analyzed secondary data from the National Tuberculosis Referral Laboratory, in the city of Maputo, Mozambique, and from the Beira Regional Tuberculosis Referral Laboratory, in the city of Beira, Mozambique. The data were based on culture-positive samples submitted to first-line drug susceptibility testing (DST) between January and December of 2011. We attempted to determine whether the frequency of DST positivity was associated with patient type or provenance. RESULTS: During the study period, 641 strains were isolated in culture and submitted to DST. We found that 374 (58.3%) were resistant to at least one antituberculosis drug and 280 (43.7%) were resistant to multiple antituberculosis drugs. Of the 280 multidrug-resistant tuberculosis cases, 184 (65.7%) were in previously treated patients, most of whom were from southern Mozambique. Two (0.71%) of the cases of multidrug-resistant tuberculosis were confirmed to be cases of extensively drug-resistant tuberculosis. Multidrug-resistant tuberculosis was most common in males, particularly those in the 21-40 year age bracket. CONCLUSIONS: M. tuberculosis resistance to antituberculosis drugs is high in Mozambique, especially in previously treated patients. The frequency of M. tuberculosis strains that were resistant to isoniazid, rifampin, and streptomycin in combination was found to be high, particularly in samples from previously treated patients. PMID:24831398

  17. Clinical profile of drug resistant tuberculosis in children.

    PubMed

    Shah, Ira; Chilkar, Sujeet

    2012-09-01

    This Cross-sectional observational study was conducted to determine the clinical profile of drug-resistant tuberculosis in children. Patients were classified as monoresistant TB, polyresistant TB, multidrug resistant (MDR)-TB and extensively drug resistant (XDR - TB). We coined a term called as Partial XDR-TB when isolates of Mycobacterium tuberculosis were confirmed to be resistant in vitro to be MDR along with either a fluoroquinolone or an aminoglycoside resistance (apart from streptomycin). Of 500 children analysed, 34 (6.8%) had drug resistant TB. Mean age of presentation was 6.8 ± 3.2 years (Male: Female ratio 13:21). 18 (52.9%) children had been treated for tuberculosis in the past (1 defaulted), 7 patients had been in contact with an adult suffering from drug resistant TB and 3 patients (10.3%) were HIV co-infected. Fourteen children (41.2%) had MDR TB, 11 (32.4%) had Partial XDR, 1 each (2.9%) had polyresistant TB and XDR TB. Clinical features of DR-TB are similar in all age groups. Past history of TB with treatment with antitubercular agents, and contact with adults suffering with drug-resistant TB are important risk factors in development of drug-resistant -TB in children. PMID:22728624

  18. Update of the Drug Resistance Mutations in HIV-1.

    PubMed

    Johnson, Victoria A; Brun-Vezinet, Francoise; Clotet, Bonaventura; Gunthard, Huldrych F; Kuritzkes, Daniel R; Pillay, Deenan; Schapiro, Jonathan M; Richman, Douglas D

    2008-12-01

    The International AIDS Society-USA (IAS-USA) Drug Resistance Mutations Group reviews new data on HIV-1 drug resistance that have been published or presented at recent scientific meetings to maintain a current list of mutations associated with antiretroviral drug resistance.This December 2008 version of the IAS-USA drug resistance mutations figures updates those published in this journal in March/April 2008 (Johnson VA, Brun-Vezinet F, Clotet B, et al, Top HIV Med, 2008;16:62-68). The compilation includes mutations that may contribute to a reduced virologic response to HIV-1 drugs. It should not be assumed that the list presented here is exhaustive. Drugs that have been approved by the US Food and Drug Administration (US FDA) as well as any drugs available in expanded access programs are included and listed in alphabetical order by drug class. The figures are designed for practitioners to use in identifying key mutations associated with viral resistance to antiretroviral drugs and in making therapeutic decisions. PMID:19106428

  19. Totally drug-resistant tuberculosis and adjunct therapies.

    PubMed

    Parida, S K; Axelsson-Robertson, R; Rao, M V; Singh, N; Master, I; Lutckii, A; Keshavjee, S; Andersson, J; Zumla, A; Maeurer, M

    2015-04-01

    The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options. PMID:24809736

  20. Rapid evolution of drug resistance of multiple myeloma in the microenvironment with drug gradients

    NASA Astrophysics Data System (ADS)

    Wu, Amy; Zhang, Qiucen; Lambert, Guillaume; Khin, Zayar; Silva, Ariosto; Gatenby, Robert; Kim, John; Pourmand, Nader; Austin, Robert; Sturm, James

    2013-03-01

    Drug resistance in cancer is usually caused by the spatial drug gradients in tumor environment. Here, we culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region for 12 days. The myeloma cells grew rapidly and formed 3D colonies in the regions with less drug concentration. However, we have seen emergent colonies forming in regions with drug concentration above the minimal inhibitory concentration in less than one week. Once the cells have occupied the regions with less drug concentration, they tend to migrate toward the regions with higher drug concentration in a collective behavior. To characterize their resistance, we collect them from this microfluidic system, for further analysis of the dose response. We find that the IC50 (drug concentration that inhibits 50% of controlled population) of the cells, undergone a drug gradient, increase 16-fold of the wildtype cells. We further discover that these resistant cells express more Multidrug Resistance (mdr) protein, which pumps out the drugs and causes drug resistance, than the wildtype. Our current works on RNA-sequencing analysis may discover other biomolecular mechanisms that may confer the drug resistance.

  1. Understanding Drug Resistance in Breast Cancer with Mathematical Oncology

    PubMed Central

    Brocato, Terisse; Dogra, Prashant; Koay, Eugene J.; Day, Armin; Chuang, Yao-Li; Wang, Zhihui; Cristini, Vittorio

    2014-01-01

    Chemotherapy is mainstay of treatment for the majority of patients with breast cancer, but results in only 26% of patients with distant metastasis living 5 years past treatment in the United States, largely due to drug resistance. The complexity of drug resistance calls for an integrated approach of mathematical modeling and experimental investigation to develop quantitative tools that reveal insights into drug resistance mechanisms, predict chemotherapy efficacy, and identify novel treatment approaches. This paper reviews recent modeling work for understanding cancer drug resistance through the use of computer simulations of molecular signaling networks and cancerous tissues, with a particular focus on breast cancer. These mathematical models are developed by drawing on current advances in molecular biology, physical characterization of tumors, and emerging drug delivery methods (e.g., nanotherapeutics). We focus our discussion on representative modeling works that have provided quantitative insight into chemotherapy resistance in breast cancer and how drug resistance can be overcome or minimized to optimize chemotherapy treatment. We also discuss future directions of mathematical modeling in understanding drug resistance. PMID:24891927

  2. Antimicrobial (Drug) Resistance: Methicillin-Resistant Staphylococcus aureus (MRSA)

    MedlinePlus

    ... Share this: Main Content Area Methicillin-Resistant Staphylococcus aureus (MRSA) During the past four decades, methicillin-resistant Staphylococcus aureus , or MRSA, has evolved from a controllable nuisance ...

  3. A rapid screening method for detecting active compounds against erythromycin-resistant bacterial strains of Finnish origin.

    PubMed

    Kreander, K; Vuorela, P; Tammela, P

    2005-01-01

    A rapid and simple microdilution technique on 96-well microplate based on turbidimetry was optimized and validated for screening of antimicrobial activity against erythromycin-resistant bacterial strains of Streptococcus pyogenes and Staphylococcus simulans isolated from Finnish patients. Using S. pyogenes ATCC 12351 as reference strain the developed method was evaluated by reproducibility measurements and using parameters typically employed for screening methods, i.e. signal-to-background, signal-to-noise and a screening-window coefficient, the Z' factor. The method was further used for screening a group of natural compounds and their synthetic derivatives against resistant bacterial strains. Of these, octyl and dodecyl gallates, and usnic and ursolic acids were the most active. The described method is a rapid, homogeneous, cost-effective and easy-to-perform system for screening of new potential antimicrobial agents in drug discovery. PMID:16681145

  4. Exposing Plasmids as the Achilles’ Heel of Drug-Resistant Bacteria

    PubMed Central

    Williams, Julia J.; Hergenrother, Paul J.

    2008-01-01

    Many multi-drug resistant bacterial pathogens harbor large plasmids that encode proteins conferring resistance to antibiotics. While the acquisition of these plasmids often enables bacteria to survive in the presence of antibiotics, it is possible that plasmids also represent a vulnerability that can be exploited in tailored antibacterial therapy. This review highlights three recently described strategies designed to specifically combat bacteria harboring such plasmids: Inhibition of plasmid conjugation, inhibition of plasmid replication, and exploitation of plasmid-encoded toxin-antitoxin systems. PMID:18625335

  5. Fitness of Leishmania donovani parasites resistant to drug combinations.

    PubMed

    García-Hernández, Raquel; Gómez-Pérez, Verónica; Castanys, Santiago; Gamarro, Francisco

    2015-04-01

    Drug resistance represents one of the main problems for the use of chemotherapy to treat leishmaniasis. Additionally, it could provide some advantages to Leishmania parasites, such as a higher capacity to survive in stress conditions. In this work, in mixed populations of Leishmania donovani parasites, we have analyzed whether experimentally resistant lines to one or two combined anti-leishmanial drugs better support the stress conditions than a susceptible line expressing luciferase (Luc line). In the absence of stress, none of the Leishmania lines showed growth advantage relative to the other when mixed at a 1:1 parasite ratio. However, when promastigotes from resistant lines and the Luc line were mixed and exposed to different stresses, we observed that the resistant lines are more tolerant of different stress conditions: nutrient starvation and heat shock-pH stress. Further to this, we observed that intracellular amastigotes from resistant lines present a higher capacity to survive inside the macrophages than those of the control line. These results suggest that resistant parasites acquire an overall fitness increase and that resistance to drug combinations presents significant differences in their fitness capacity versus single-drug resistant parasites, particularly in intracellular amastigotes. These results contribute to the assessment of the possible impact of drug resistance on leishmaniasis control programs. PMID:25849149

  6. PfCRT and its role in antimalarial drug resistance

    PubMed Central

    Ecker, Andrea; Lehane, Adele M.; Clain, Jrme; Fidock, David A.

    2012-01-01

    Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the Chloroquine Resistance Transporter (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes. PMID:23020971

  7. Developing new drugs for the treatment of drug-resistant tuberculosis: a regulatory perspective.

    PubMed

    Sacks, Leonard V; Behrman, Rachel E

    2008-08-01

    Simplifying and shortening treatment for drug-sensitive tuberculosis and providing new treatment options for drug-resistant tuberculosis constitute two principal goals in the development of novel drugs for tuberculosis. Demonstration of clinical efficacy in drug-sensitive tuberculosis is challenging, given high success rates for existing regimens, concerns about substituting an investigational agent for the most effective agents in a regimen and difficulties in determining the effect size of the components of a combination regimen. Large and prolonged studies would be needed either to show superiority over existing regimens or statistically defensible non-inferiority compared to existing regimens. In contrast, exploring efficacy of novel treatments in the setting of drug-resistant disease may present certain opportunities. In drug-resistant disease, the efficacy of existing regimens is comparatively poor, and companion drugs used to treat drug-resistant disease are weak or ineffective, enabling demonstration of the effect of the new drug. Other advantages of this approach, which has been used successfully in the development of antiretroviral agents, include the possibility of demonstrating drug efficacy using smaller studies, the possibility of accelerated approval based on a surrogate endpoint and the opportunity to address an urgent public health need. Experience with the activity and the safety of new agents in drug-resistant disease may provide a platform from which their indication can be broadened to include drug-sensitive disease. PMID:18762157

  8. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine

    PubMed Central

    Volm, Manfred; Efferth, Thomas

    2015-01-01

    Drug resistance still impedes successful cancer chemotherapy. A major goal of early concepts in individualized therapy was to develop in vitro tests to predict tumors’ drug responsiveness. We have developed an in vitro short-term test based on nucleic acid precursor incorporation to determine clinical drug resistance. This test detects inherent and acquired resistance in vitro and transplantable syngeneic and xenografted tumors in vivo. In several clinical trials, clinical resistance was predictable with more than 90% accuracy, while drug sensitivity was detected with less accuracy (~60%). Remarkably, clinical cross-resistance to numerous drugs (multidrug resistance, broad spectrum resistance) was detectable by a single compound, doxorubicin, due to its multifactorial modes of action. The results of this predictive test were in good agreement with predictive assays of other authors. As no predictive test has been established as yet for clinical diagnostics, the identification of sensitive drugs may not reach sufficiently high reliability for clinical routine. A meta-analysis of the literature published during the past four decades considering test results of more than 15,000 tumor patients unambiguously demonstrated that, in the majority of studies, resistance was correctly predicted with an accuracy between 80 and 100%, while drug sensitivity could only be predicted with an accuracy of 50–80%. This synopsis of the published literature impressively illustrates that prediction of drug resistance could be validated. The determination of drug resistance was reliable independent of tumor type, test assay, and drug used in these in vitro tests. By contrast, chemosensitivity could not be predicted with high reliability. Therefore, we propose a rethinking of the “chemosensitivity” concept. Instead, predictive in vitro tests may reliably identify drug-resistant tumors. The clinical consequence imply to subject resistant tumors not to chemotherapy, but to other new treatment options, such as antibody therapy, adoptive immune therapy, hyperthermia, gene therapy, etc. The high accuracy to predict resistant tumors may be exploited to develop new strategies for individualized cancer therapy. This new concept bears the potential of a revival of predictive tests for personalized medicine. PMID:26734568

  9. Geographical variation in cloacal microflora and bacterial antibiotic resistance in a threatened avian scavenger in relation to diet and livestock farming practices.

    PubMed

    Blanco, Guillermo; Lemus, Jesús A; Grande, Javier; Gangoso, Laura; Grande, Juan M; Donázar, José A; Arroyo, Bernardo; Frías, Oscar; Hiraldo, Fernando

    2007-07-01

    The impact on wildlife health of the increase in the use of antimicrobial agents with the intensification of livestock production remains unknown. The composition, richness and prevalence of cloacal microflora as well as bacterial resistance to antibiotics in nestlings and full-grown Egyptian vultures Neophron percnopterus were assessed in four areas of Spain in which the degree of farming intensification differs. Differences in diet composition, especially the role of stabled livestock carrion, appear to govern the similarities of bacterial flora composition among continental populations, while the insular vulture population (Fuerteventura, Canary Islands) showed differences attributed to isolation. Evidence of a positive relationship between the consumption of stabled livestock carrion and bacterial resistance to multiple antibiotics was found. Bacterial resistance was high for semisynthetic penicillins and enrofloxacin, especially in the area with the most intensive stabled livestock production. The pattern of antibiotic resistance was similar for the different bacterial species within each area. Bacterial resistance to antibiotics may be determined by resistance of bacteria present in the livestock meat remains that constituted the food of this species, as indicated by the fact that resistance to each antibiotic was correlated in Escherichia coli isolated from swine carrion and Egyptian vulture nestlings. In addition, resistance in normal faecal bacteria (present in the microflora of both livestock and vultures) was higher than in Staphylococcus epidermidis, a species indicator of the transient flora acquired presumably through the consumption of wild rabbits. Potential negative effects of the use of antimicrobials in livestock farming included the direct ingestion of these drug residues and the effects of bacterial antibiotic resistance on the health of scavengers. PMID:17564607

  10. Origin of Robustness in Generating Drug-Resistant Malaria Parasites

    PubMed Central

    Kümpornsin, Krittikorn; Modchang, Charin; Heinberg, Adina; Ekland, Eric H.; Jirawatcharadech, Piyaporn; Chobson, Pornpimol; Suwanakitti, Nattida; Chaotheing, Sastra; Wilairat, Prapon; Deitsch, Kirk W.; Kamchonwongpaisan, Sumalee; Fidock, David A.; Kirkman, Laura A.; Yuthavong, Yongyuth; Chookajorn, Thanat

    2014-01-01

    Biological robustness allows mutations to accumulate while maintaining functional phenotypes. Despite its crucial role in evolutionary processes, the mechanistic details of how robustness originates remain elusive. Using an evolutionary trajectory analysis approach, we demonstrate how robustness evolved in malaria parasites under selective pressure from an antimalarial drug inhibiting the folate synthesis pathway. A series of four nonsynonymous amino acid substitutions at the targeted enzyme, dihydrofolate reductase (DHFR), render the parasites highly resistant to the antifolate drug pyrimethamine. Nevertheless, the stepwise gain of these four dhfr mutations results in tradeoffs between pyrimethamine resistance and parasite fitness. Here, we report the epistatic interaction between dhfr mutations and amplification of the gene encoding the first upstream enzyme in the folate pathway, GTP cyclohydrolase I (GCH1). gch1 amplification confers low level pyrimethamine resistance and would thus be selected for by pyrimethamine treatment. Interestingly, the gch1 amplification can then be co-opted by the parasites because it reduces the cost of acquiring drug-resistant dhfr mutations downstream in the same metabolic pathway. The compensation of compromised fitness by extra GCH1 is an example of how robustness can evolve in a system and thus expand the accessibility of evolutionary trajectories leading toward highly resistant alleles. The evolution of robustness during the gain of drug-resistant mutations has broad implications for both the development of new drugs and molecular surveillance for resistance to existing drugs. PMID:24739308

  11. Bacterial fitness shapes the population dynamics of antibiotic-resistant and -susceptible bacteria in a model of combined antibiotic and anti-virulence treatment

    PubMed Central

    Ternent, Lucy; Dyson, Rosemary J.; Krachler, Anne-Marie; Jabbari, Sara

    2015-01-01

    Bacterial resistance to antibiotic treatment is a huge concern: introduction of any new antibiotic is shortly followed by the emergence of resistant bacterial isolates in the clinic. This issue is compounded by a severe lack of new antibiotics reaching the market. The significant rise in clinical resistance to antibiotics is especially problematic in nosocomial infections, where already vulnerable patients may fail to respond to treatment, causing even greater health concern. A recent focus has been on the development of anti-virulence drugs as a second line of defence in the treatment of antibiotic-resistant infections. This treatment, which weakens bacteria by reducing their virulence rather than killing them, should allow infections to be cleared through the body׳s natural defence mechanisms. In this way there should be little to no selective pressure exerted on the organism and, as such, a predominantly resistant population should be less likely to emerge. However, before the likelihood of resistance to these novel drugs emerging can be predicted, we must first establish whether such drugs can actually be effective. Many believe that anti-virulence drugs would not be powerful enough to clear existing infections, restricting their potential application to prophylaxis. We have developed a mathematical model that provides a theoretical framework to reveal the circumstances under which anti-virulence drugs may or may not be successful. We demonstrate that by harnessing and combining the advantages of antibiotics with those provided by anti-virulence drugs, given infection-specific parameters, it is possible to identify treatment strategies that would efficiently clear bacterial infections, while preventing the emergence of antibiotic-resistant subpopulations. Our findings strongly support the continuation of research into anti-virulence drugs and demonstrate that their applicability may reach beyond infection prevention. PMID:25701634

  12. AcrB drug-binding pocket substitution confers clinically relevant resistance and altered substrate specificity.

    PubMed

    Blair, Jessica M A; Bavro, Vassiliy N; Ricci, Vito; Modi, Niraj; Cacciotto, Pierpaolo; Kleinekathӧfer, Ulrich; Ruggerone, Paolo; Vargiu, Attilio V; Baylay, Alison J; Smith, Helen E; Brandon, Yvonne; Galloway, David; Piddock, Laura J V

    2015-03-17

    The incidence of multidrug-resistant bacterial infections is increasing globally and the need to understand the underlying mechanisms is paramount to discover new therapeutics. The efflux pumps of Gram-negative bacteria have a broad substrate range and transport antibiotics out of the bacterium, conferring intrinsic multidrug resistance (MDR). The genomes of pre- and posttherapy MDR clinical isolates of Salmonella Typhimurium from a patient that failed antibacterial therapy and died were sequenced. In the posttherapy isolate we identified a novel G288D substitution in AcrB, the resistance-nodulation division transporter in the AcrAB-TolC tripartite MDR efflux pump system. Computational structural analysis suggested that G288D in AcrB heavily affects the structure, dynamics, and hydration properties of the distal binding pocket altering specificity for antibacterial drugs. Consistent with this hypothesis, recreation of the mutation in standard Escherichia coli and Salmonella strains showed that G288D AcrB altered substrate specificity, conferring decreased susceptibility to the fluoroquinolone antibiotic ciprofloxacin by increased efflux. At the same time, the substitution increased susceptibility to other drugs by decreased efflux. Information about drug transport is vital for the discovery of new antibacterials; the finding that one amino acid change can cause resistance to some drugs, while conferring increased susceptibility to others, could provide a basis for new drug development and treatment strategies. PMID:25737552

  13. [Application of HIV drug resistance testing according to guidelines].

    PubMed

    Oette, M; Göbels, K; Reuter, S; Koch, S; Kaiser, R; Häussinger, D

    2009-11-01

    Guidelines for application of HIV drug resistance testing have recently been develeped in Europe and the USA. This article discusses these recommendations. Since the widespread use of highly active antiretroviral therapy (HAART), quality of life has been improved for the majority of HIV-infected patients and the mortality rate has declined significantly. However, an incomplete suppression of viral replication results in selection of resistant viral strains resulting in a loss of HAART efficacy and worsening in the quality of life. Resistance testing is likely to improve virological monitoring of untreated but especially in pre-treated patients. Genotypical and phenotypical assays present similar results, but genotypical testing is the method of choice initially. Translation of resistance testing into clinical decisions-making requires consideration of a patient's history, interpretation of results by a validated algorithm, and expert advice. Problems of adherence should be avoided by counselling and therapeutic drug monitoring. Resistance testing or storage of a patient's plasma sample should be undertaken as early as possible in the disease history. If this is not possible, treatment with HAART, including a boosted protease inhibitor, is warranted. European and USA guidelines present similar recommendations. HIV drug resistance is preventable by rational choice of drug combinations in HAART. After development of resistance-associated mutations, drug resistance testing can preserve future treatment options and preventing further clinical deterioration. The method has been incorporated into national and international guidelines on the basis of good scientific evidence. PMID:19894202

  14. TRANSFORMATION OF ANTHURIUM WITH TRANSGENES FOR BACTERIAL BLIGHT AND NEMATODE RESISTANCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Anthurium transformation was undertaken to engineer plants for resistance to bacterial blight caused by Xanthomonas axonopodis pv. dieffenbachiae and to the nematodes Radopholus simile and Meloidogyne javanica. Agrobacterium tumefaciens transformation of embryogenic calli of ‘Marian Seefurth’ was sh...

  15. Registration of Common Bacterial Blight Resistant White Kidney Bean Germplasm Line USWK-CBB-17

    Technology Transfer Automated Retrieval System (TEKTRAN)

    White kidney bean germplasm line USWK-CBB-17 was developed by USDA-ARS in cooperation with the Idaho Agricultural Experiment Station and released in 2006. This line was bred with a high level of resistance to common bacterial blight caused by Xanthomonas axonopodis pv. phaseoli (Xap). Common bacteri...

  16. 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.

  17. Drug resistance in cancer: molecular evolution and compensatory proliferation.

    PubMed

    Friedman, Ran

    2016-03-15

    Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP. PMID:26909596

  18. Extensively drug resistant tuberculosis (XDR-TB): A potential threat.

    PubMed

    Marwar, Anaga; Shaker, Ivvala Anand; Palawan, Hemraz; Nanadal; Ranjith, M S; GokulShankar

    2010-12-01

    Emergence of extensively drug resistant tuberculosis (XDR-TB) has been reported by more than 55 countries. XDR-TB is considered as untreatable and highly fatal disease. In developing countries like India, number of cases of multi-drug resistant tuberculosis (MDR-TB) and XDR-TB are increasing. Emergence of resistance to Isoniazid and Rifampicin, the two most effective and well tolerated agents, coupled with resistance to second line agents pose limited treatment options for XDR-TB. The present minireview provides information about the seriousness of XDR-TB and the drugs available for its treatment. Although considered a fatal disorder, judicious use of combination of drugs, retaining their antimycobacterial activity, can improve the clinical outcome of XDR-TB. Only such an approach can provide some hope for the patients of XDR-TB. PMID:24825999

  19. Antibiotics in Animal Feed Contribute to Drug-Resistant Germs

    MedlinePlus

    ... nlm.nih.gov/medlineplus/news/fullstory_158316.html Antibiotics in Animal Feed Contribute to Drug-Resistant Germs: ... THURSDAY, April 14, 2016 (HealthDay News) -- Use of antibiotics in farm animal feed is helping drive the ...

  20. The First Global Forum on Bacterial Infections calls for urgent action to contain antibiotic resistance.

    PubMed

    Vlieghe, Erika

    2012-02-01

    The 1st Global Forum on Bacterial Infections: Balancing Treatment Access and Antibiotic Resistance was organized by the Center for Disease Dynamics, Economics and Policy and the Public Health Foundation of India for researchers, policymakers, clinicians and public health program managers dealing with the problems of bacterial infection and antibiotic resistance in low- and middle-income countries. This meeting was the first gathering of its kind to be held in a developing country. PMID:22339188

  1. 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

  2. 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

  3. Drug resistance and biochemical characteristics of Salmonella from turkeys.

    PubMed Central

    Poppe, C; Kolar, J J; Demczuk, W H; Harris, J E

    1995-01-01

    A study was conducted to determine the antibiotic resistance and biochemical characteristics of 2690 Salmonella strains belonging to 52 serovars and isolated from environmental and feed samples from 270 turkey flocks in Canada. Resistance of the Salmonella strains to the aminoglycoside antibiotics varied widely; none of the strains were resistant to amikacin, 14.2% were resistant to neomycin, 25.8% were resistant to gentamicin, and 27.7% of the strains were resistant to kanamycin. Most strains (97.6%) were resistant to the aminocyclitol, spectinomycin. Regarding resistance to the beta-lactam antibiotics, 14.3% and 14.4% of the strains were resistant to ampicillin and carbenicillin, respectively, whereas only 5 (0.2%) of the strains were resistant to cephalothin. None of the strains were resistant to the fluoroquinolone ciprofloxacin or to polymyxin B. Resistance to chloramphenicol and nitrofurantoin was found in 2.4% and 7% of the strains, respectively. Only 1.7% of the strains were resistant to the trimethoprimsulfamethoxazole combination, whereas 58.1% were resistant to sulfisoxazole. Thirty-eight percent of the strains were resistant to tetracycline. Salmonella serovars differed markedly in their drug resistance profiles. Biochemical characterization of the Salmonella showed that the S. anatum, S. saintpaul and S. reading serovars could be divided into distinct biotypes. PMID:8548684

  4. Nanodrug Formed by Coassembly of Dual Anticancer Drugs to Inhibit Cancer Cell Drug Resistance

    PubMed Central

    Zhao, Yuanyuan; Chen, Fei; Pan, Yuanming; Li, Zhipeng; Xue, Xiangdong; Okeke, Chukwunweike Ikechukwu; Wang, Yifeng; Li, Chan; Peng, Ling; Wang, Paul C.; Ma, Xiaowei; Liang, Xing-Jie

    2016-01-01

    Carrier-free pure nanodrugs (PNDs) that are composed entirely of pharmaceutically active molecules are regarded as promising candidates to be the next generation of drug formulations and are mainly formulated from supramolecular self-assembly of drug molecules. It benefits from the efficient use of drug compounds with poor aqueous solubility and takes advantage of nanoscale drug delivery systems. Here, a type of all-in-one nanoparticle consisting of multiple drugs with enhanced synergistic antiproliferation efficiency against drug-resistant cancer cells has been created. To nanoparticulate the anticancer drugs, 10-hydroxycamptothecin (HCPT) and doxorubicin (DOX) were chosen as a typical model. The resulting HD nanoparticles (HD NPs) were formulated by a “green” and convenient self-assembling method, and the water-solubility of 10-hydroxycamptothecin (HCPT) was improved 50-fold after nanosizing by coassembly with DOX. The formation process was studied by observing the morphological changes at various reaction times and molar ratios of DOX to HCPT. Molecular dynamics (MD) simulations showed that DOX molecules tend to assemble around HCPT molecules through intermolecular forces. With the advantage of nanosizing, HD NPs could improve the intracellular drug retention of DOX to as much as 2-fold in drug-resistant cancer cells (MCF-7R). As a dual-drug-loaded nanoformulation, HD NPs effectively enhanced drug cytotoxicity to drug-resistant cancer cells. The combination of HCPT and DOX exhibited a synergistic effect as the nanosized HD NPs improved drug retention in drug-resistant cancer cells against P-gp efflux in MCF-7R cells. Furthermore, colony forming assays were applied to evaluate long-term inhibition of cancer cell proliferation, and these assays confirmed the greatly improved cytotoxicity of HD NPs in drug-resistant cells compared to free drugs. PMID:26270258

  5. Drug resistance analysis by next generation sequencing in Leishmania

    PubMed Central

    Leprohon, Philippe; Fernandez-Prada, Christopher; Gazanion, Élodie; Monte-Neto, Rubens; Ouellette, Marc

    2014-01-01

    The use of next generation sequencing has the power to expedite the identification of drug resistance determinants and biomarkers and was applied successfully to drug resistance studies in Leishmania. This allowed the identification of modulation in gene expression, gene dosage alterations, changes in chromosome copy numbers and single nucleotide polymorphisms that correlated with resistance in Leishmania strains derived from the laboratory and from the field. An impressive heterogeneity at the population level was also observed, individual clones within populations often differing in both genotypes and phenotypes, hence complicating the elucidation of resistance mechanisms. This review summarizes the most recent highlights that whole genome sequencing brought to our understanding of Leishmania drug resistance and likely new directions. PMID:25941624

  6. An antibiotic protocol to minimize emergence of drug-resistant tuberculosis

    NASA Astrophysics Data System (ADS)

    de Espíndola, Aquino L.; Girardi, Daniel; Penna, T. J. P.; Bauch, Chris T.; Troca Cabella, Brenno C.; Martinez, Alexandre Souto

    2014-04-01

    A within-host model of the spread of tuberculosis is proposed here where the emergence of drug resistance and bacterial dormancy are simultaneously combined. We consider both sensitive and resistant strains of tuberculosis pathogens as well as a dormant state of these bacteria. The dynamics of the within-host system is modeled by a set of coupled differential equations which are numerically solved to find a relation between the within-host bacterial populations and the host health states. The values of the parameters were taken from the current literature when available; a sensitivity analysis was performed for the others. Antibiotic treatment for standard, intermittent and oscillating intermittent protocols is analyzed for different conditions. Our results suggest that the oscillating protocol is the most effective one, that would imply a lower treatment cost.

  7. Serotype distribution and drug resistance in Streptococcus pneumoniae, Palestinian Territories.

    PubMed

    Kattan, Randa; Abu Rayyan, Amal; Zheiman, Inas; Idkeidek, Suzan; Baraghithi, Sabri; Rishmawi, Nabeel; Turkuman, Sultan; Abu-Diab, Afaf; Ghneim, Riyad; Zoughbi, Madeleine; Dauodi, Rula; Ghneim, Raed; Issa, Abed-El-Razeq; Siryani, Issa; Al Qas, Randa; Liddawi, Rawan; Khamash, Hatem; Kanaan, Moein; Marzouqa, Hiyam; Hindiyeh, Musa Y

    2011-01-01

    To determine antimicrobial drug resistance of Streptococcus pneumoniae serotypes, we analyzed isolates from blood cultures of sick children residing in the West Bank before initiation of pneumococcal vaccination. Of 120 serotypes isolated, 50.8%, 73.3%, and 80.8% of the bacteremia cases could have been prevented by pneumococcal conjugate vaccines. Serotype 14 was the most drug-resistant serotype isolated. PMID:21192863

  8. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

    PubMed Central

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-01-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

  9. Using Aspergillus nidulans to identify antifungal drug resistance mutations.

    PubMed

    He, Xiaoxiao; Li, Shengnan; Kaminskyj, Susan G W

    2014-02-01

    Systemic fungal infections contribute to at least 10% of deaths in hospital settings. Most antifungal drugs target ergosterol (polyenes) or its biosynthetic pathway (azoles and allylamines), or beta-glucan synthesis (echinocandins). Antifungal drugs that target proteins are prone to the emergence of resistant strains. Identification of genes whose mutations lead to targeted resistance can provide new information on those pathways. We used Aspergillus nidulans as a model system to exploit its tractable sexual cycle and calcofluor white as a model antifungal agent to cross-reference our results with other studies. Within 2 weeks from inoculation on sublethal doses of calcofluor white, we isolated 24 A. nidulans adaptive strains from sectoring colonies. Meiotic analysis showed that these strains had single-gene mutations. In each case, the resistance was specific to calcofluor white, since there was no cross-resistance to caspofungin (echinocandin). Mutation sites were identified in two mutants by next-generation sequencing. These were confirmed by reengineering the mutation in a wild-type strain using a gene replacement strategy. One of these mutated genes was related to cell wall synthesis, and the other one was related to drug metabolism. Our strategy has wide application for many fungal species, for antifungal compounds used in agriculture as well as health care, and potentially during protracted drug therapy once drug resistance arises. We suggest that our strategy will be useful for keeping ahead in the drug resistance arms race. PMID:24363365

  10. Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors

    PubMed Central

    Sarkar, S.; Cohen, N.; Sabhachandani, P.; Konry, T.

    2015-01-01

    Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions. PMID:26456240

  11. Phenotypic drug profiling in droplet microfluidics for better targeting of drug-resistant tumors.

    PubMed

    Sarkar, S; Cohen, N; Sabhachandani, P; Konry, T

    2015-12-01

    Acquired drug resistance is a key factor in the failure of chemotherapy. Due to intratumoral heterogeneity, cancer cells depict variations in intracellular drug uptake and efflux at the single cell level, which may not be detectable in bulk assays. In this study we present a droplet microfluidics-based approach to assess the dynamics of drug uptake, efflux and cytotoxicity in drug-sensitive and drug-resistant breast cancer cells. An integrated droplet generation and docking microarray was utilized to encapsulate single cells as well as homotypic cell aggregates. Drug-sensitive cells showed greater death in the presence or absence of Doxorubicin (Dox) compared to the drug-resistant cells. We observed heterogeneous Dox uptake in individual drug-sensitive cells while the drug-resistant cells showed uniformly low uptake and retention. Dox-resistant cells were classified into distinct subsets based on their efflux properties. Cells that showed longer retention of extracellular reagents also demonstrated maximal death. We further observed homotypic fusion of both cell types in droplets, which resulted in increased cell survival in the presence of high doses of Dox. Our results establish the applicability of this microfluidic platform for quantitative drug screening in single cells and multicellular interactions. PMID:26456240

  12. The multiple facets of drug resistance: one history, different approaches

    PubMed Central

    2014-01-01

    Some cancers like melanoma and pancreatic and ovarian cancers, for example, commonly display resistance to chemotherapy, and this is the major obstacle to a better prognosis of patients. Frequently, literature presents studies in monolayer cell cultures, 3D cell cultures or in vivo studies, but rarely the same work compares results of drug resistance in different models. Several of these works are presented in this review and show that usually cells in 3D culture are more resistant to drugs than monolayer cultured cells due to different mechanisms. Searching for new strategies to sensitize different tumors to chemotherapy, many methods have been studied to understand the mechanisms whereby cancer cells acquire drug resistance. These methods have been strongly advanced along the years and therapies using different drugs have been increasingly proposed to induce cell death in resistant cells of different cancers. Recently, cancer stem cells (CSCs) have been extensively studied because they would be the only cells capable of sustaining tumorigenesis. It is believed that the resistance of CSCs to currently used chemotherapeutics is a major contributing factor in cancer recurrence and later metastasis development. This review aims to appraise the experimental progress in the study of acquired drug resistance of cancer cells in different models as well as to understand the role of CSCs as the major contributing factor in cancer recurrence and metastasis development, describing how CSCs can be identified and isolated. PMID:24775603

  13. New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria.

    PubMed

    Andersson, Jourdan A; Fitts, Eric C; Kirtley, Michelle L; Ponnusamy, Duraisamy; Peniche, Alex G; Dann, Sara M; Motin, Vladimir L; Chauhan, Sadhana; Rosenzweig, Jason A; Sha, Jian; Chopra, Ashok K

    2016-06-01

    Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens. PMID:27067323

  14. The potential application of photodynamic therapy in drug-resistant tuberculosis.

    PubMed

    Chang, Ji-Eun; Oak, Chul-Ho; Sung, Nackmoon; Jheon, Sanghoon

    2015-09-01

    Tuberculosis (TB) is an infectious bacterial disease that has historically created a high global health burden. Unfortunately, the emergence of drug-resistant TB (DR-TB), which includes multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB), has greatly affected the treatment of TB. Anti-TB chemotherapy drugs are classified into five groups to facilitate application of effective guidelines for the treatment regimen. However, chemotherapy has a limited ability to treat DR-TB, and therefore a novel alternative treatment for DR-TB is required. In this review, we focused on photodynamic therapy (PDT) as potential treatment for DR-TB. PDT is a widely used cancer treatment that combines photosensitizers and harmless laser light to produce reactive oxygen species that selectively damage the target cells. Initially, PDT was originally developed to target pathogenic microorganisms but fell into disuse because of adverse reactions. Recently, photodynamic antimicrobial chemotherapy is attracting attention again as an alternative treatment for bacterial infections. In our previous study, we suggested that PDT could be a novel option to treat MDR- and XDR-TB in vitro. Despite the limited previous studies regarding PDT in TB models, fast-developing bronchoscopic technologies and clinician experience will soon facilitate the clinical application of safe and minimally invasive PDT for TB. PMID:25907636

  15. Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens.

    PubMed

    He, Yan; Tian, Jun; Chen, Xintao; Sun, Weiguang; Zhu, Hucheng; Li, Qin; Lei, Liang; Yao, Guangmin; Xue, Yongbo; Wang, Jianping; Li, Hua; Zhang, Yonghui

    2016-01-01

    Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1-8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1-8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens. PMID:27063778

  16. Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

    PubMed Central

    He, Yan; Tian, Jun; Chen, Xintao; Sun, Weiguang; Zhu, Hucheng; Li, Qin; Lei, Liang; Yao, Guangmin; Xue, Yongbo; Wang, Jianping; Li, Hua; Zhang, Yonghui

    2016-01-01

    Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1–8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1–8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens. PMID:27063778

  17. Effect of Vibration on Bacterial Growth and Antibiotic Resistance

    NASA Technical Reports Server (NTRS)

    Juergensmeyer, Elizabeth A.; Juergensmeyer, Margaret A.

    2004-01-01

    The purpose of this research grant was to provide a fundamental, systematic investigation of the effects of oscillatory acceleration on bacterial proliferation and their responses to antibiotics in a liquid medium.

  18. 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

  19. The interplay between drug resistance and fitness in malaria parasites

    PubMed Central

    Rosenthal, Philip J.

    2013-01-01

    Summary Controlling the spread of antimalarial drug resistance, especially resistance of Plasmodium falciparum to artemisinin-based combination therapies, is a high priority. Available data indicate that, as with other microorganisms, the spread of drug-resistant malaria parasites is limited by fitness costs that frequently accompany resistance. Resistance-mediating polymorphisms in malaria parasites have been identified in putative drug transporters and in target enzymes. The impacts of these polymorphisms on parasite fitness have been characterized in vitro and in animal models. Additional insights have come from analyses of samples from clinical studies, both evaluating parasites under different selective pressures and determining the clinical consequences of infection with different parasites. With some exceptions, resistance-mediating polymorphisms lead to malaria parasites that, compared to wild type, grow less well in culture and in animals, and are replaced by wild type when drug pressure diminishes in the clinical setting. In some cases, the fitness costs of resistance may be offset by compensatory mutations that increase virulence or changes that enhance malaria transmission. However, not enough is known about effects of resistance mediators on parasite fitness. A better appreciation of the costs of fitness-mediating mutations will facilitate the development of optimal guidelines for the treatment and prevention of malaria. PMID:23899091

  20. 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…

  1. Demonstration of Plasmid-Mediated Drug Resistance in Mycobacterium abscessus

    PubMed Central

    Matsumoto, Cristianne Kayoko; Bispo, Paulo José Martins; Santin, Katiane; Nogueira, Christiane Lourenço

    2014-01-01

    Plasmid-mediated kanamycin resistance was detected in a strain of Mycobacterium abscessus subsp. bolletii responsible for a nationwide epidemic of surgical infections in Brazil. The plasmid did not influence susceptibility to tobramycin, streptomycin, trimethoprim-sulfamethoxazole, clarithromycin, or ciprofloxacin. Plasmid-mediated drug resistance has not been described so far in mycobacteria. PMID:24574286

  2. The culturable intestinal microbiota of triploid and diploid juvenile Atlantic salmon (Salmo salar) - a comparison of composition and drug resistance

    PubMed Central

    2011-01-01

    Background With the increased use of ploidy manipulation in aquaculture and fisheries management this investigation aimed to determine whether triploidy influences culturable intestinal microbiota composition and bacterial drug resistance in Atlantic salmon (Salmo salar). The results could provide answers to some of the physiological differences observed between triploid and diploid fish, especially in terms of fish health. Results No ploidy effect was observed in the bacterial species isolated, however, triploids were found to contain a significant increase in total gut microbiota levels, with increases in Pseudomonas spp., Pectobacterium carotovorum, Psychrobacter spp., Bacillus spp., and Vibrio spp., (12, 42, 9, 10, and 11% more bacteria in triploids than diploids, respectively), whereas a decrease in Carnobacterium spp., within triploids compared to diploids was close to significant (8% more bacteria in diploids). With the exception of gentamicin, where no bacterial resistance was observed, bacterial isolates originating from triploid hosts displayed increased resistance to antibacterials, three of which were significant (tetracycline, trimethoprim, and sulphonamide). Conclusion Results indicate that triploidy influences both the community and drug resistance of culturable intestinal microbiota in juvenile salmon. These results demonstrate differences that are likely to contribute to the health of triploid fish and have important ramifications on the use of antibacterial drugs within aquaculture. PMID:22094054

  3. Exploring the links between antibiotic occurrence, antibiotic resistance, and bacterial communities in water supply reservoirs.

    TOXLINE Toxicology Bibliographic Information

    Huerta B; Marti E; Gros M; Lpez P; Pompo M; Armengol J; Barceló D; Balczar JL; Rodrguez-Mozaz S; Marcé R

    2013-07-01

    Antibiotic resistance represents a growing global health concern due to the overuse and misuse of antibiotics. There is, however, little information about how the selective pressure of clinical antibiotic usage can affect environmental communities in aquatic ecosystems and which bacterial groups might be responsible for dissemination of antibiotic resistance genes (ARGs) into the environment. In this study, chemical and biological characterization of water and sediments from three water supply reservoirs subjected to a wide pollution gradient allowed to draw an accurate picture of the concentration of antibiotics and prevalence of ARGs, in order to evaluate the potential role of ARGs in shaping bacterial communities, and to identify the bacterial groups most probably carrying and disseminating ARGs. Results showed significant correlation between the presence of ARG conferring resistance to macrolides and the composition of bacterial communities, suggesting that antibiotic pollution and the spreading of ARG might play a role in the conformation of bacterial communities in reservoirs. Results also pointed out the bacterial groups Actinobacteria and Firmicutes as the ones probably carrying and disseminating ARGs. The potential effect of antibiotic pollution and the presence of ARGs on the composition of bacterial communities in lacustrine ecosystems prompt the fundamental question about potential effects on bacterial-related ecosystem services supplied by lakes and reservoirs.

  4. The Warburg effect and drug resistance.

    PubMed

    Bhattacharya, Bhaskar; Mohd Omar, Mohd Feroz; Soong, Richie

    2016-03-01

    : The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development. PMID:26750865

  5. The Warburg effect and drug resistance

    PubMed Central

    Mohd Omar, Mohd Feroz; Soong, Richie

    2016-01-01

      The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development. PMID:26750865

  6. Anti-mycobacterial activity of garlic (Allium sativum) against multi-drug resistant and non-multi-drug resistant mycobacterium tuberculosis.

    PubMed

    Hannan, Abdul; Ikram Ullah, Muhammad; Usman, Muhammad; Hussain, Shahid; Absar, Muhammad; Javed, Khursheed

    2011-01-01

    Emergence of multi-drug resistant (MDR) and extensively drug resistant (XDR) TB throughout the developing world is very disturbing in the present scenario of TB management. There is a fundamental need to explore alternative anti-TB agents. Hence natural plants should be investigated to understand their antimicrobial properties and safety. Garlic (Allium sativum) is one of natural plant which possesses variety of biological properties like anti-tumor, anti-hyperlipedemic and anti-microbial etc. The present study was evaluated for anti-bacterial activity of garlic against non-MDR and MDR isolates of M. tuberculosis. A total of 20 clinical isolates of MTB including 15 MDR and 5 non-MDR were investigated. Ethanolic extract of garlic was prepared by maceration method. Minimum inhibitory concentration (MIC) was performed by using 7H9 middle brook broth dilution technique. MIC of garlic extract was ranged from 1 to 3 mg/ml; showing inhibitory effects of garlic against both non-MDR and MDR M. tuberculosis isolates. Alternate medicine practices with plant extracts including garlic should be considered to decrease the burden of drug resistance and cost in the management of diseases. The use of garlic against MDR-TB may be of great importance regarding public health. PMID:21190924

  7. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells.

    PubMed

    Ramirez, Michael; Rajaram, Satwik; Steininger, Robert J; Osipchuk, Daria; Roth, Maike A; Morinishi, Leanna S; Evans, Louise; Ji, Weiyue; Hsu, Chien-Hsiang; Thurley, Kevin; Wei, Shuguang; Zhou, Anwu; Koduru, Prasad R; Posner, Bruce A; Wu, Lani F; Altschuler, Steven J

    2016-01-01

    Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a 'persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit-and may even provide a latent reservoir of cells for-the emergence of heterogeneous drug-resistance mechanisms. PMID:26891683

  8. Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells

    PubMed Central

    Ramirez, Michael; Rajaram, Satwik; Steininger, Robert J.; Osipchuk, Daria; Roth, Maike A.; Morinishi, Leanna S.; Evans, Louise; Ji, Weiyue; Hsu, Chien-Hsiang; Thurley, Kevin; Wei, Shuguang; Zhou, Anwu; Koduru, Prasad R.; Posner, Bruce A.; Wu, Lani F.; Altschuler, Steven J.

    2016-01-01

    Cancer therapy has traditionally focused on eliminating fast-growing populations of cells. Yet, an increasing body of evidence suggests that small subpopulations of cancer cells can evade strong selective drug pressure by entering a ‘persister' state of negligible growth. This drug-tolerant state has been hypothesized to be part of an initial strategy towards eventual acquisition of bona fide drug-resistance mechanisms. However, the diversity of drug-resistance mechanisms that can expand from a persister bottleneck is unknown. Here we compare persister-derived, erlotinib-resistant colonies that arose from a single, EGFR-addicted lung cancer cell. We find, using a combination of large-scale drug screening and whole-exome sequencing, that our erlotinib-resistant colonies acquired diverse resistance mechanisms, including the most commonly observed clinical resistance mechanisms. Thus, the drug-tolerant persister state does not limit—and may even provide a latent reservoir of cells for—the emergence of heterogeneous drug-resistance mechanisms. PMID:26891683

  9. Identification of pyruvate kinase in methicillin-resistant Staphylococcus aureus as a novel antimicrobial drug target.

    PubMed

    Zoraghi, Roya; See, Raymond H; Axerio-Cilies, Peter; Kumar, Nag S; Gong, Huansheng; Moreau, Anne; Hsing, Michael; Kaur, Sukhbir; Swayze, Richard D; Worrall, Liam; Amandoron, Emily; Lian, Tian; Jackson, Linda; Jiang, Jihong; Thorson, Lisa; Labriere, Christophe; Foster, Leonard; Brunham, Robert C; McMaster, William R; Finlay, B Brett; Strynadka, Natalie C; Cherkasov, Artem; Young, Robert N; Reiner, Neil E

    2011-05-01

    Novel classes of antimicrobials are needed to address the challenge of multidrug-resistant bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). Using the architecture of the MRSA interactome, we identified pyruvate kinase (PK) as a potential novel drug target based upon it being a highly connected, essential hub in the MRSA interactome. Structural modeling, including X-ray crystallography, revealed discrete features of PK in MRSA, which appeared suitable for the selective targeting of the bacterial enzyme. In silico library screening combined with functional enzymatic assays identified an acyl hydrazone-based compound (IS-130) as a potent MRSA PK inhibitor (50% inhibitory concentration [IC50] of 0.1 μM) with >1,000-fold selectivity over human PK isoforms. Medicinal chemistry around the IS-130 scaffold identified analogs that more potently and selectively inhibited MRSA PK enzymatic activity and S. aureus growth in vitro (MIC of 1 to 5 μg/ml). These novel anti-PK compounds were found to possess antistaphylococcal activity, including both MRSA and multidrug-resistant S. aureus (MDRSA) strains. These compounds also exhibited exceptional antibacterial activities against other Gram-positive genera, including enterococci and streptococci. PK lead compounds were found to be noncompetitive inhibitors and were bactericidal. In addition, mutants with significant increases in MICs were not isolated after 25 bacterial passages in culture, indicating that resistance may be slow to emerge. These findings validate the principles of network science as a powerful approach to identify novel antibacterial drug targets. They also provide a proof of principle, based upon PK in MRSA, for a research platform aimed at discovering and optimizing selective inhibitors of novel bacterial targets where human orthologs exist, as leads for anti-infective drug development. PMID:21357306

  10. Comprehensive screening of genes resistant to an anticancer drug in esophageal squamous cell carcinoma

    PubMed Central

    TSUTSUI, MAI; KAWAKUBO, HIROFUMI; HAYASHIDA, TESTSU; FUKUDA, KAZUMASA; NAKAMURA, RIEKO; TAKAHASHI, TSUNEHIRO; WADA, NORIHITO; SAIKAWA, YOSHIRO; OMORI, TAI; TAKEUCHI, HIROYA; KITAGAWA, YUKO

    2015-01-01

    Drug resistance to chemotherapy is a major issue in esophageal cancer management. Drug resistance may be mediated by genetic changes in the tumor; therefore, the identification of gene mutations may lead to better therapeutic outcomes. We used a novel method involving transposons to screen and identify drug-resistant genes. Transposons are DNA sequences that move from one location on the gene to another. A modified piggyBac transposon was designed as an insertion mutagen, and a cytomegalovirus (CMV) promoter sequence was added to induce strong transcription. When the transposon is inserted to the upstream of a certain gene, the gene will be overexpressed while when intserted down or intragenically, it will be downregulated. After establishing a transposon-tagged cell library, we treated cell lines derived from esophageal squamous cell carcinomas (ESCC) [Tohoku esophagus (TE)] with cisplatin (CDDP). We performed splinkerette PCR and TOPO cloning on the resistant colonies. Bacterial colonies were sequenced, and next-generation sequencing was used to identify the overexpressed/downregulated sequences as candidate genes for CDDP resistance. We established 4 cell lines of transposon-tagged cells, TE4, 5, 9 and 15. We treated the two relatively viable cell lines, TE4 and TE15, with CDDP. We identified 37 candidate genes from 8 resistant colonies. Eight genes were overexpressed whilst 29 were downregulated. Among these genes was Janus kinase 2 (JAK2) that is implicated in the progression of myeloproliferative neoplasms. We identified 37 candidate genes responsible for CDDP resistance in the two cell lines derived from ESCC cells. The method is inexpensive, relatively simple, and capable of introducing activating and de-activating mutations in the genome, allowing for drug-resistant genes to be identified. PMID:26202837

  11. An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance

    PubMed Central

    Abed, Nadia; Saïd-Hassane, Fatouma; Zouhiri, Fatima; Mougin, Julie; Nicolas, Valérie; Desmaële, Didier; Gref, Ruxandra; Couvreur, Patrick

    2015-01-01

    The “Golden era” of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55–63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells. PMID:26311631

  12. Learning the ABC of oral fungal drug resistance.

    PubMed

    Cannon, R D; Holmes, A R

    2015-12-01

    ATP-binding cassette (ABC) proteins are ubiquitous in prokaryotes and eukaryotes. They are involved in energy-dependent transport of molecules across membranes. ABC proteins are often promiscuous transporters that can translocate a variety of substrates. In oral fungi, especially in Candida species, they have been implicated as major contributors to the high-level azole resistance of clinical isolates from infections that do not respond to drug therapy. Although this is predominantly due to efflux of azoles from the cells, ABC proteins can contribute to fungal drug resistance in other ways as well. Cells in biofilms are notoriously resistant to antifungal agents. ABC proteins can contribute to this resistance through the efflux of drugs. Biofilms are complex communities of myriad microorganisms which, to survive in such a milieu, need to communicate with, and respond to, other microorganisms and their products. ABC proteins are involved in the secretion of fungal mating factors and quorum sensing molecules. These molecules affect biofilm structure and behavior that can result in increased drug resistance. Hence, ABC proteins make multiple contributions to oral fungal drug resistance through a variety of responses to environmental signals. PMID:26042641

  13. Treatment of post-burns bacterial infections by bacteriophages, specifically ubiquitous Pseudomonas spp. notoriously resistant to antibiotics.

    PubMed

    Ahmad, S I

    2002-04-01

    Post-burn microbial infections are a major problem in recovering from the trauma of third-degree burns, and the survival of patients can depend upon the severity of the burn and the infections encountered. Within 24 hours, patients can start suffering from opportunistic bacterial attacks, which can vary from simple infection, such as those easily treatable by antibiotics, to more complicated types, which may have natural or acquired resistance to drugs. Infection by multiple drug-resistant bacteria can create additional complexity to the problem. As an alternative to treating bacterial infections by antibiotics, bacteriophages have been in use in certain parts of the world, such as at Tbilisi in Georgia and in Poland, and this approach has now been more widely recognized. Results have shown that phage therapy has an 80% success rate against Enterococcus infections and up to 90% against Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Klebsiella pneumoniae. Here it is proposed that bacteriophages can effectively be used for the treatment of post-burn infections, particularly the ubiquitous opportunistic pathogens, Pseudomonas spp., known to be notoriously resistant to a variety of antibiotics. This kind of treatment may be of particular importance in Third World countries where the incidence of burns and infections, due to lack of stringent safety regulations and proper hygiene respectively, may be more common and where cocktails of antibiotics may be less affordable. Phages that can possibly be employed in the treatment and their advantages compared to the use of antibiotics are also highlighted. PMID:12027527

  14. Surveillance for Antimicrobial Drug Resistance in Under-Resourced Countries

    PubMed Central

    Mary, Catherine; Altmann, Dany M.; Doumbo, Ogobara; Morpeth, Susan; Bhutta, Zulfiqar A.; Klugman, Keith P.

    2014-01-01

    Antimicrobial drug resistance is usually not monitored in under-resourced countries because they lack surveillance networks, laboratory capacity, and appropriate diagnostics. This accelerating problem accounts for substantial number of excess deaths, especially among infants. Infections particularly affected by antimicrobial drug resistance include tuberculosis, malaria, severe acute respiratory infections, and sepsis caused by gram-negative bacteria. Nonetheless, mapping antimicrobial drug resistance is feasible in under-resourced countries, and lessons can be learned from previous successful efforts. Specimen shipping conditions, data standardization, absence of contamination, and adequate diagnostics must be ensured. As a first step toward solving this problem, we propose that a road map be created at the international level to strengthen antimicrobial resistance surveillance in under-resourced countries. This effort should include a research agenda; a map of existing networks and recommendations to unite them; and a communication plan for national, regional, and international organizations and funding agencies. PMID:24564906

  15. Resistance to targeted cancer drugs through hepatocyte growth factor signaling

    PubMed Central

    Heynen, Guus JJE; Fonfara, Aldona; Bernards, René

    2014-01-01

    Cancer therapeutics that target a signaling pathway to which the cancer cells are addicted can deliver dramatic initial responses, but resistance is nearly always inevitable. A variety of mechanisms that cancer cells employ to escape from targeted cancer drugs have been described. We review here the role of Hepatocyte Growth Factor (HGF) and its receptor MET in drug resistance. We present data demonstrating that HGF can confer resistance to a number of kinase inhibitors in a variety of cancer cell lines and discuss our results in relation to the findings of others. Together, these data point at a major role for HGF/MET signaling in resistance to a variety of targeted cancer drugs. PMID:25426675

  16. Cancer Drug Resistance: A Brief Overview from a Genetic Viewpoint.

    PubMed

    Rueff, José; Rodrigues, António Sebastião

    2016-01-01

    Cancer drug resistance leading to therapeutic failure in the treatment of many cancers encompasses various mechanisms and may be intrinsic relying on the patient's genetic makeup or be acquired by tumors that are initially sensitive to cancer drugs. All in all, it may be responsible for treatment failure in over 90 % of patients with metastatic cancer. Cancer drug resistance, in particular acquired resistance, may stem from the micro-clonality/micro-genetic heterogeneity of the tumors whereby, among others, the following mechanisms may entail resistance: altered expression of drug influx/efflux transporters in the tumor cells mediating lower drug uptake and/or greater efflux of the drug; altered role of DNA repair and impairment of apoptosis; role of epigenomics/epistasis by methylation, acetylation, and altered levels of microRNAs leading to alterations in upstream or downstream effectors; mutation of drug targets in targeted therapy and alterations in the cell cycle and checkpoints; and tumor microenvironment that are briefly reviewed. PMID:26910065

  17. Investigational new drugs for the treatment of resistant pneumococcal infections.

    PubMed

    Hoffman-Roberts, Holly L; C Babcock, Emily; Mitropoulos, Isaac F

    2005-08-01

    Antibiotic resistance in Streptococcus pneumoniae is not only increasing with penicillin but also with other antimicrobial classes including the macrolides, tetracyclines and sulfonamides. This trend with antibiotic resistance has highlighted the need for the further development of new anti-infectives for the treatment of pneumococcal infections, particularly against multi-drug resistant pneumococci. Several new drugs with anti-pneumococcal activity are at various stages of development and will be discussed in this review. Two new cephalosporins with activity against S. pneumoniae include ceftobiprole and RWJ-54428. Faropenem is in a new class of beta-lactam antibiotics called the penems. Structurally, the penems are a hybrid between the penicillins and cephalosporins. Sitafloxacin and garenoxacin are two new quinolones that are likely to have a role in treating pneumococcal infections. Oritavancin and dalbavancin are glycopeptides with activity against methicillin-resistant S. aureus and vancomycin-resistant Enterococcus spp. as well as multi-drug resistant pneumococci. Tigecycline is the first drug in a new class of anti-infectives called the glycycyclines that has activity against penicillin-resistant pneumococci. PMID:16050791

  18. Response to selection for bacterial cold water disease resistance in rainbow trout

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Previous studies indicate that resistance to experimental bacterial cold water disease (BCWD) challenge is heritable and thus may be improved through selective breeding. Our objective was to estimate response after one generation of genetic selection for resistance to BCWD in a pedigreed population ...

  19. EPISTATIC INTERACTION BETWEEN TWO MAJOR QTL CONDITIONING RESISTANCE TO COMMON BACTERIAL BLIGHT IN COMMON BEAN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Resistance to common bacterial blight in common bean is a complex trait that is quantitatively inherited. Combining QTL is the current strategy for improving resistance, but interactions among different QTL are unknown. We examined the interaction between two independent QTL present in dry bean bre...

  20. Phenotypic Resistance and the Dynamics of Bacterial Escape from Phage Control

    PubMed Central

    Bull, James J.; Vegge, Christina Skovgaard; Schmerer, Matthew; Chaudhry, Waqas Nasir; Levin, Bruce R.

    2014-01-01

    The canonical view of phage - bacterial interactions in dense, liquid cultures is that the phage will eliminate most of the sensitive cells; genetic resistance will then ascend to restore high bacterial densities. Yet there are various mechanisms by which bacteria may remain sensitive to phages but still attain high densities in their presence – because bacteria enter a transient state of reduced adsorption. Importantly, these mechanisms may be cryptic and inapparent prior to the addition of phage yet result in a rapid rebound of bacterial density after phage are introduced. We describe mathematical models of these processes and suggest how different types of this ‘phenotypic’ resistance may be elucidated. We offer preliminary in vitro studies of a previously characterized E. coli model system and Campylobacter jejuni illustrating apparent phenotypic resistance. As phenotypic resistance may be specific to the receptors used by phages, awareness of its mechanisms may identify ways of improving the choice of phages for therapy. Phenotypic resistance can also explain several enigmas in the ecology of phage-bacterial dynamics. Phenotypic resistance does not preclude the evolution of genetic resistance and may often be an intermediate step to genetic resistance. PMID:24743264

  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. Defensive remodeling: How bacterial surface properties and biofilm formation promote resistance to antimicrobial peptides.

    PubMed

    Nuri, Reut; Shprung, Tal; Shai, Yechiel

    2015-11-01

    Multidrug resistance bacteria are a major concern worldwide. These pathogens cannot be treated with conventional antibiotics and thus alternative therapeutic agents are needed. Antimicrobial peptides (AMPs) are considered to be good candidates for this purpose. Most AMPs are short and positively charged amphipathic peptides, which are found in all known forms of life. AMPs are known to kill bacteria by binding to the negatively charged bacterial surface, and in most cases cause membrane disruption. Resistance toward AMPs can be developed, by modification of bacterial surface molecules, secretion of protective material and up-regulation or elimination of specific proteins. Because of the general mechanisms of attachment and action of AMPs, bacterial resistance to AMPs often involves biophysical and biochemical changes such as surface rigidity, cell wall thickness, surface charge, as well as membrane and cell wall modification. Here we focus on the biophysical, surface and surrounding changes that bacteria undergo in acquiring resistance to AMPs. In addition we discuss the question of whether bacterial resistance to administered AMPs might compromise our innate immunity to endogenous AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides. PMID:26051126

  3. Antimicrobial Action of Water-Soluble β-Chitosan against Clinical Multi-Drug Resistant Bacteria

    PubMed Central

    Park, Seong-Cheol; Nam, Joung-Pyo; Kim, Jun-Ho; Kim, Young-Min; Nah, Jae-Woon; Jang, Mi-Kyeong

    2015-01-01

    Recently, the number of patients infected by drug-resistant pathogenic microbes has increased remarkably worldwide, and a number of studies have reported new antibiotics from natural sources. Among them, chitosan, with a high molecular weight and α-conformation, exhibits potent antimicrobial activity, but useful applications as an antibiotic are limited by its cytotoxicity and insolubility at physiological pH. In the present study, the antibacterial activity of low molecular weight water-soluble (LMWS) α-chitosan (α1k, α5k, and α10k with molecular masses of 1, 5, and 10 kDa, respectively) and β-chitosan (β1k, β5k, and β10k) was compared using a range of pathogenic bacteria containing drug-resistant bacteria isolated from patients at different pH. Interestingly, β5k and β10k exhibited potent antibacterial activity, even at pH 7.4, whereas only α10k was effective at pH 7.4. The active target of β-chitosan is the bacterial membrane, where the leakage of calcein is induced in artificial PE/PG vesicles, bacterial mimetic membrane. Moreover, scanning electron microscopy showed that they caused significant morphological changes on the bacterial surfaces. An in vivo study utilizing a bacteria-infected mouse model found that LMWS β-chitosan could be used as a candidate in anti-infective or wound healing therapeutic applications. PMID:25867474

  4. Dry-Heat Resistance of Bacterial Spores Recovered from Mariner-Mars 1969 Spacecraft

    PubMed Central

    Wardle, M. D.; Brewer, W. A.; Peterson, M. L.

    1971-01-01

    The dry-heat resistances of 70 bacterial spore isolates recovered from Mariner-Mars 1969 spacecraft were determined and expressed as D values (decimal reduction times). Fifty per cent of the spore isolates had D values of 60 min or less at 125 C. Of organisms with D values greater than 60 min, four were selected for a study of the effect of sporulation medium and suspension menstruum on dry-heat resistance. Both sporulation medium and suspension menstruum were found to affect significantly the dry-heat resistance of the bacterial spores tested. Images PMID:16349903

  5. Treatment of drug-resistant Shigella infections.

    PubMed

    Klontz, Karl C; Singh, Nalini

    2015-01-01

    Since the introduction of sulfonamides in the late 1930s, selective pressure and the widespread dissemination of mobile genetic elements conferring antimicrobial resistance have forced clinicians to seek successive agents for the treatment of multidrug-resistant shigellosis. Over the decades, the principal antibiotics used to treat Shigella infections have included tetracycline, chloramphenicol, ampicillin, trimethoprim-sulfamethoxazole, and nalidixic acid. Presently, ciprofloxacin, azithromycin, and ceftriaxone serve as the mainstays of treatment, although growing evidence has documented decreased susceptibility or full resistance to these agents in some regions. With diminishing pharmaceutical options available, there is an enhanced need for preventive measures in the form of improved sanitation and hygiene standards, strict use of currently effective agents, and a safe and effective licensed vaccine. PMID:25399653

  6. Establishing Drug Resistance in Microorganisms by Mass Spectrometry

    NASA Astrophysics Data System (ADS)

    Demirev, Plamen A.; Hagan, Nathan S.; Antoine, Miquel D.; Lin, Jeffrey S.; Feldman, Andrew B.

    2013-08-01

    A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and 13C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well.

  7. The global spread of drug-resistant influenza

    PubMed Central

    Chao, Dennis L.; Bloom, Jesse D.; Kochin, Beth F.; Antia, Rustom; Longini, Ira M.

    2012-01-01

    Resistance to oseltamivir, the most widely used influenza antiviral drug, spread to fixation in seasonal influenza A(H1N1) between 2006 and 2009. This sudden rise in resistance seemed puzzling given the low overall level of the oseltamivir usage and the lack of a correlation between local rates of resistance and oseltamivir usage. We used a stochastic simulation model and deterministic approximations to examine how such events can occur, and in particular to determine how the rate of fixation of the resistant strain depends both on its fitness in untreated hosts as well as the frequency of antiviral treatment. We found that, for the levels of antiviral usage in the population, the resistant strain will eventually spread to fixation, if it is not attenuated in transmissibility relative to the drug-sensitive strain, but not at the speed observed in seasonal H1N1. The extreme speed with which the resistance spread in seasonal H1N1 suggests that the resistant strain had a transmission advantage in untreated hosts, and this could have arisen from genetic hitchhiking, or from the mutations responsible for resistance and compensation. Importantly, our model also shows that resistant virus will fail to spread if it is even slightly less transmissible than its sensitive counterparta finding of relevance given that resistant pandemic influenza (H1N1) 2009 may currently suffer from a small, but nonetheless experimentally perceptible reduction in transmissibility. PMID:21865253

  8. Zingiber officinale (ginger) compounds have tetracycline-resistance modifying effects against clinical extensively drug-resistant Acinetobacter baumannii.

    PubMed

    Wang, Hui-Min; Chen, Chung-Yi; Chen, Hsi-An; Huang, Wan-Chun; Lin, Wei-Ru; Chen, Tun-Chieh; Lin, Chun-Yu; Chien, Hsin-Ju; Lu, Po-Liang; Lin, Chiu-Mei; Chen, Yen-Hsu

    2010-12-01

    Extensively drug-resistant Acinetobacter baumannii (XDRAB) is a growing and serious nosocomial infection worldwide, such that developing new agents against it is critical. The antimicrobial activities of the rhizomes from Zingiber officinale, known as ginger, have not been proven in clinical bacterial isolates with extensive drug-resistance. This study aimed to investigate the effects of four known components of ginger, [6]-dehydrogingerdione, [10]-gingerol, [6]-shogaol and [6]-gingerol, against clinical XDRAB. All these compounds showed antibacterial effects against XDRAB. Combined with tetracycline, they showed good resistance modifying effects to modulate tetracycline resistance. Using the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method, these four ginger compounds demonstrated antioxidant properties, which were inhibited by MnO₂, an oxidant without antibacterial effects. After the antioxidant property was blocked, their antimicrobial effects were abolished significantly. These results indicate that ginger compounds have antioxidant effects that partially contribute to their antimicrobial activity and are candidates for use in the treatment of infections with XDRAB. PMID:20564496

  9. Induction of anti-actin drug resistance in Tetrahymena.

    PubMed

    Zackroff, Robert V; Hufnagel, Linda A

    2002-01-01

    Both cytochalasin D and latrunculin B reversibly inhibited Tetrahymena phagocytosis at concentrations similar to those effective in mammalian systems, even though ciliate actins are known to be highly divergent from mammalian actins. Overnight exposure to relatively low (0.25 microM) concentrations of latrunculin B induced resistance in Tetrahymena to the inhibitory effects of that drug, as well as cross-resistance to cytochalasin D. However, much higher (> 30 microM) concentrations of cytochalasin D were required for induction of cross-resistance to latrunculin B. Anti-actin drug resistance in Tetrahymena may involve a general multidrug resistance mechanism and/or specific feedback regulation of F-actin assembly and stability. PMID:12503683

  10. Modeling the evolution of drug resistance in malaria

    PubMed Central

    Fogel, Gary B.

    2012-01-01

    Plasmodium falciparum, the causal agent of malaria, continues to evolve resistance to frontline therapeutics such as chloroquine and sulfadoxine-pyrimethamine. Here we study the amino acid replacements in dihydrofolate reductase (DHFR) that confer resistance to pyrimethamine while still binding the natural DHFR substrate, 7,8-dihydrofolate, and cofactor, NADPH. The chain of amino acid replacements that has led to resistance can be inferred in a computer, leading to a broader understanding of the coevolution between the drug and target. This in silico approach suggests that only a small set of specific active site replacements in the proper order could have led to the resistant strains in the wild today. A similar approach can be used on any target of interest to anticipate likely pathways of future resistance for more effective drug development. PMID:23179493

  11. Development of a risk reduction intervention to reduce bacterial and viral infections for injection drug users

    PubMed Central

    Phillips, Kristina T.; Altman, Jennifer K.; Corsi, Karen F.; Stein, Michael D.

    2016-01-01

    Bacterial infections are widespread problems among drug injectors, requiring novel preventive intervention. As part of a NIDA-funded study, we developed an intervention based on the Information-Motivation-Behavioral Skills Model, past research, injection hygiene protocols, and data collected from focus groups with 32 injectors in Denver in 2009. Qualitative responses from focus groups indicated that most participants had experienced skin abscesses and believed that bacterial infections were commonly a result of drug cut, injecting intramuscularly, and reusing needles. Access to injection supplies and experiencing withdrawal were the most frequently reported barriers to utilizing risk reduction. Implications for intervention development are discussed. PMID:23017057

  12. Mechanisms of anti-retroviral drug resistance: implications for novel drug discovery and development.

    PubMed

    Emamzadeh-Fard, Sahra; Esmaeeli, Shooka; Arefi, Khalilullah; Moradbeigi, Majedeh; Heidari, Behnam; Fard, Sahar E; Paydary, Koosha; Seyedalinaghi, Seyedahmad

    2013-10-01

    Anti-retroviral drug resistance evolves as an inevitable consequence of expanded combination Anti-retroviral Therapy (cART). According to each drug class, resistance mutations may occur due to the infidel nature of HIV reverse transcriptase (RT) and inadequate drug pressures. Correspondingly, resistance to Nucleoside Reverse Transcriptase Inhibitors (NRTIs) occurs due to incorporation impairment of the agent or its removal from the elongating viral DNA chain. With regard to Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), resistance mutations may alter residues of the RT hydrophobic pocket and demonstrate high level of cross resistance. However, resistance to Protease Inhibitors requires complex accumulation of primary and secondary mutations that substitute amino acids in proximity to the viral protease active site. Resistance to novel entry inhibitors may also evolve as a result of mutations that affect the interactions between viral glycoprotein and CD4 or the chemokine receptors. According to the current studies, future drug initiative programs should consider agents that possess higher genetic barrier toward resistance for ascertaining adequate drug efficacy among patients who have failed first-line regimens. PMID:24712673

  13. Non-toxic antimicrobials that evade drug resistance

    PubMed Central

    Davis, Stephen A.; Vincent, Benjamin M.; Endo, Matthew M.; Whitesell, Luke; Marchillo, Karen; Andes, David R.; Lindquist, Susan; Burke, Martin D.

    2015-01-01

    Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. But this benefit often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report dramatically less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and bind their target (the fungal sterol, ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. Surprisingly, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies. PMID:26030729

  14. Evolution of resistance to a last-resort antibiotic in Staphyloccocus aureus via bacterial competition

    PubMed Central

    Koch, Gudrun; Yepes, Ana; Frstner, Konrad U.; Wermser, Charlotte; Stengel, Stephanie T.; Modamio, Jennifer; Ohlsen, Knut; Foster, Kevin R.; Lopez, Daniel

    2014-01-01

    Summary Antibiotic resistance is a key medical concern, with antibiotic use likely being an important cause. However, here we describe an alternative route to clinically-relevant antibiotic resistance that occurs solely due to competitive interactions between bacterial cells. We consistently observe that isolates of Methicillin-resistant Staphylococcus aureus diversify spontaneously into two distinct, sequentially arising strains. The first evolved strain outgrows the parent strain via secretion of surfactants and a toxic bacteriocin. The second is resistant to the bacteriocin. Importantly, this second strain is also resistant to intermediate levels of vancomycin. This so-called VISA (vancomycin-intermediate S. aureus) phenotype is seen in many hard-to-treat clinical isolates. This strain diversification also occurs during in vivo infection in a mouse model, consistent with the fact that both coevolved phenotypes resemble strains commonly found in clinic. Our study shows how competition between coevolving bacterial strains can generate antibiotic resistance and recapitulate key clinical phenotypes. PMID:25171407

  15. Efflux pump-mediated drug resistance in Burkholderia.

    PubMed

    Podnecky, Nicole L; Rhodes, Katherine A; Schweizer, Herbert P

    2015-01-01

    Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in Burkholderia cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND) family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA, and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance. PMID:25926825

  16. Efflux pump-mediated drug resistance in Burkholderia

    PubMed Central

    Podnecky, Nicole L.; Rhodes, Katherine A.; Schweizer, Herbert P.

    2015-01-01

    Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in Burkholderia cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND) family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA, and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance. PMID:25926825

  17. Potential risk for drug resistance globalization at the Hajj.

    PubMed

    Al-Tawfiq, J A; Memish, Z A

    2015-02-01

    Antibiotics were once considered the miracle cure for infectious diseases. The tragedy would be the loss of these miracles as we witness increased antibiotic resistance throughout the world. One of the concerns during mass gatherings is the transmission of antibiotic resistance. Hajj is one of the most common recurring mass gatherings, attracting millions of people from around the world. The transmission of drug-resistant organisms during the Hajj is not well described. In the current review, we summarize the available literature on the transmission and acquisition of antibiotic resistance during the Hajj and present possible solutions. PMID:25682276

  18. Will drug resistance against dolutegravir in initial therapy ever occur?

    PubMed Central

    Wainberg, Mark A.; Han, Ying-Shan

    2015-01-01

    Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI) and INSTIs are the latest class of potent anti-HIV drugs. Compared to the first generation INSTIs, raltegravir, and elvitegravir, DTG shows a limited cross-resistance profile. More interestingly, clinical resistance mutations to DTG in treatment-naive patents have not been observed to this date. This review summarizes recent studies on resistance mutations to DTG and on our understanding of the mechanisms of resistance to DTG as well as future directions for research. PMID:25972810

  19. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014.

    PubMed

    Hu, F-P; Guo, Y; Zhu, D-M; Wang, F; Jiang, X-F; Xu, Y-C; Zhang, X-J; Zhang, C-X; Ji, P; Xie, Y; Kang, M; Wang, C-Q; Wang, A-M; Xu, Y-H; Shen, J-L; Sun, Z-Y; Chen, Z-J; Ni, Y-X; Sun, J-Y; Chu, Y-Z; Tian, S-F; Hu, Z-D; Li, J; Yu, Y-S; Lin, J; Shan, B; Du, Y; Han, Y; Guo, S; Wei, L-H; Wu, L; Zhang, H; Kong, J; Hu, Y-J; Ai, X-M; Zhuo, C; Su, D-H; Yang, Q; Jia, B; Huang, W

    2016-03-01

    With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22 774 and 84 572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies. PMID:27000156

  20. Drug resistance in non-subtype B HIV-1.

    PubMed

    Kantor, Rami; Katzenstein, David

    2004-03-01

    Treatment of HIV-1 with antiretroviral therapy may select mutations in the pol gene associated with resistance to reverse transcriptase inhibitors and protease inhibitors. To provide durable clinical benefit, emergence of drug resistance is countered by prescription of alternative drug regimens. Data on sequential treatments that are effective after virologic failure and the selection of drug resistance is largely confined to HIV-1 subtype B, the clade that has circulated in North America and Europe. However, HIV-1 subtype B currently accounts for only 12% of the estimated 40 million HIV infected individuals worldwide. The global HIV-1 epidemic includes infection with nine identified HIV-1 group M subtypes (A-K), as well as distinct sub-subtypes and numerous chimerical or recombinant forms. Increasing access to treatment of HIV-1 in the developing world and increasing non-subtype B infection through travel and migration pose new questions about the susceptibility and response of these diverse HIV-1 viruses to antiretroviral drugs. Here we review HIV diversity and the published literature on drug resistance, comparing the known resistance mutations in individuals infected with subtype B to the growing experience in the treatment of non-subtype B HIV-1 worldwide. PMID:14962783

  1. Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses.

    PubMed

    Bao, Ju; Marathe, Bindumadhav; Govorkova, Elena A; Zheng, Jie J

    2016-03-01

    The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti-influenza drug. However, oseltamivir-resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir-resistant, alternative therapy options are needed. Herein, we show that a structure-based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir-resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild-type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir-resistance mutation itself caused susceptibility to these drugs. PMID:26833677

  2. Antifungal drug resistance evokedvia RNAi-dependent epimutations

    PubMed Central

    Calo, Silvia; Shertz-Wall, Cecelia; Lee, Soo Chan; Bastidas, Robert J.; Nicolás, Francisco E.; Granek, Joshua A.; Mieczkowski, Piotr; Torres-Martinez, Santiago; Ruiz-Vazquez, Rosa M.; Cardenas, Maria E.; Heitman, Joseph

    2014-01-01

    Microorganisms evolve via mechanisms spanning sexual/parasexual reproduction, mutators, aneuploidy, Hsp90, and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidyl-prolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin1. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth2. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance (FK506R) and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the FKBP12 fkbA gene, giving rise to drug-resistant epimutants. FK506R epimutants readily reverted to the drug-sensitive wild-type (WT) phenotype when grown without drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNA (sRNA) and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves generation of a double-stranded RNA (dsRNA) trigger intermediate from the fkbA mature mRNA to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes. PMID:25079329

  3. Drug-resistant tuberculosis in the WHO Western Pacific Region

    PubMed Central

    Hiatt, Tom; Hennig, Cornelia; Nishikiori, Nobuyuki

    2014-01-01

    Objective To review the latest information about tuberculosis (TB) drug resistance and programmatic management of drug-resistant TB in the Western Pacific Region of the World Health Organization (WHO). Methods We analysed routine data reported by countries to WHO from 2007 to 2013, focusing on data from the following: surveillance and surveys of drug resistance, management of drug-resistant TB and financing related to multidrug-resistant TB (MDR-TB) management. Results In the Western Pacific Region, 4% (95% confidence interval [CI]: 3–6) of new and 22% (95% CI: 18–26) of previously treated TB cases were estimated to have MDR-TB; this means that in 2013, there were an estimated 71 000 (95% CI: 47 000–94 000) MDR-TB cases among notified pulmonary TB cases in this Region. The coverage of drug susceptibility testing (DST) among new and previously treated TB cases was 3% and 20%, respectively. In 2013, 11 153 cases were notified—16% of the estimated MDR-TB cases. Among the notified cases, 6926 or 62% were enrolled in treatment. Among all enrolled MDR-TB cases, 34% had second-line DST and of these, 13% were resistant to fluoroquinolones (FQ) and/or second-line injectable agents. The 2011 cohort of MDR-TB showed a 52% treatment success. Over the last five years, case notification and enrolment have increased more than five times, but the gap between notification and enrolment widened. Discussion The increasing trend in detection and enrolment of MDR-TB cases demonstrates readiness to scale up programmatic management of drug-resistant TB at the country level. However, considerable challenges remain. PMID:25685604

  4. Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

    PubMed Central

    Ndieyira, Joseph W.; Watari, Moyu; McKendry, Rachel A.

    2013-01-01

    The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity1-5. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures1,6,7. We developed a new model1 which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful agents to combat superbug infections. PMID:24192763

  5. Homeless individuals and drug-resistant tuberculosis in south Texas.

    PubMed

    Morris, J T; McAllister, C K

    1992-09-01

    Drug-resistant tuberculosis was found in 21 percent of homeless individuals in New York City between 1982 and 1987. To see if this relationship existed in south Texas, we evaluated all admissions to a Texas Health Department facility with culture-proven tuberculosis. Four hundred forty-three patients were admitted between September 1987 and October 1990. Twenty-six, (5.9 percent) of these patients were identified as homeless. Alcoholism, tobacco abuse, divorce, and unemployment were common demographic characteristics. Six male patients and one female patient (27 percent) had Mycobacterium tuberculosis resistant to one or more antituberculosis drugs. Five were Hispanic, one was white, and one was black. The six male patients had resistance to only one drug, either rifampin or ethambutol. The female patient had resistance to streptomycin, isoniazid, and rifampin. These findings illustrate that drug-resistant tuberculosis exists among homeless individuals in south Texas. As the number of homeless people increases, physicians need to recognize that pulmonary tuberculosis is a frequent infection in this population and that the causal mycobacteria may well be resistant to one or more antituberculosis agents. PMID:1516406

  6. Rewired Metabolism in Drug-resistant Leukemia Cells

    PubMed Central

    Stäubert, Claudia; Bhuiyan, Hasanuzzaman; Lindahl, Anna; Broom, Oliver Jay; Zhu, Yafeng; Islam, Saiful; Linnarsson, Sten; Lehtiö, Janne; Nordström, Anders

    2015-01-01

    Cancer cells that escape induction therapy are a major cause of relapse. Understanding metabolic alterations associated with drug resistance opens up unexplored opportunities for the development of new therapeutic strategies. Here, we applied a broad spectrum of technologies including RNA sequencing, global untargeted metabolomics, and stable isotope labeling mass spectrometry to identify metabolic changes in P-glycoprotein overexpressing T-cell acute lymphoblastic leukemia (ALL) cells, which escaped a therapeutically relevant daunorubicin treatment. We show that compared with sensitive ALL cells, resistant leukemia cells possess a fundamentally rewired central metabolism characterized by reduced dependence on glutamine despite a lack of expression of glutamate-ammonia ligase (GLUL), a higher demand for glucose and an altered rate of fatty acid β-oxidation, accompanied by a decreased pantothenic acid uptake capacity. We experimentally validate our findings by selectively targeting components of this metabolic switch, using approved drugs and starvation approaches followed by cell viability analyses in both the ALL cells and in an acute myeloid leukemia (AML) sensitive/resistant cell line pair. We demonstrate how comparative metabolomics and RNA expression profiling of drug-sensitive and -resistant cells expose targetable metabolic changes and potential resistance markers. Our results show that drug resistance is associated with significant metabolic costs in cancer cells, which could be exploited using new therapeutic strategies. PMID:25697355

  7. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    PubMed

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed. PMID:26906649

  8. Overcoming Target-Mediated Quinolone Resistance in Topoisomerase IV by Introducing Metal Ion-Independent Drug-Enzyme Interactions

    PubMed Central

    Aldred, Katie J.; Schwanz, Heidi A.; Li, Gangqin; McPherson, Sylvia A.; Turnbough, Charles L.; Kerns, Robert J.; Osheroff, Neil

    2013-01-01

    Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs, but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. Based on our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα. PMID:24047414

  9. Evolution of drug resistance in Salmonella panama isolates in Chile.

    PubMed Central

    Cordano, A M; Virgilio, R

    1996-01-01

    In a search for Salmonella isolates in the environment in Chile in 1975, drug-susceptible strains of Salmonella panama were recovered for the first time from river water and vegetables in the vicinity of Santiago. Two to 3 years later, antibiotic-resistant S. panama began to appear in a variety of sources (meat, animals, vegetables, etc.), giving rise to a human epidemic that involved the entire nation. Of 139 clinical isolates studied, 7 were drug susceptible, 11 were resistant only to nitrofurans, and 3 were streptomycin, spectinomycin, and nitrofuran resistant; none of these 21 isolates harbored plasmid DNA. Most isolates (n = 107) were resistant to nitrofurans (chromosomal) and to streptomycin, spectinomycin, sulfonamides, tetracycline, and mercuric and tellurite salts; this multidrug resistance was encoded on a 218-kb plasmid classified in a number of strains as being in the IncHI2 group. From 1982 to 1993, 11 isolates acquired an additional self-transferable plasmid coding for resistance to any one of ampicillin (61 kb), ampicillin and trimethoprim (65 kb), ampicillin, trimethoprim, streptomycin, and sulfonamides (71 kb), ampicillin, gentamicin, kanamycin, and tetracycline (120 kb), or a nontransferable plasmid of approximately 6 kb encoding resistance to ampicillin or kanamycin. With the exception of ampicillin or ampicillin and trimethoprim resistance, S. panama isolates from foodstuffs, mainly pork meat products, and animals had resistance patterns that were the same as those found in clinical specimens. Remarkably, strains from goats and goat cheese and from shellfish isolated in particular rural regions were either drug susceptible or resistant only to streptomycin-spectinomycin encoded on a mobile genetic element and to nitrofurans. The report describes the arrival of a susceptible S. panama strain, its spread all over the country, and the evolution of progressively complex resistance patterns. PMID:8834876

  10. Electronic transduction of HIV-1 drug resistance in AIDS patients.

    PubMed

    Alfonta, Lital; Blumenzweig, Immanuel; Zayats, Maya; Baraz, Lea; Kotler, Moshe; Willner, Itamar

    2004-07-01

    A drug composition consisting of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) is commonly used in AIDS therapy. A major difficulty encountered with the therapeutic composite involves the emergence of drug-resistant viruses, especially to the PIs, regarded as the most effective drugs in the composition. We present a novel bioelectronic means to detect the appearance of mutated HIV-1 exhibiting drug resistance to the PI saquinavir. The method is based on the translation of viral RNA, the association of cleaved or uncleaved Gag polyproteins at an electrode surface functionalized with the respective antibodies, and the bioelectronic detection of the Gag polyproteins associated with the surface. The bioelectronic process includes the association of anti-MA or anti-CA antibodies, the secondary binding of an antibody-horseradish peroxidase (HRP) conjugate, and the biocatalyzed precipitation of an insoluble product on the electronic transducers. Faradaic impedance measurements and quartz crystal microbalance analyses are employed to follow the autoprocessing of the Gag polyproteins. The method was applied to determine drug resistance in infected cultured cells and also in blood samples of consenting AIDS patients. The method described here is also applicable to the determination of drug effectiveness in AIDS patients and to screening of the efficiency of newly developed drugs. PMID:15239052

  11. 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

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

    PubMed

    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

  13. METHOD FOR MEASURING BACTERIAL RESISTANCE TO METALS EMPLOYING EPIFLUORESCENT MICROSCOPY

    EPA Science Inventory

    A direct viable counting method has been developed which can be used to measure resistance of bacteria to metal (DVCMR bio-assay). Results obtained using DVCMR was compared with classical culture methods and proven superior. Evaluation of test strains resistant to arsenic or mang...

  14. Effect of electron beam irradiation on bacterial cellulose membranes used as transdermal drug delivery systems

    NASA Astrophysics Data System (ADS)

    Stoica-Guzun, Anicuta; Stroescu, Marta; Tache, Florin; Zaharescu, Traian; Grosu, Elena

    2007-12-01

    Ionizing radiation is an effective energetic source for polymer surfaces modification in order to obtain transdermal systems with different controlled release properties. In this work, gamma rays have been applied to induce changes in bacterial cellulose membranes. Permeation of drug (tetracycline) was theoretically and experimentally investigated starting from the effect of γ-irradiation on membranes permeability. Release and permeation of drug from irradiated and non-irradiated membranes have been performed using a diffusion cell.

  15. Effects of temperature on biochemical reactions and drug resistance of virulent and avirulent Aeromonas salmonicida

    USGS Publications Warehouse

    Hahnel, G.B.; Gould, R.W.

    1982-01-01

    Incubation temperatures of 11°, 18° and 28° did not substantially affect biochemical reactions of either virulent or avirulent forms of Aeromonas salmonicida subspecies salmonicida. The only change observed, amygdalin fermentation, was positive at 11° and 18° but negative at 28°C. Several isolates utilized sucrose, a characteristic not normally recognized for A. salmonicida subspecies salmonicida.Antimicrobial susceptibility screening indicated resistance to novobiocin increased at the higher incubation temperatures. Standardized drug sensitivity testing procedures and precise zone diameter interpretive standards for bacterial fish pathogens are needed.

  16. New strategies against drug resistance to herpes simplex virus

    PubMed Central

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  17. New strategies against drug resistance to herpes simplex virus.

    PubMed

    Jiang, Yu-Chen; Feng, Hui; Lin, Yu-Chun; Guo, Xiu-Rong

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

  18. [Influence of chronic lead exposure on resistence to bacterial infection (author's transl)].

    PubMed

    Ewers, U; Weisser, L; Wegner, A

    1980-01-01

    Suppression by lead of resistance to bacterial or viral infections has been reported by several authors. We have studied, if a decrease of resistance to bacterial infection could be evaluated at blood lead concentrations (PbB), which correspond to the upper levels of environmental or occupational lead exposure regarded as tolerable (PbB = 35 resp. 60 microgram/100 ml). NMRI mice were chronically exposed to lead by feeding with lead acetate containing diets and given a challenge with Salmonella typhimurium. No increase of susceptibility to bacterial infection could be demonstrated at PbB < 90 microgram/100 g. At PbB > 100 microgram/100 g, however, an increase of lethality and a decrease of 50% survival times could be observed after bacterial infection. PMID:6999813

  19. Identification, characterization and antibiotic resistance of bacterial isolates obtained from waterpipe device hoses.

    PubMed

    Masadeh, Majed M; Hussein, Emad I; Alzoubi, Karem H; Khabour, Omar; Shakhatreh, Muhamad Ali K; Gharaibeh, Mahmoud

    2015-05-01

    The general lack of knowledge about the health effects of waterpipe smoking is among the reasons for its global spread. In this study, bacterial contamination of waterpipe hoses was investigated. Twenty hoses were collected from waterpipe cafés and screened for bacterial pathogens using standard culture and isolation techniques. Additionally, resistance of isolated bacteria to common antibiotics was determined by identifying the minimum inhibitory concentration (MIC) of each isolate. Forty eight bacterial isolates were detected. Isolates included both Gram-positive and Gram-negative pathogens from species that included Micrococcus (12), Corynebacterium (13) and Bacillus (9). In addition, some of the detected pathogens were found to be resistant to aztreonam (79%), cefixime (79%), norfloxacin, amoxicillin (47%), clarithromycin (46%) and enrofloxacin (38%). In conclusion, the hose of the waterpipe device is a good environment for the growth of bacterial pathogens, which can then be transmitted to users. PMID:25985311

  20. Identification, Characterization and Antibiotic Resistance of Bacterial Isolates Obtained from Waterpipe Device Hoses

    PubMed Central

    Masadeh, Majed M.; Hussein, Emad I.; Alzoubi, Karem H.; Khabour, Omar; Shakhatreh, Muhamad Ali K.; Gharaibeh, Mahmoud

    2015-01-01

    The general lack of knowledge about the health effects of waterpipe smoking is among the reasons for its global spread. In this study, bacterial contamination of waterpipe hoses was investigated. Twenty hoses were collected from waterpipe cafés and screened for bacterial pathogens using standard culture and isolation techniques. Additionally, resistance of isolated bacteria to common antibiotics was determined by identifying the minimum inhibitory concentration (MIC) of each isolate. Forty eight bacterial isolates were detected. Isolates included both Gram-positive and Gram-negative pathogens from species that included Micrococcus (12), Corynebacterium (13) and Bacillus (9). In addition, some of the detected pathogens were found to be resistant to aztreonam (79%), cefixime (79%), norfloxacin, amoxicillin (47%), clarithromycin (46%) and enrofloxacin (38%). In conclusion, the hose of the waterpipe device is a good environment for the growth of bacterial pathogens, which can then be transmitted to users. PMID:25985311

  1. Emerging Infections Program as Surveillance for Antimicrobial Drug Resistance

    PubMed Central

    Cleveland, Angela A.; See, Isaac; Lynfield, Ruth

    2015-01-01

    Across the United States, antimicrobial drug–resistant infections affect a diverse population, and effective interventions require concerted efforts across various public health and clinical programs. Since its onset in 1994, the Centers for Disease Control and Prevention Emerging Infections Program has provided robust and timely data on antimicrobial drug–resistant infections that have been used to inform public health action across a spectrum of partners with regard to many highly visible antimicrobial drug–resistance threats. These data span several activities within the Program, including respiratory bacterial infections, health care–associated infections, and some aspects of foodborne diseases. These data have contributed to estimates of national burden, identified populations at risk, and determined microbiological causes of infection and their outcomes, all of which have been used to inform national policy and guidelines to prevent antimicrobial drug–resistant infections. PMID:26291638

  2. "A'ole" Drugs! Cultural Practices and Drug Resistance of Rural Hawai'ian Youths

    ERIC Educational Resources Information Center

    Po'A-Kekuawela, Ka'Ohinani; Okamoto, Scott K.; Nebre, La Risa H.; Helm, Susana; Chin, Coralee I. H.

    2009-01-01

    This qualitative study examined how Native Hawai'ian youths from rural communities utilized cultural practices to promote drug resistance and/or abstinence. Forty-seven students from five different middle schools participated in gender-specific focus groups that focused on the cultural and environmental contexts of drug use for Native Hawai'ian…

  3. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.

    PubMed

    Aldred, Katie J; Blower, Tim R; Kerns, Robert J; Berger, James M; Osheroff, Neil

    2016-02-16

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrA(A90) and GyrA(D94). M. tuberculosis gyrase lacks a conserved serine that anchors a water-metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrA(A90)) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone-gyrase interactions. Clinically relevant mutations at GyrA(A90) and GyrA(D94) cause quinolone resistance by disrupting the bridge-enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone-enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrA(A90V) and GyrA(D94G). 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug-enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis. PMID:26792518

  4. Role of integrin alpha4 in drug resistance of leukemia.

    PubMed

    Shishido, Stephanie; Bnig, Halvard; Kim, Yong-Mi

    2014-01-01

    Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell-cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-?B signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia. PMID:24904821

  5. Role of Integrin Alpha4 in Drug Resistance of Leukemia

    PubMed Central

    Shishido, Stephanie; Bönig, Halvard; Kim, Yong-Mi

    2014-01-01

    Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell–cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-κB signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia. PMID:24904821

  6. Pattern of Drug Resistance and Risk Factors Associated with Development of Drug Resistant Mycobacterium tuberculosis in Pakistan

    PubMed Central

    Ullah, Irfan; Javaid, Arshad; Tahir, Zarfishan; Ullah, Obaid; Shah, Aamer Ali; Hasan, Fariha; Ayub, Najma

    2016-01-01

    Background Drug resistant tuberculosis (DR-TB) is a major public health problem in developing countries such as Pakistan. Objective The current study was conducted to assess the frequency of drug resistant tuberculosis including multi drug resistance (MDR- TB) as well as risk factors for development of DR-TB, in Punjab, Pakistan. Methodology Drug susceptibility testing (DST) was performed, using proportion method, for 2367 culture positive Mycobacterium tuberculosis (MTB) cases that were enrolled from January 2012 to December 2013 in the province of Punjab, Pakistan, against first-line anti-tuberculosis drugs. The data was analyzed using statistical software; SPSS version 18. Results Out of 2367 isolates, 273 (11.5%) were resistant to at least one anti-TB drug, while 221 (9.3%) showed MDR- TB. Risk factors for development of MDR-TB were early age (ranges between 10–25 years) and previously treated TB patients. Conclusion DR-TB is a considerable problem in Pakistan. Major risk factors are previous history of TB treatment and younger age group. It emphasizes the need for effective TB control Program in the country. PMID:26809127

  7. Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance.

    PubMed Central

    Speer, B S; Shoemaker, N B; Salyers, A A

    1992-01-01

    Tetracycline has been a widely used antibiotic because of its low toxicity and broad spectrum of activity. However, its clinical usefulness has been declining because of the appearance of an increasing number of tetracycline-resistant isolates of clinically important bacteria. Two types of resistance mechanisms predominate: tetracycline efflux and ribosomal protection. A third mechanism of resistance, tetracycline modification, has been identified, but its clinical relevance is still unclear. For some tetracycline resistance genes, expression is regulated. In efflux genes found in gram-negative enteric bacteria, regulation is via a repressor that interacts with tetracycline. Gram-positive efflux genes appear to be regulated by an attenuation mechanism. Recently it was reported that at least one of the ribosome protection genes is regulated by attenuation. Tetracycline resistance genes are often found on transmissible elements. Efflux resistance genes are generally found on plasmids, whereas genes involved in ribosome protection have been found on both plasmids and self-transmissible chromosomal elements (conjugative transposons). One class of conjugative transposon, originally found in streptococci, can transfer itself from streptococci to a variety of recipients, including other gram-positive bacteria, gram-negative bacteria, and mycoplasmas. Another class of conjugative transposons has been found in the Bacteroides group. An unusual feature of the Bacteroides elements is that their transfer is enhanced by preexposure to tetracycline. Thus, tetracycline has the double effect of selecting for recipients that acquire a resistance gene and stimulating transfer of the gene. PMID:1423217

  8. Distribution and drug resistance profile of methicillin-resistant Staphylococcus aureus after orthopaedic surgery.

    PubMed

    Song, Wen Chao; Zhang, Si Sen; Gong, Yu Hong

    2015-05-01

    This paper is aimed to comprehend clinical distribution and drug-resistance situation of methicillin-resistant Staphylococcus aureus. This study applied automatic microbe instrument Microscan W/A 96 for strain identification and drug susceptibility screening on the isolated strains. It was found that 312 MRSA strains were isolated in three years, which account for 58.1% of Staphylococcus aureus. MRSA were mainly focused in wound secretion, purulent sputum and prostatic fluid and a few of them were isolated from blood specimens; Endemic area distribution was mainly located in intensive care unit, neurosurgery, respiratory department, dermatology, orthopaedic burns and orthopaedics. MRSA strains showed high drug resistance of 82.37%~100% to most of the antibiotics including vancomycin, cotrimoxazole and rifampicin. Strain was 100% resistance towards ampicillin, amoxicillin/acid, cefalotin, cefazolin, tienam, benzylpenicillin, penicillin and tetracycline and 90% strains resisted clindamycin, cefotaxime, clarithromycin and gentamicin. PMID:26051737

  9. Efficacy of OH-CATH30 and its analogs against drug-resistant bacteria in vitro and in mouse models.

    PubMed

    Li, Sheng-An; Lee, Wen-Hui; Zhang, Yun

    2012-06-01

    Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 μg/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD(50)) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria. PMID:22491685

  10. Bacterial Community Shift Drives Antibiotic Resistance Promotion during Drinking Water Chlorination.

    PubMed

    Jia, Shuyu; Shi, Peng; Hu, Qing; Li, Bing; Zhang, Tong; Zhang, Xu-Xiang

    2015-10-20

    For comprehensive insights into the effects of chlorination, a widely used disinfection technology, on bacterial community and antibiotic resistome in drinking water, this study applied high-throughput sequencing and metagenomic approaches to investigate the changing patterns of antibiotic resistance genes (ARGs) and bacterial community in a drinking water treatment and distribution system. At genus level, chlorination could effectively remove Methylophilus, Methylotenera, Limnobacter, and Polynucleobacter, while increase the relative abundance of Pseudomonas, Acidovorax, Sphingomonas, Pleomonas, and Undibacterium in the drinking water. A total of 151 ARGs within 15 types were detectable in the drinking water, and chlorination evidently increased their total relative abundance while reduced their diversity in the opportunistic bacteria (p < 0.05). Residual chlorine was identified as the key contributing factor driving the bacterial community shift and resistome alteration. As the dominant persistent ARGs in the treatment and distribution system, multidrug resistance genes (mainly encoding resistance-nodulation-cell division transportation system) and bacitracin resistance gene bacA were mainly carried by chlorine-resistant bacteria Pseudomonas and Acidovorax, which mainly contributed to the ARGs abundance increase. The strong correlation between bacterial community shift and antibiotic resistome alteration observed in this study may shed new light on the mechanism behind the chlorination effects on antibiotic resistance. PMID:26397118

  11. Resistance to anti-peptide deformylase drugs.

    PubMed

    Giglione, Carmela; Meinnel, Thierry

    2001-06-01

    Recent work has assessed the potential of peptide deformylase (PDF) as a target for broad spectrum antibacterial agents. By using a number of approaches, including proteomics, researchers at Roche have shown that the molecules they had selected in vitro were able to target PDF in vivo. However, the authors, having observed resistance occurring at a rather high frequency and on the basis of the recent discovery of a deformylase homologue in humans, suggest that PDF 'may not be an optimal target for broad spectrum antibacterial agents'. We link these data to results published by other laboratories and conclude that PDF deserves to still be considered a valuable target for new antibiotics. PMID:12540274

  12. 77 FR 60126 - Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-02

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-D-0971; Formerly Docket FDA-2008-N-0041... guidance as ``the recent or acute onset of inflammation of the middle ear caused by a bacterial...

  13. Rainbow trout (Oncorhynchus mykiss) resistance to columnaris disease is heritable and favorably correlated with bacterial cold water disease resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Columnaris disease (CD), caused by Flabobacterium columnare, is an emerging disease affecting rainbow trout aquaculture. Objectives of this study were to 1) estimate heritability of innate CD resistance in a rainbow trout line (ARS-Fp-R) previously selected four generations for improved bacterial co...

  14. Bacterial panicle blight resistance QTL in rice (Oryza sativa L.) and their association with resistance to other diseases

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial panicle blight (BPB) of rice (Oryza sativa L.) occurs when the bacterium Burkholderia glumae infects and colonizes emerging and flowering panicles, causing kernels to abort. To identify quantitative trait loci (QTL) for BPB resistance, a population of 300 recombinant inbred lines (RILs) d...

  15. [Drug-resistant tuberculosis : Epidemiology, diagnostics and therapy].

    PubMed

    Grobusch, M P; Schaumburg, F; Altpeter, E; Bélard, S

    2016-02-01

    Drug-resistant tuberculosis (DR-TB) is one of the serious problems in the fight against tuberculosis on a global scale. This review article describes in brief the global epidemiology, diagnostics and treatment of DR-TB. The situation in Germany, Switzerland and Austria is addressed in detail. The article concludes with a presentation of current research topics in the field of resistant TB. PMID:26795948

  16. Bacterial antibiotic resistance in soils irrigated with reclaimed municipal wastewater

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Wastewater reclamation for municipal irrigation and groundwater recharge is an increasingly attractive option for extending water supplies. However, public health concerns include the potential for development of antibiotic resistance (AR) in soil bacteria after exposure to residual chemicals in rec...

  17. Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens

    PubMed Central

    Karuppiah, Ponmurugan; Rajaram, Shyamkumar

    2012-01-01

    Objective To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. Methods The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Results Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Conclusions Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary. PMID:23569978

  18. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy

    PubMed Central

    Lee, Jinsoo; Son, Kwanghyun; Hwang, Gwiseo

    2016-01-01

    Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT) has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p = 0.0284, Fisher's exact test). Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children. PMID:27047568

  19. Development of a protocol for predicting bacterial resistance to microbicides.

    PubMed

    Knapp, Laura; Amézquita, Alejandro; McClure, Peter; Stewart, Sara; Maillard, Jean-Yves

    2015-04-01

    Regulations dealing with microbicides in Europe and the United States are evolving and now require data on the risk of the development of resistance in organisms targeted by microbicidal products. There is no standard protocol to assess the risk of the development of resistance to microbicidal formulations. This study aimed to validate the use of changes in microbicide and antibiotic susceptibility as initial markers for predicting microbicide resistance and cross-resistance to antibiotics. Three industrial isolates (Pseudomonas aeruginosa, Burkholderia cepacia, and Klebsiella pneumoniae) and two Salmonella enterica serovar Typhimurium strains (SL1344 and 14028S) were exposed to a shampoo, a mouthwash, eye makeup remover, and the microbicides contained within these formulations (chlorhexidine digluconate [CHG] and benzalkonium chloride [BZC]) under realistic, in-use conditions. Baseline and postexposure data were compared. No significant increases in the MIC or the minimum bactericidal concentration (MBC) were observed for any strain after exposure to the three formulations. Increases as high as 100-fold in the MICs and MBCs of CHG and BZC for SL1344 and 14028S were observed but were unstable. Changes in antibiotic susceptibility were not clinically significant. The use of MICs and MBCs combined with antibiotic susceptibility profiling and stability testing generated reproducible data that allowed for an initial prediction of the development of resistance to microbicides. These approaches measure characteristics that are directly relevant to the concern over resistance and cross-resistance development following the use of microbicides. These are low-cost, high-throughput techniques, allowing manufacturers to provide to regulatory bodies, promptly and efficiently, data supporting an early assessment of the risk of resistance development. PMID:25636848

  20. Development of a Protocol for Predicting Bacterial Resistance to Microbicides

    PubMed Central

    Knapp, Laura; Amézquita, Alejandro; McClure, Peter; Stewart, Sara

    2015-01-01

    Regulations dealing with microbicides in Europe and the United States are evolving and now require data on the risk of the development of resistance in organisms targeted by microbicidal products. There is no standard protocol to assess the risk of the development of resistance to microbicidal formulations. This study aimed to validate the use of changes in microbicide and antibiotic susceptibility as initial markers for predicting microbicide resistance and cross-resistance to antibiotics. Three industrial isolates (Pseudomonas aeruginosa, Burkholderia cepacia, and Klebsiella pneumoniae) and two Salmonella enterica serovar Typhimurium strains (SL1344 and 14028S) were exposed to a shampoo, a mouthwash, eye makeup remover, and the microbicides contained within these formulations (chlorhexidine digluconate [CHG] and benzalkonium chloride [BZC]) under realistic, in-use conditions. Baseline and postexposure data were compared. No significant increases in the MIC or the minimum bactericidal concentration (MBC) were observed for any strain after exposure to the three formulations. Increases as high as 100-fold in the MICs and MBCs of CHG and BZC for SL1344 and 14028S were observed but were unstable. Changes in antibiotic susceptibility were not clinically significant. The use of MICs and MBCs combined with antibiotic susceptibility profiling and stability testing generated reproducible data that allowed for an initial prediction of the development of resistance to microbicides. These approaches measure characteristics that are directly relevant to the concern over resistance and cross-resistance development following the use of microbicides. These are low-cost, high-throughput techniques, allowing manufacturers to provide to regulatory bodies, promptly and efficiently, data supporting an early assessment of the risk of resistance development. PMID:25636848

  1. Ecology and evolution as targets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance.

    PubMed

    Baquero, Fernando; Coque, Teresa M; de la Cruz, Fernando

    2011-08-01

    In recent years, the explosive spread of antibiotic resistance determinants among pathogenic, commensal, and environmental bacteria has reached a global dimension. Classical measures trying to contain or slow locally the progress of antibiotic resistance in patients on the basis of better antibiotic prescribing policies have clearly become insufficient at the global level. Urgent measures are needed to directly confront the processes influencing antibiotic resistance pollution in the microbiosphere. Recent interdisciplinary research indicates that new eco-evo drugs and strategies, which take ecology and evolution into account, have a promising role in resistance prevention, decontamination, and the eventual restoration of antibiotic susceptibility. This minireview summarizes what is known and what should be further investigated to find drugs and strategies aiming to counteract the "four P's," penetration, promiscuity, plasticity, and persistence of rapidly spreading bacterial clones, mobile genetic elements, or resistance genes. The term "drug" is used in this eco-evo perspective as a tool to fight resistance that is able to prevent, cure, or decrease potential damage caused by antibiotic resistance, not necessarily only at the individual level (the patient) but also at the ecological and evolutionary levels. This view offers a wealth of research opportunities for science and technology and also represents a large adaptive challenge for regulatory agencies and public health officers. Eco-evo drugs and interventions constitute a new avenue for research that might influence not only antibiotic resistance but the maintenance of a healthy interaction between humans and microbial systems in a rapidly changing biosphere. PMID:21576439

  2. Analysis of drug-resistant gene detection of blaOXA-like genes from Acinetobacter baumannii.

    PubMed

    Yang, D K; Liang, H J; Gao, H L; Wang, X W; Wang, Y

    2015-01-01

    Our study determines the resistance gene profile of a set of Acinetobacter baumannii hospital isolates. A. baumannii is responsible for nosocomial outbreaks and sporadic infections. We extracted and PCR amplified bacterial DNA isolated from patients with ages below 60 years (23.36%) and above 60 years (76.64%). Most of the patients were admitted in the ICU (36.13%) and pneumology departments (28.47%). Of 164 isolated strains, 16 (9.75%) contained OXA-51, 8 (4.88%) contained OXA-58, and 140 (85.37%) contained both OXA-51 and OXA-23. Additionally, 8 (7.41%) strains containing OXA-58 and 100 (92.59%) strains containing both OXA-51 and OXA-23 showed multidrug-resistance. Drug resistance rates of A. baumannii to amikacin, tobramycin-levofloxacin, and cotrimoxazole were above 90%, while drug resistance rates to ampicillin, cefotetan, cefazolin, cefoperazone, and nitrofurantoin were 100%. In conclusion, we found that isolated strains containing OXA-51 and OXA-23 were more likely to be resistant or have decreased sensitivity to carbapenems. PMID:26782550

  3. Cancer cells acquire resistance to anticancer drugs: an update.

    PubMed

    Lu, Hsing-Pang; Chao, Chuck C K

    2012-01-01

    The efficacy of cancer chemotherapy is often affected by the emergence of resistant can-cer cells. While biochemical and pharmaco-logical mechanisms have been proposed to ex-plain chemo-resistance, the genes involved in this process have not been fully identified. We previously used genomic DNA microarrays and quantitative RT-PCR to identify the genes associated with resistance to chemotherapeutic drugs, particularly to the genotoxic agent cisplatin. Notably, knockdown of the cisplatin resistance (CPR) genes that we identified was shown to reduce chemoresistance and to suppress the growth of tumor xenographs in cisplatin-treated mice, indicating that the newly identified CPR genes may represent potential therapy candidates to limit chemo-resistance and to improve the efficacy of anticancer drugs. In addition to genetic mutations, re-searchers have found that epigenetic changes and alternative splicing of specific genes may also allow cancer cells to become resistant to chemotherapeutic drugs. In this article, the authors present an overview of the latest findings in this field, including genetic changes, epigenetic changes and alternative splicing. PMID:23442359

  4. Correlation Models between Environmental Factors and Bacterial Resistance to Antimony and Copper

    PubMed Central

    Shi, Zunji; Cao, Zhan; Qin, Dong; Zhu, Wentao; Wang, Qian; Li, Mingshun; Wang, Gejiao

    2013-01-01

    Antimony (Sb) and copper (Cu) are toxic heavy metals that are associated with a wide variety of minerals. Sb(III)-oxidizing bacteria that convert the toxic Sb(III) to the less toxic Sb(V) are potentially useful for environmental Sb bioremediation. A total of 125 culturable Sb(III)/Cu(II)-resistant bacteria from 11 different types of mining soils were isolated. Four strains identified as Arthrobacter, Acinetobacter and Janibacter exhibited notably high minimum inhibitory concentrations (MICs) for Sb(III) (>10 mM),making them the most highly Sb(III)-resistant bacteria to date. Thirty-six strains were able to oxidize Sb(III), including Pseudomonas-, Comamonas-, Acinetobacter-, Sphingopyxis-, Paracoccus- Aminobacter-, Arthrobacter-, Bacillus-, Janibacter- and Variovorax-like isolates. Canonical correspondence analysis (CCA) revealed that the soil concentrations of Sb and Cu were the most obvious environmental factors affecting the culturable bacterial population structures. Stepwise linear regression was used to create two predictive models for the correlation between soil characteristics and the bacterial Sb(III) or Cu(II) resistance. The concentrations of Sb and Cu in the soil was the significant factors affecting the bacterial Sb(III) resistance, whereas the concentrations of S and P in the soil greatly affected the bacterial Cu(II) resistance. The two stepwise linear regression models that we derived are as follows: and [where the MICSb(III) and MICCu(II) represent the average bacterial MIC for the metal of each soil (µM), and the CSb, CCu, CS and CP represent concentrations for Sb, Cu, S and P (mg/kg) in soil, respectively, p<0.01]. The stepwise linear regression models we developed suggest that metals as well as other soil physicochemical parameters can contribute to bacterial resistance to metals. PMID:24205252

  5. Wear and corrosion resistance of anti-bacterial Ti-Cu-N coatings on titanium implants

    NASA Astrophysics Data System (ADS)

    Wu, Haibo; Zhang, Xiangyu; He, Xiaojing; Li, Meng; Huang, Xiaobo; Hang, Ruiqiang; Tang, Bin

    2014-10-01

    Anti-bacterial coatings with excellent wear and corrosion resistance play a vital role in ensuring the durability of implant materials in constant use. To this end, a novel anti-bacterial surface modification by combining magnetron sputtering with plasma nitriding was adopted in this paper to fabricate Cu-bearing Ti-based nitrides coatings (Ti-Cu-N) on titanium surface. The anti-bacterial properties of Ti-Cu-N coatings were evaluated. The microstructures and composition of the coatings were investigated by using FESEM, EDS, GDOES, XRD. The wear and corrosion resistance of the coatings were investigated. The results confirmed that an anti-bacterial Ti-Cu-N coating with a thickness of 6 μm and good adhesive strength to substrate was successfully achieved on titanium surface. As implied by XRD, the coatings were consisted of TiN, Ti2N, TiN0.3 phases. The surface micro-hardness and wear resistance of Ti-Cu-N coatings were significantly enhanced after plasma nitriding treatment. The analysis of potentiodynamic polarization curves and Nyquist plots obtained in 0.9 wt.% NaCl solution suggested that the Ti-Cu-N coatings also exhibited an excellent corrosion resistance. As mentioned above, it can be concluded that the duplex-treatment reported here was a versatile approach to develop anti-bacterial Ti-Cu-N coatings with excellent comprehensive properties on titanium implants.

  6. A new common bacterial blight resistance QTL in VAX 1 common bean and interaction of the new QTL, SAP6 and SU91 with bacterial strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common bacterial blight (CBB) is a severe disease in common bean. New resistance QTL should facilitate development of cultivars with high levels of resistance. Our objectives were to (i) identify new resistance QTL in VAX 1 and verify presence in VAX 3, (ii) determine interaction of new QTL with exi...

  7. Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options.

    PubMed

    Zumla, Alimuddin; Memish, Ziad A; Maeurer, Markus; Bates, Matthew; Mwaba, Peter; Al-Tawfiq, Jaffar A; Denning, David W; Hayden, Frederick G; Hui, David S

    2014-11-01

    The emergence and spread of antimicrobial-resistant bacterial, viral, and fungal pathogens for which diminishing treatment options are available is of major global concern. New viral respiratory tract infections with epidemic potential, such as severe acute respiratory syndrome, swine-origin influenza A H1N1, and Middle East respiratory syndrome coronavirus infection, require development of new antiviral agents. The substantial rise in the global numbers of patients with respiratory tract infections caused by pan-antibiotic-resistant Gram-positive and Gram-negative bacteria, multidrug-resistant Mycobacterium tuberculosis, and multiazole-resistant fungi has focused attention on investments into development of new drugs and treatment regimens. Successful treatment outcomes for patients with respiratory tract infections across all health-care settings will necessitate rapid, precise diagnosis and more effective and pathogen-specific therapies. This Series paper describes the development and use of new antimicrobial agents and immune-based and host-directed therapies for a range of conventional and emerging viral, bacterial, and fungal causes of respiratory tract infections. PMID:25189352

  8. Drug resistance mediated by AEG-1/MTDH/LYRIC

    PubMed Central

    Meng, Xiangbing; Thiel, Kristina W; Leslie, Kimberly K

    2014-01-01

    AEG-1/MTDH/LYRIC has been shown to promote cancer progression and development. Overexpression of AEG-1/MTDH/LYRIC correlates with angiogenesis, metastasis and chemoresistance to various chemotherapy agents in cancer cells originating from a variety of tissues. In this review article, we focus on the role of AEG-1/MTDH/LYRIC in drug resistance. Mechanistic studies have shown that AEG-1/MTDH/LYRIC is involved in classical oncogenic pathways including Ha-Ras, myc, NF?B and PI3K/Akt. AEG-1/MTDH/LYRIC also promotes protective autophagy by activating AMP kinase and autophagy-related gene 5. Another reported mechanism by which AEG-1/MTDH/LYRIC regulates drug resistance is by increasing loading of multidrug resistance gene (MDR) 1 mRNA to the polysome, thereby facilitating MDR1 protein translation. More recently, a novel function for AEG-1/MTDH/LYRIC as an RNA binding protein was elucidated, which has the potential to impact expression of drug sensitivity or resistance genes. Finally, AEG-1/MTDH/LYRIC acts in microRNA-directed gene silencing via an interaction with staphylococcal nuclease and tudor domain containing 1 (SND1), a component of the RNA-induced silencing complex. Altered microRNA expression and activity induced by AEG-1/MTDH/LYRIC represents an additional way that AEG-1/MTDH/LYRIC may cause drug resistance in cancer. The multiple functions of AEG-1/MTDH/LYRIC in drug resistance highlight that it is a viable target as an anti-cancer agent for a wide variety of cancers. PMID:23889990

  9. Genome analysis of 17 extensively drug-resistant strains reveals new potential mutations for resistance.

    PubMed

    Guio, H; Tarazona, D; Galarza, M; Borda, V; Curitomay, R

    2014-01-01

    We report the whole-genome sequence of an extensively drug-resistant (XDR) tuberculosis (TB) strain of Latin American-Mediterranean (LAM) lineage. This strain is phenotypically resistant to aminoglycosides, but carries no related mutations in rrs, tlyA, and eis. Through genome analysis comparison with 16 XDR strains, we found 218 non-synonymous single nucleotide polymorphisms (SNPs) shared that could confer resistance. PMID:25081269

  10. Design strategies of novel NNRTIs to overcome drug resistance.

    PubMed

    Zhan, Peng; Liu, Xinyong; Li, Zhenyu; Pannecouque, Christophe; De Clercq, Erik

    2009-01-01

    Nonnucleoside reverse transcriptase inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 reverse transcriptase (RT). However, to a great extent, the efficacy of NNRTI drugs is impaired by rapid emergence of drug-resistance mutations. Fortunately, detailed analysis of a wide range of crystal structures of HIV-1 RT/NNRTI complexes together with data on drug resistance mutations has identified factors important for design of inhibitors and resilience to mutations, such as, exhibiting conformational flexibility and positional adaptability of NNRTIs, forming extensive main chain hydrogen bonding, targeting highly conserved residues in HIV-1 RT and possessing unconventional mechanisms for NNRTI-mediated inhibition of RT. Besides, the plasticity of NNRTIs binding pocket (NNIBP) also provides a broad space for the discovery of new generations of NNRTIs. For instance, the composite binding pocket, integrated all available crystal structure information about the NNRTI binding site of HIV RT, was demonstrated to be an effective tool to better understand the flexible nature of the binding pocket and to identify specific inhibitors. The RT/solvent interface proved to be an attractive site for incorporating a moiety to improve water solubility and pharmacokinetics or introducing a second pharmacophore to construct multifunctional ligand. Totally, the characterization of NNRTIs and NNIBP may help in the design of more effective drugs that are potent toward wild type and drug-resistant strains of RT. In this paper we attempt to translate the general knowledge gained from a large number of related literature into a set of medicinal chemistry strategies to improve the drug resistance profile of NNRTIs. PMID:19747133

  11. 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

  12. Getting personal perspectives on individualized treatment duration in multidrug-resistant and extensively drug-resistant tuberculosis.

    PubMed

    Heyckendorf, Jan; Olaru, Ioana D; Ruhwald, Morten; Lange, Christoph

    2014-08-15

    Tuberculosis (TB) differs from most other bacterial infectious diseases by a very long duration of combination antibiotic therapy required to achieve relapse-free cure. Although the standard recommended "short-course" treatment length for TB is 6 months, the World Health Organization recommends a duration of 20 months for the treatment of patients with multidrug-resistant and extensively drug-resistant TB (M/XDR-TB). Apart from the long duration of anti-TB therapy, treatment of M/XDR-TB is very expensive and often associated with adverse drug events. The optimal duration for treatment of TB likely differs between individuals and depends on a variety of variables, such as the extent of the disease, the immune status of the host, and the virulence and the drug resistance of the causative strain of Mycobacterium tuberculosis. Some patients with M/XDR-TB may have to be treated with currently available antituberculosis drug regimens for more than 20 months, whereas much shorter treatment durations may be possible to achieve cure for the majority of patients with M/XDR-TB. Personalization of the duration of treatment for TB, especially for patients with M/XDR-TB, would be highly desired. Until recently there has been little interest in the identification of biosignatures that could eventually lead to individual recommendations for the duration of anti-TB therapy. This pulmonary perspective reviews the knowledge on clinical and radiological scores, host- and pathogen disease-related profiles, molecules, and signatures that are currently explored as biomarkers to personalize the duration of therapy in TB. PMID:24941306

  13. Antibiotic-resistant gram-negative bacterial infections in patients with cancer.

    PubMed

    Perez, Federico; Adachi, Javier; Bonomo, Robert A

    2014-11-15

    Patients with cancer are at high risk for infections caused by antibiotic resistant gram-negative bacteria. In this review, we summarize trends among the major pathogens and clinical syndromes associated with antibiotic resistant gram-negative bacterial infection in patients with malignancy, with special attention to carbapenem and expanded-spectrum β-lactam resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia--all major threats to our cancer patients. Optimal therapy for these antibiotic-resistant pathogens still remains to be determined. PMID:25352627

  14. Antibiotic-Resistant Gram-Negative Bacterial Infections in Patients With Cancer

    PubMed Central

    Perez, Federico; Adachi, Javier; Bonomo, Robert A.

    2014-01-01

    Patients with cancer are at high risk for infections caused by antibiotic resistant gram-negative bacteria. In this review, we summarize trends among the major pathogens and clinical syndromes associated with antibiotic resistant gram-negative bacterial infection in patients with malignancy, with special attention to carbapenem and expanded-spectrum β-lactam resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia—all major threats to our cancer patients. Optimal therapy for these antibiotic-resistant pathogens still remains to be determined. PMID:25352627

  15. Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?

    PubMed Central

    Beceiro, Alejandro; Tomás, María

    2013-01-01

    SUMMARY Hosts and bacteria have coevolved over millions of years, during which pathogenic bacteria have modified their virulence mechanisms to adapt to host defense systems. Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. However, although antimicrobial resistance and bacterial virulence have developed on different timescales, they share some common characteristics. This review considers how bacterial virulence and fitness are affected by antibiotic resistance and also how the relationship between virulence and resistance is affected by different genetic mechanisms (e.g., coselection and compensatory mutations) and by the most prevalent global responses. The interplay between these factors and the associated biological costs depend on four main factors: the bacterial species involved, virulence and resistance mechanisms, the ecological niche, and the host. The development of new strategies involving new antimicrobials or nonantimicrobial compounds and of novel diagnostic methods that focus on high-risk clones and rapid tests to detect virulence markers may help to resolve the increasing problem of the association between virulence and resistance, which is becoming more beneficial for pathogenic bacteria. PMID:23554414

  16. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors.

    PubMed

    Zhang, Gao; Frederick, Dennie T; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Ope, Omotayo; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C; Schuchter, Lynn M; Gangadhar, Tara C; Amaravadi, Ravi K; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Liu, Qin; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A; Wargo, Jennifer A; Avadhani, Narayan G; Lu, Yiling; Mills, Gordon B; Altieri, Dario C; Flaherty, Keith T; Herlyn, Meenhard

    2016-05-01

    Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. PMID:27043285

  17. Microparticle drug sequestration provides a parallel pathway in the acquisition of cancer drug resistance.

    PubMed

    Gong, Joyce; Luk, Frederick; Jaiswal, Ritu; George, Anthony M; Grau, Georges Emile Raymond; Bebawy, Mary

    2013-12-01

    Expanding on our previous findings demonstrating that microparticles (MPs) spread cancer multidrug resistance, we now show that MPs sequester drugs, reducing the free drug concentration available to cells. MPs were isolated from drug-sensitive and drug-resistant sub-clones of a human breast adenocarcinoma cell line and from human acute lymphoblastic leukemia cells. MPs were assessed for size, mitochondria, RNA and phospholipid content, P-glycoprotein (P-gp) expression and orientation and ATPase activity relative to drug sequestration capacity. Of the drug classes examined, MPs sequestered the anthracycline class to a significant degree. The degree of sequestration was likely due to the size of MPs and thus the amount of cargo they contain, to which the anthracyclines bind. Moreover, a proportion of the P-gp present on MPs was inside-out in orientation, enabling it to influx drugs rather than its typical efflux function. This was confirmed by surface immunofluorescence and by assessment of drug-stimulated ATPase activity following MP permeabilization. Thus we determined that breast cancer MPs carried a proportion of their P-gp oriented inside-out, providing active sequestration within the microvesicular compartment. These results demonstrate a capacity for MPs to sequester chemotherapeutic drugs, which has a predominantly active sequestration component for MPs derived from drug-resistant cells and a predominantly passive component for MPs derived from drug-sensitive cells. This reduction in available drug concentration has potential to contribute to a parallel pathway and complements that of the intercellular transfer of P-gp. These findings lend further support to the role of MPs in limiting the successful management of cancer. PMID:24095666

  18. Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

    PubMed Central

    Upcroft, Peter; Upcroft, Jacqueline A.

    2001-01-01

    The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance. PMID:11148007

  19. Examination of Bacterial Resistance to Exogenous Nitric Oxide

    PubMed Central

    Privett, Benjamin J.; Broadnax, Angela D.; Bauman, Susanne J.; Riccio, Daniel A.; Schoenfisch, Mark H.

    2012-01-01

    While much research has been directed to harnessing the antimicrobial properties of exogenous NO, the possibility of bacteria developing resistance to such therapy has not been thoroughly studied. Herein, we evaluate potential NO resistance using spontaneous and serial passage mutagenesis assays. Specifically, Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa were systematically exposed to NO-releasing 75mol% MPTMS-TEOS nitrosothiol particles at or below minimum inhibitory concentration (MIC) levels. In the spontaneous mutagenesis assay, bacteria that survived exposure to lethal concentrations of NO showed no increase in MIC. Similarly, no increase in MIC was observed in the serial passage mutagenesis assay after exposure of these species to sub-inhibitory concentrations of NO through 20 d. PMID:22349019

  20. Interferon in resistance to bacterial and protozoan infections

    NASA Technical Reports Server (NTRS)

    Sonnenfeld, Gerald; Gould, Cheryl L.; Kierszenbaum, Felipe; Degee, Antonie L. W.; Mansfield, John M.

    1986-01-01

    The effects of genetic differences in mouse strains on the modulation of protozoan infections by interferon (IFN) were investigated. In one set of experiments, three different strains of mice were injected with T. cruzi, and their sera were assayed at five time intervals for IFN titer. A greater quantity of IFN was produced by mouse strains that were susceptible to T. cruzi infection than by the more resistant strain. In another set of experiments, spleen cell cultures from inbred strains of mice were challenged with an antigen made from T.b. rhodesiense. The cells from mice resistant to infection, produced greater amounts of IFN-gamma than did cells from the susceptible mice. In a third set of experiments, it was found that mice injected with T.b. rhodesiense before being infected with a diabetogenic virus (EMC-D) were resistant to the effects of the virus and did not produce virus-specific antibody.

  1. PREVALENCE OF MULTI-DRUG RESISTANT SALMONELLA IN DAIRY CATTLE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To determine the prevalence of multi-drug resistant (MDR) Salmonella in dairy cattle and which groups of cattle may be more likely to harbor MDR Salmonella, we sampled animals on four commercial dairy farms that all utilized a central calf/heifer raising facility. Fecal samples were obtained from h...

  2. Induced Bacterial Cross-Resistance toward Host Antimicrobial Peptides: A Worrying Phenomenon

    PubMed Central

    Fleitas, Osmel; Franco, Octávio L.

    2016-01-01

    Bacterial resistance to conventional antibiotics has reached alarming levels, threatening to return to the pre-antibiotic era. Therefore, the search for new antimicrobial compounds that overcome the resistance phenomenon has become a priority. Antimicrobial peptides (AMPs) appear as one of the most promising antibiotic medicines. However, in recent years several AMP-resistance mechanisms have been described. Moreover, the AMP-resistance phenomenon has become more complex due to its association with cross-resistance toward AMP effectors of the host innate immune system. In this context, the use of AMPs as a therapeutic option could be potentially hazardous, since bacteria could develop resistance toward our innate immune system. Here, we review the findings of major studies that deal with the AMP cross-resistance phenomenon. PMID:27047486

  3. Antibiotic Resistant Bacterial Profiles of Anaerobic Swine Lagoon Effluent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although land application of swine manure lagoon effluent is a common and effective method of disposal, the presence of antibiotic-resistant bacteria, both pathogenic and commensal can complicate already understood issues associated with its safe disposal. The aim of this study was to assess antibi...

  4. Antibiotic resistant bacterial profiles of anaerobic swine lagoon effluent

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Although land application of swine manure lagoon effluent is a common and effective method of disposal, the presence of antibiotic-resistant bacteria, both pathogenic and commensal can complicate already understood issues associated with its safe disposal. To better understand this, more data is ne...

  5. Modeling mass drug treatment and resistant filaria disease transmission

    NASA Astrophysics Data System (ADS)

    Fuady, A. M.; Nuraini, N.; Soewono, E.; Tasman, H.; Supriatna, A. K.

    2014-03-01

    It has been indicated that a long term application of combined mass drug treatment may contribute to the development of drug resistance in lymphatic filariasis. This phenomenon is not well understood due to the complexity of filaria life cycle. In this paper we formulate a mathematical model for the spread of mass drug resistant in a filaria endemic region. The model is represented in a 13-dimensional Host-Vector system. The basic reproductive ratio of the system which is obtained from the next generation matrix, and analysis of stability of both the disease free equilibrium and the coexistence equilibria are shown. Numerical simulation for long term dynamics for possible field conditions is also shown.

  6. 2014 Update of the drug resistance mutations in HIV-1.

    PubMed

    Wensing, Annemarie M; Calvez, Vincent; Günthard, Huldrych F; Johnson, Victoria A; Paredes, Roger; Pillay, Deenan; Shafer, Robert W; Richman, Douglas D

    2014-01-01

    This July 2014 edition of the IAS-USA drug resistance mutations list updates the figures last published in March 2013. The following mutations have been added to existing classes or drugs: K65E/N has been added to the bars for the nucleoside and nucleotide analogue reverse transcriptase inhibitors (nRTIs) abacavir, didanosine, emtricitabine, lamivudine, stavudine, and tenofovir; L100I has been added to the bar for the nonnucleoside analogue reverse transcriptase inhibitor (NNRTI) rilpivirine; and F121Y has been added to the bars for the integrase strand transfer inhibitors (InSTIs) dolutegravir, elvitegravir, and raltegravir. With regard to protease inhibitors (PIs), it cannot be excluded that drug resistance may be selected for outside the protease encoding region. PMID:25101529

  7. Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

    PubMed Central

    Yang, Wen-Chi; Lin, Sheng-Fung

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID:26649299

  8. Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis

    PubMed Central

    Rodrigues, Liliana; Villellas, Cristina; Bailo, Rebeca; Viveiros, Miguel

    2013-01-01

    Efflux pumps are membrane proteins capable of actively transporting a broad range of substrates from the cytoplasm to the exterior of the cell. Increased efflux activity in response to drug treatment may be the first step in the development of bacterial drug resistance. Previous studies showed that the efflux pump Mmr was significantly overexpressed in strains exposed to isoniazid. In the work to be described, we constructed mutants lacking or overexpressing Mmr in order to clarify the role of this efflux pump in the development of resistance to isoniazid and other drugs in M. tuberculosis. The mmr knockout mutant showed an increased susceptibility to ethidium bromide, tetraphenylphosphonium, and cetyltrimethylammonium bromide (CTAB). Overexpression of mmr caused a decreased susceptibility to ethidium bromide, acriflavine, and safranin O that was obliterated in the presence of the efflux inhibitors verapamil and carbonyl cyanide m-chlorophenylhydrazone. Isoniazid susceptibility was not affected by the absence or overexpression of mmr. The fluorometric method allowed the detection of a decreased efflux of ethidium bromide in the knockout mutant, whereas the overexpressed strain showed increased efflux of this dye. This increased efflux activity was inhibited in the presence of efflux inhibitors. Under our experimental conditions, we have found that efflux pump Mmr is mainly involved in the susceptibility to quaternary compounds such as ethidium bromide and disinfectants such as CTAB. The contribution of this efflux pump to isoniazid resistance in Mycobacterium tuberculosis still needs to be further elucidated. PMID:23165464

  9. Quantitative Trait Loci Mapping for Bacterial Blight Resistance in Rice Using Bulked Segregant Analysis

    PubMed Central

    Han, Xueying; Yang, Yong; Wang, Xuming; Zhou, Jie; Zhang, Wenhao; Yu, Chulang; Cheng, Chen; Cheng, Ye; Yan, Chengqi; Chen, Jianping

    2014-01-01

    Oryza meyeriana is highly resistant to rice bacterial blight (BB) and this resistance trait has been transferred to cultivated rice (O. sativa) using asymmetric somatic hybridization. However, no resistance genes have yet been cloned. In the present study, a progeny of the somatic hybridization with high BB resistance was crossed with a rice cultivar with high BB susceptibility to develop an F2 population. Using bulked segregant analysis (BSA), 17 polymorphic markers that were linked to rice BB resistance were obtained through scanning a total of 186 simple sequence repeats (SSR) and sequence-tagged site (STS) markers, evenly distributed on 12 chromosomes. A genetic linkage map was then constructed based on the 17 linkage markers and the F2 segregating population, which was followed by mapping for quantitative trait loci (QTLs) for BB resistance. Three QTLs were identified on chromosomes 1, 3 and 5, respectively, and the alleles of the resistant parent at any of the QTLs increased BB resistance. All of the three QTLs had a strong effect on resistance, explaining about 21.5%, 12.3% and 39.2% of the resistance variance, respectively. These QTLs were different from the loci of the BB resistance genes that have been identified in previous studies. The QTLs mapped in this work will facilitate the isolation of novel BB resistance genes and their utilization in rice resistance breeding. PMID:24995697

  10. Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors

    NASA Astrophysics Data System (ADS)

    Longo, G.; Alonso-Sarduy, L.; Rio, L. Marques; Bizzini, A.; Trampuz, A.; Notz, J.; Dietler, G.; Kasas, S.

    2013-07-01

    The widespread misuse of drugs has increased the number of multiresistant bacteria, and this means that tools that can rapidly detect and characterize bacterial response to antibiotics are much needed in the management of infections. Various techniques, such as the resazurin-reduction assays, the mycobacterial growth indicator tube or polymerase chain reaction-based methods, have been used to investigate bacterial metabolism and its response to drugs. However, many are relatively expensive or unable to distinguish between living and dead bacteria. Here we show that the fluctuations of highly sensitive atomic force microscope cantilevers can be used to detect low concentrations of bacteria, characterize their metabolism and quantitatively screen (within minutes) their response to antibiotics. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing that live bacteria produced larger cantilever fluctuations than bacteria exposed to antibiotics. Our preliminary experiments suggest that the fluctuation is associated with bacterial metabolism.

  11. Insights into the amplification of bacterial resistance to erythromycin in activated sludge.

    PubMed

    Guo, Mei-Ting; Yuan, Qing-Bin; Yang, Jian

    2015-10-01

    Wastewater treatment plants are significant reservoirs for antimicrobial resistance. However, little is known about wastewater treatment effects on the variation of antibiotic resistance. The shifts of bacterial resistance to erythromycin, a macrolide widely used in human medicine, on a lab-scale activated sludge system fed with real wastewater was investigated from levels of bacteria, community and genes, in this study. The resistance variation of total heterotrophic bacteria was studied during the biological treatment process, based on culture dependent method. The alterations of bacterial community resistant to erythromycin and nine typical erythromycin resistance genes were explored with molecular approaches, including high-throughput sequencing and quantitative polymerase chain reaction. The results revealed that the total heterotrophs tolerance level to erythromycin concentrations (higher than 32 mg/L) was significantly amplified during the activated sludge treatment, with the prevalence increased from 9.6% to 21.8%. High-throughput sequencing results demonstrated an obvious increase of the total heterotrophic bacterial diversity resistant to erythromycin. Proteobacteria and Bacteroidetes were the two dominant phyla in the influent and effluent of the bioreactor. However, the prevalence of Proteobacteria decreased from 76% to 59% while the total phyla number increased greatly from 18 to 29 through activated sludge treatment. The gene proportions of erm(A), mef(E) and erm(D) were greatly amplified after biological treatment. It is proposed that the transfer of antibiotic resistance genes through the variable mixtures of bacteria in the activated sludge might be the reason for the antibiotic resistance amplification. The amplified risk of antibiotic resistance in wastewater treatment needs to be paid more attention. PMID:25957255

  12. Nanomechanical detection of antibiotic-mucopeptide binding in a model for superbug drug resistance

    NASA Astrophysics Data System (ADS)

    Ndieyira, Joseph Wafula; Watari, Moyu; Barrera, Alejandra Donoso; Zhou, Dejian; Vögtli, Manuel; Batchelor, Matthew; Cooper, Matthew A.; Strunz, Torsten; Horton, Mike A.; Abell, Chris; Rayment, Trevor; Aeppli, Gabriel; McKendry, Rachel A.

    2008-11-01

    The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements have quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions activated by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also have an impact on our understanding of antibiotic drug action in bacteria.

  13. Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis

    PubMed Central

    Yu, Linda Chia-Hui; Shih, Yi-An; Wu, Li-Ling; Lin, Yang-Ding; Kuo, Wei-Ting; Peng, Wei-Hao; Lu, Kuo-Shyan; Wei, Shu-Chen; Turner, Jerrold R.

    2014-01-01

    Antibiotic usage promotes intestinal colonization of antibiotic-resistant bacteria. However, whether resistant bacteria gain dominance in enteric microflora or disseminate to extraintestinal viscera remains unclear. Our aim was to investigate temporal diversity changes in microbiota and transepithelial routes of bacterial translocation after antibiotic-resistant enterobacterial colonization. Mice drinking water with or without antibiotics were intragastrically gavaged with ampicillin-resistant (Amp-r) nonpathogenic Escherichia coli (E. coli) and given normal water afterward. The composition and spatial distribution of intestinal bacteria were evaluated using 16S rDNA sequencing and fluorescence in situ hybridization. Bacterial endocytosis in epithelial cells was examined using gentamicin resistance assay and transmission electromicroscopy. Paracellular permeability was assessed by tight junctional immunostaining and measured by tissue conductance and luminal-to-serosal dextran fluxes. Our results showed that antibiotic treatment enabled intestinal colonization and transient dominance of orally acquired Amp-r E. coli in mice. The colonized Amp-r E. coli peaked on day 3 postinoculation and was competed out after 1 wk, as evidenced by the recovery of commensals, such as Escherichia, Bacteroides, Lachnospiraceae, Clostridium, and Lactobacillus. Mucosal penetration and extraintestinal dissemination of exogenous and endogenous enterobacteria were correlated with abnormal epithelial transcytosis but uncoupled with paracellular tight junctional damage. In conclusion, antibiotic-induced enteric dysbiosis predisposes to exogenous infection and causes systemic dissemination of both antibiotic-resistant and commensal enterobacteria through transcytotic routes across epithelial layers. These results may help explain the susceptibility to sepsis in antibiotic-resistant enteric bacterial infection. PMID:25059827

  14. Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis.

    PubMed

    Yu, Linda Chia-Hui; Shih, Yi-An; Wu, Li-Ling; Lin, Yang-Ding; Kuo, Wei-Ting; Peng, Wei-Hao; Lu, Kuo-Shyan; Wei, Shu-Chen; Turner, Jerrold R; Ni, Yen-Hsuan

    2014-10-15

    Antibiotic usage promotes intestinal colonization of antibiotic-resistant bacteria. However, whether resistant bacteria gain dominance in enteric microflora or disseminate to extraintestinal viscera remains unclear. Our aim was to investigate temporal diversity changes in microbiota and transepithelial routes of bacterial translocation after antibiotic-resistant enterobacterial colonization. Mice drinking water with or without antibiotics were intragastrically gavaged with ampicillin-resistant (Amp-r) nonpathogenic Escherichia coli (E. coli) and given normal water afterward. The composition and spatial distribution of intestinal bacteria were evaluated using 16S rDNA sequencing and fluorescence in situ hybridization. Bacterial endocytosis in epithelial cells was examined using gentamicin resistance assay and transmission electromicroscopy. Paracellular permeability was assessed by tight junctional immunostaining and measured by tissue conductance and luminal-to-serosal dextran fluxes. Our results showed that antibiotic treatment enabled intestinal colonization and transient dominance of orally acquired Amp-r E. coli in mice. The colonized Amp-r E. coli peaked on day 3 postinoculation and was competed out after 1 wk, as evidenced by the recovery of commensals, such as Escherichia, Bacteroides, Lachnospiraceae, Clostridium, and Lactobacillus. Mucosal penetration and extraintestinal dissemination of exogenous and endogenous enterobacteria were correlated with abnormal epithelial transcytosis but uncoupled with paracellular tight junctional damage. In conclusion, antibiotic-induced enteric dysbiosis predisposes to exogenous infection and causes systemic dissemination of both antibiotic-resistant and commensal enterobacteria through transcytotic routes across epithelial layers. These results may help explain the susceptibility to sepsis in antibiotic-resistant enteric bacterial infection. PMID:25059827

  15. Resistance of Aerosolized Bacterial Viruses to Relative Humidity and Temperature

    PubMed Central

    Verreault, Daniel; Marcoux-Voiselle, Mélissa; Turgeon, Nathalie; Moineau, Sylvain

    2015-01-01

    The use of aerosolized bacteriophages as surrogates for hazardous viruses might simplify and accelerate the discovery of links between viral components and their persistence in the airborne state under diverse environmental conditions. In this study, four structurally distinct lytic phages, MS2 (single-stranded RNA [ssRNA]), ϕ6 (double-stranded RNA [dsRNA]), ϕX174 (single-stranded DNA [ssDNA]), and PR772 (double-stranded DNA [dsDNA]), were nebulized into a rotating chamber and exposed to various levels of relative humidity (RH) and temperature as well as to germicidal UV radiation. The aerosolized viral particles were allowed to remain airborne for up to 14 h before being sampled for analysis by plaque assays and quantitative PCRs. Phages ϕ6 and MS2 were the most resistant at low levels of relative humidity, while ϕX174 was more resistant at 80% RH. Phage ϕ6 lost its infectivity immediately after exposure to 30°C and 80% RH. The infectivity of all tested phages rapidly declined as a function of the exposure time to UVC radiation, phage MS2 being the most resistant. Taken altogether, our data indicate that these aerosolized phages behave differently under various environmental conditions and highlight the necessity of carefully selecting viral simulants in bioaerosol studies. PMID:26253683

  16. Resistance of Aerosolized Bacterial Viruses to Relative Humidity and Temperature.

    PubMed

    Verreault, Daniel; Marcoux-Voiselle, Mlissa; Turgeon, Nathalie; Moineau, Sylvain; Duchaine, Caroline

    2015-10-01

    The use of aerosolized bacteriophages as surrogates for hazardous viruses might simplify and accelerate the discovery of links between viral components and their persistence in the airborne state under diverse environmental conditions. In this study, four structurally distinct lytic phages, MS2 (single-stranded RNA [ssRNA]), ?6 (double-stranded RNA [dsRNA]), ?X174 (single-stranded DNA [ssDNA]), and PR772 (double-stranded DNA [dsDNA]), were nebulized into a rotating chamber and exposed to various levels of relative humidity (RH) and temperature as well as to germicidal UV radiation. The aerosolized viral particles were allowed to remain airborne for up to 14 h before being sampled for analysis by plaque assays and quantitative PCRs. Phages ?6 and MS2 were the most resistant at low levels of relative humidity, while ?X174 was more resistant at 80% RH. Phage ?6 lost its infectivity immediately after exposure to 30C and 80% RH. The infectivity of all tested phages rapidly declined as a function of the exposure time to UVC radiation, phage MS2 being the most resistant. Taken altogether, our data indicate that these aerosolized phages behave differently under various environmental conditions and highlight the necessity of carefully selecting viral simulants in bioaerosol studies. PMID:26253683

  17. Multidrug-Resistant Bacterial Donor-Derived Infections in Solid Organ Transplantation.

    PubMed

    Lewis, Jessica D; Sifri, Costi D

    2016-06-01

    Although rare, donor-derived infections (DDIs) caused by multidrug-resistant (MDR) bacteria can have devastating consequences for organ transplant recipients. Recognition of MDR bacterial DDIs can be challenging, as MDR bacteria are prevalent in most hospitals and distinguishing their transmission through transplantation from other, more typical routes of acquisition are difficult. New technologies such as whole genome sequencing have recently proven to be a powerful advance in the investigation of MDR bacterial DDIs. Once recognized, the optimal treatment of MDR bacterial DDIs is not clear. Herein, we review the clinical manifestations, outcomes, and management of MDR bacterial DDIs, and identify areas of uncertainty toward which the transplant community should direct further research efforts. PMID:27115701

  18. Response to selection for bacterial cold water disease resistance in rainbow trout

    Technology Transfer Automated Retrieval System (TEKTRAN)

    A family-based selection program was initiated at the National Center for Cool and Cold Water Aquaculture in 2005 to improve resistance to bacterial cold water disease (BCWD) in rainbow trout. The objective of this study was to estimate response to 2 generations of selection. A total of 14,841 juven...

  19. 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...

  20. RELEASE OF COMMON BACTERIAL BLIGHT RESISTANT WHITE KIDNEY BEAN GERMPLASM LINE USWK-CBB-17

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The Agricultural Research Service, U.S. Department of Agriculture, and the Idaho Agricultural Experiment Station announce the release of USWK-CBB-17 white kidney (Phaseolus vulgaris L.) germplasm line with a high level of resistance to common bacterial blight caused by Xanthomonas axonopodis pv. ph...

  1. Development of candidate gene markers associated to common bacterial blight resistance in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common bacterial blight (CBB), caused by Xanthomonas axonopodis pv. phaseoli (Xap), is a major yield-limiting factor of common bean (Phaseolus vulgaris L.) production around the world. Two major CBB-resistant quantitative trait loci (QTL), linked to the sequence characterized amplified region marker...

  2. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis

    NASA Astrophysics Data System (ADS)

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-01

    Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr00290g

  3. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    PubMed

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria. PMID:25898991

  4. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter

    PubMed Central

    Petersen, Ines; Gabryszewski, Stanislaw J.; Johnston, Geoffrey L.; Dhingra, Satish K.; Ecker, Andrea; Lewis, Rebecca E.; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp H.; Palatulan, Eugene; Johnson, David J.; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M.; Lanzer, Michael; Fidock, David A.

    2015-01-01

    Summary The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria. PMID:25898991

  5. Extended spectrum â-lactamase producing multidrug resistant clinical bacterial isolates at National Public Health Laboratory, Nepal.

    PubMed

    Poudyal, S; Bhatta, D R; Shakya, G; Upadhyaya, B; Dumre, S P; Buda, G; Kandel, B P

    2011-03-01

    Extended Spectrum â-lactamase (ESBL) producing multidrug resistant bacteria complicate therapeutic management and limit treatment options. Therefore, detection of ESBL-producing multidrug resistant (MDR) pathogens has a paramount importance. Between April 2009 and January 2010, a prospective study was carried out in National Public Health Laboratory with an objective to determine the status of ESBL producing MDR bacterial isolates from different clinical samples. Identification of the isolates was done by standard microbiological techniques and antibiotic susceptibility testing was done by Kirby Bauer disc diffusion method following Clinical and Laboratory Standard Institute (CLSI) guidelines. ESBL screening among MDR isolates was done using Ceftriaxone, Aztreonam, Cefotaxime, Ceftazidime and Cefpodoxime followed by confirmation using MASTDISCS ID ES2L Detection Discs (CPD10). Data analysis was done by SPSS 16 software. Of the 314 bacterial isolates from 1601 different clinical specimens, 199 (63.4%) were MDR. Cefotaxime was found the reliable screening agent for ESBL detection with sensitivity and positive predictive value of 98.6% and 76.4% respectively. Sixtey nine (62.7%) isolates of the 110 tested MDR isolates were ESBL positive with at least one of the Combined Disk (CD) Assays. Escherichia coli (80%) was the major ESBL producer followed by Klebsiella pneumoniae (5.8%). A statistically significant relationship was found between increasing spectrum of drug resistance and ESBL production (p<0.05). Thus it is concluded that a higher rate of ESBL production prevail among MDR clinical bacterial isolates underscoring the need for routine ESBL detection in clinical laboratories. PMID:21991699

  6. Epidemiology of emerging/re-emerging antimicrobial-resistant bacterial pathogens.

    PubMed

    McCormick, J B

    1998-02-01

    The rapid global expansion of bacteria resistant to antimicrobials is the most important development over the past year in emerging bacterial diseases. The critical events are the emergence of Staphylococcus aureus with decreased sensitivity to vancomycin, worldwide resistance to penicillin in Streptococcus pneumoniae, and the remorseless progression of multiply-resistant Mycobacterium tuberculosis. Most startling was the isolation from a human in Madagascar of a plague bacillus possessing a plasmid readily transferable to Escherichia coli, which confers multiple antibiotic resistance. The hospital environment continues to see the transmission of resistant organisms, notably vancomycin-resistant enterococci. Finally, as food markets become more open around the world, food-borne outbreaks of E. coli O157 and cholera demonstrate how difficult it can be to establish effective health and safety barriers. PMID:10066471

  7. Recommendations for treating children with drug-resistant tuberculosis.

    PubMed

    Galli, Luisa; Lancella, Laura; Garazzino, Silvia; Tadolini, Marina; Matteelli, Alberto; Migliori, Giovanni Battista; Principi, Nicola; Villani, Alberto; Esposito, Susanna

    2016-03-01

    Tuberculosis (TB) is still one of the most difficult infectious diseases to treat, and the second most frequent cause of death due to infectious disease throughout the world. The number of cases of multidrug-resistant (MDR-TB) and extensively drug-resistant TB (XDR-TB), which are characterised by high mortality rates, is increasing. The therapeutic management of children with MDR- and XDR-TB is complicated by a lack of knowledge, and the fact that many potentially useful drugs are not registered for pediatric use and there are no formulations suitable for children in the first years of life. Furthermore, most of the available drugs are burdened by major adverse events that need to be taken into account, particularly in the case of prolonged therapy. This document describes the recommendations of a group of scientific societies on the therapeutic approach to pediatric MDR- and XDR-TB. On the basis of a systematic literature review and their personal clinical experience, the experts recommend that children with active TB caused by a drug-resistant strain of Mycobacterium tuberculosis should always be referred to a specialised centre because of the complexity of patient management, the paucity of pediatric data, and the high incidence of adverse events due to second-line anti-TB treatment. PMID:26821118

  8. Genetic Variability of HIV-1 for Drug Resistance Assay Development.

    PubMed

    Clutter, Dana S; Sánchez, Patricia Rojas; Rhee, Soo-Yon; Shafer, Robert W

    2016-01-01

    A hybridization-based point-of-care (POC) assay for HIV-1 drug resistance would be useful in low- and middle-income countries (LMICs) where resistance testing is not routinely available. The major obstacle in developing such an assay is the extreme genetic variability of HIV-1. We analyzed 27,203 reverse transcriptase (RT) sequences from the Stanford HIV Drug Resistance Database originating from six LMIC regions. We characterized the variability in a 27-nucleotide window surrounding six clinically important drug resistance mutations (DRMs) at positions 65, 103, 106, 181, 184, and 190. The number of distinct codons at each DRM position ranged from four at position 184 to 11 at position 190. Depending on the mutation, between 11 and 15 of the 24 flanking nucleotide positions were variable. Nonetheless, most flanking sequences differed from a core set of 10 flanking sequences by just one or two nucleotides. Flanking sequence variability was also lower in each LMIC region compared with overall variability in all regions. We also describe an online program that we developed to perform similar analyses for mutations at any position in RT, protease, or integrase. PMID:26875985

  9. HIV Drug-Resistant Patient Information Management, Analysis, and Interpretation

    PubMed Central

    Mars, Maurice

    2012-01-01

    Introduction The science of information systems, management, and interpretation plays an important part in the continuity of care of patients. This is becoming more evident in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the leading cause of death in sub-Saharan Africa. The high replication rates, selective pressure, and initial infection by resistant strains of HIV infer that drug resistance will inevitably become an important health care concern. This paper describes proposed research with the aim of developing a physician-administered, artificial intelligence-based decision support system tool to facilitate the management of patients on antiretroviral therapy. Methods This tool will consist of (1) an artificial intelligence computer program that will determine HIV drug resistance information from genomic analysis; (2) a machine-learning algorithm that can predict future CD4 count information given a genomic sequence; and (3) the integration of these tools into an electronic medical record for storage and management. Conclusion The aim of the project is to create an electronic tool that assists clinicians in managing and interpreting patient information in order to determine the optimal therapy for drug-resistant HIV patients. PMID:23611761

  10. Application of Metabolomics in Drug Resistant Breast Cancer Research

    PubMed Central

    Shajahan-Haq, Ayesha N.; Cheema, Mehar S.; Clarke, Robert

    2015-01-01

    The metabolic profiles of breast cancer cells are different from normal mammary epithelial cells. Breast cancer cells that gain resistance to therapeutic interventions can reprogram their endogenous metabolism in order to adapt and proliferate despite high oxidative stress and hypoxic conditions. Drug resistance in breast cancer, regardless of subgroups, is a major clinical setback. Although recent advances in genomics and proteomics research has given us a glimpse into the heterogeneity that exists even within subgroups, the ability to precisely predict a tumor’s response to therapy remains elusive. Metabolomics as a quantitative, high through put technology offers promise towards devising new strategies to establish predictive, diagnostic and prognostic markers of breast cancer. Along with other “omics” technologies that include genomics, transcriptomics, and proteomics, metabolomics fits into the puzzle of a comprehensive systems biology approach to understand drug resistance in breast cancer. In this review, we highlight the challenges facing successful therapeutic treatment of breast cancer and the innovative approaches that metabolomics offers to better understand drug resistance in cancer. PMID:25693144

  11. Genetic Variability of HIV-1 for Drug Resistance Assay Development

    PubMed Central

    Clutter, Dana S.; Sánchez, Patricia Rojas; Rhee, Soo-Yon; Shafer, Robert W.

    2016-01-01

    A hybridization-based point-of-care (POC) assay for HIV-1 drug resistance would be useful in low- and middle-income countries (LMICs) where resistance testing is not routinely available. The major obstacle in developing such an assay is the extreme genetic variability of HIV-1. We analyzed 27,203 reverse transcriptase (RT) sequences from the Stanford HIV Drug Resistance Database originating from six LMIC regions. We characterized the variability in a 27-nucleotide window surrounding six clinically important drug resistance mutations (DRMs) at positions 65, 103, 106, 181, 184, and 190. The number of distinct codons at each DRM position ranged from four at position 184 to 11 at position 190. Depending on the mutation, between 11 and 15 of the 24 flanking nucleotide positions were variable. Nonetheless, most flanking sequences differed from a core set of 10 flanking sequences by just one or two nucleotides. Flanking sequence variability was also lower in each LMIC region compared with overall variability in all regions. We also describe an online program that we developed to perform similar analyses for mutations at any position in RT, protease, or integrase. PMID:26875985

  12. Antimalarial drug resistance in Bangladesh, 1996-2012.

    PubMed

    Haque, Ubydul; Glass, Gregory E; Haque, Waziul; Islam, Nazrul; Roy, Shyamal; Karim, Jahirul; Noedl, Harald

    2013-12-01

    Malaria remains an important health problem in Bangladesh, with approximately 14 million people at risk. Antimalarial drug resistance is a major obstacle to the control of malaria in endemic countries. In 2012, Bangladesh reported an estimated 29 522 malaria episodes, of which 94% were reported as being caused by Plasmodium falciparum. In this study, we reviewed and summarized antimalarial drug resistance data from Bangladesh published until June 2013. We searched published sources for data referring to any type of P. falciparum drug resistance (in vivo, in vitro, or molecular) and found 169 articles published in peer-reviewed journals. Of these, 143 articles were excluded because they did not meet our inclusion criteria. After detailed review of the remaining 26 articles, 14 were selected for evaluation. Published studies indicate that P. falciparum shows varying levels of resistance to chloroquine, mefloquine and sulfadoxine-pyrimethamine. Combination therapy of chloroquine and primaquine has proven ineffective and combinations of sulfadoxine-pyrimethamine with either quinine or chloroquine have also shown poor efficacy. Recent studies indicate that artemisinin derivatives, such as artesunate, remain highly efficacious in treating P. falciparum malaria. Available data suggest that artemisinins, quinine, doxycyline, mefloquine-artesunate and azithromycin-artesunate combination therapy remain efficacious in the treatment of P. falciparum malaria in Bangladesh. PMID:24127210

  13. Modeling HIV-1 Drug Resistance as Episodic Directional Selection

    PubMed Central

    Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L.; Scheffler, Konrad

    2012-01-01

    The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance. PMID:22589711

  14. Role of wild birds as carriers of multi-drug resistant Escherichia coli and Escherichia vulneris

    PubMed Central

    Shobrak, Mohammed Y.; Abo-Amer, Aly E.

    2014-01-01

    Emergence and distribution of multi-drug resistant (MDR) bacteria in environments pose a risk to human and animal health. A total of 82 isolates of Escherichia spp. were recovered from cloacal swabs of migrating and non-migrating wild birds. All bacterial isolates were identified and characterized morphologically and biochemically. 72% and 50% of isolates recovered from non-migrating and migrating birds, respectively, showed positive congo red dye binding (a virulence factor). Also, hemolysin production (a virulence factor) was showed in 8% of isolates recovered from non-migrating birds and 75% of isolates recovered from migrating birds. All isolates recovered from non-migrating birds were found resistant to Oxacillin while all isolates recovered from migrating birds demonstrated resistance to Oxacillin, Chloramphenicol, Oxytetracycline and Lincomycin. Some bacterial isolates recovered from non-migrating birds and migrating birds exhibited MDR phenotype. The MDR isolates were further characterized by API 20E and 16S rRNA as E. coli and E. vulneris. MDR Escherichia isolates contain ~1–5 plasmids of high-molecular weights. Accordingly, wild birds could create a potential threat to human and animal health by transmitting MDR bacteria to water streams and other environmental sources through their faecal residues, and to remote regions by migration. PMID:25763023

  15. Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment

    SciTech Connect

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E. )

    1990-09-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.

  16. Report: Bacterial susceptibility and resistance analysis of traumatic osteomyelitis.

    PubMed

    Geng, Xiaolin; Lu, Tan; Zhang, Jun; Zhou, Qinglan; Liang, Qiudong

    2016-01-01

    with the rapid development of industry, agriculture and transportation, the high energy trauma happened accordingly, thus greatly increased the incidence of traumatic osteomyelitis. The clinical traumatic osteomyelitis was mainly the local bone tissue inflammation caused by bacteria infection as trauma or iatrogenic causes. The delaying recovery could cause bone defection or bone nonunion. The purpose of this paper was to contribute new reference for the clinical prevention and treatment through tremendous of disease-causing bacteria susceptibility and resistance analysis of osteomyelitis. PMID:27005502

  17. Emergence and natural selection of drug-resistant prions

    PubMed Central

    2010-01-01

    Drug resistance is a refractory barrier in the battle against many fatal diseases caused by rapidly evolving agents, including HIV, apicomplexans and specific cancers. Emerging evidence suggests that drug resistance might extend to lethal prion disorders and related neurodegenerative amyloidoses. Prions are self-replicating protein conformers, usually ‘cross-β’ amyloid polymers, which are naturally transmitted between individuals and promote phenotypic change. Prion conformers are catalytic templates that specifically convert other copies of the same protein to the prion form. Once in motion, this chain reaction of conformational replication can deplete all non-prion copies of a protein. Typically, prions exist as ensembles of multiple structurally distinct, self-replicating forms or ‘strains’. Each strain confers a distinct phenotype and replicates at different rates depending on the environment. As replicators, prions are units of selection. Thus, natural selection inescapably enriches or depletes various prion strains from populations depending on their conformational fitness (ability to self-replicate) in the prevailing environment. The most successful prions confer advantages to their host as with numerous yeast prions. Here, I review recent evidence that drug-like small molecules can antagonize some prion strains but simultaneously select for drug-resistant prions composed of mammalian PrP or the yeast prion protein, Sup35. For Sup35, the drug-resistant strain configures original intermolecular amyloid contacts that are not ordinarily detected. Importantly, a synergistic small-molecule cocktail counters prion diversity by eliminating multiple Sup35 prion strains. Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude. PMID:20422111

  18. Bacterial resistance evolution by recruitment of super-integron gene cassettes.

    PubMed

    Rowe-Magnus, Dean A; Guerout, Anne-Marie; Mazel, Didier

    2002-03-01

    The capture and spread of antibiotic resistance determinants by integrons underlies the rapid evolution of multiple antibiotic resistance among diverse Gram-negative clinical isolates. The association of multiple resistance integrons (MRIs) with mobile DNA elements facilitates their transit across phylogenetic boundaries and augments the potential impact of integrons on bacterial evolution. Recently, ancestral chromosomal versions, the super-integrons (SIs), were found to be genuine components of the genomes of diverse bacterial species. SIs possess evolutionary characteristics and stockpiles of adaptive functions, including cassettes related to antibiotic resistance determinants previously characterized in clinical isolates, which suggest that MRIs and their resistance genes were originally recruited from SIs and their pool of amassed genes. However, the recombination activity of integrons has never been demonstrated in a bacterium other than Escherichia coli. We introduced a naturally occurring MRI (TpR, SulR) on a conjugative plasmid into Vibrio cholerae, a species known to harbour a SI. We show that MRIs can randomly recruit genes directly from the cache of SI cassettes. By applying a selective constraint for the development of antibiotic resistance, we demonstrate bacterial resistance evolution through the recruitment a novel, but phenotypically silent, chloramphenicol acetyltransferase gene from the V. cholerae SI and its precise insertion into the MRI. The resulting resistance profile (CmR, TpR, SulR) could then be disseminated by conjugation to other clinically relevant pathogens at high frequency. These results demonstrate that otherwise phenotypically sensitive strains may still be a genetic source for the evolution of resistance to clinically relevant antibiotics through integron-mediated recombination events. PMID:11952913

  19. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates

    PubMed Central

    Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

    2015-01-01

    The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate. PMID:26217333

  20. MRJP1-containing glycoproteins isolated from honey, a novel antibacterial drug candidate with broad spectrum activity against multi-drug resistant clinical isolates.

    PubMed

    Brudzynski, Katrina; Sjaarda, Calvin; Lannigan, Robert

    2015-01-01

    The emergence of extended- spectrum β-lactamase (ESBL) is the underlying cause of growing antibiotic resistance among Gram-negative bacteria to β-lactam antibiotics. We recently reported the discovery of honey glycoproteins (glps) that exhibited a rapid, concentration-dependent antibacterial activity against both Gram-positive Bacillus subtilis and Gram-negative Escherichia coli that resembled action of cell wall-active β-lactam drugs. Glps showed sequence identity with the Major Royal Jelly Protein 1 (MRJP1) precursor that harbors three antimicrobial peptides: Jelleins 1, 2, and 4. Here, we used semi-quantitative radial diffusion assay and broth microdilution assay to evaluate susceptibility of a number of multi-drug resistant (MDR) clinical isolates to the MRJP1-contaning honey glycoproteins. The MDR bacterial strains comprised three methicillin-resistant Staphylococcus aureus (MRSA), four Pseudomonas aeruginosa, two Klebsiella pneumoniae, two vancomycin-resistant Enterococci (VRE), and five ESBL identified as one Proteus mirabilis, three E. coli, and one E. coli NDM. Their resistance to different classes of antibiotics was confirmed using automated system Vitek 2. MDR isolates differed in their susceptibility to glps with MIC90 values ranging from 4.8 μg/ml against B. subtilis to 14.4 μg/ml against ESBL K. pneumoniae, Klebsiella spp. ESBL and E. coli and up to 33 μg/ml against highly resistant strains of P. aeruginosa. Glps isolated from different honeys showed a similar ability to overcome bacterial resistance to β-lactams suggesting that (a) their mode of action is distinct from other classes of β-lactams and that (b) the common glps structure was the lead structure responsible for the activity. The results of the current study together with our previous evidence of a rapid bactericidal activity of glps demonstrate that glps possess suitable characteristics to be considered a novel antibacterial drug candidate. PMID:26217333

  1. Insights into the mechanism of drug resistance. X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

    SciTech Connect

    Liu, Zhigang; Yedidi, Ravikiran S.; Wang, Yong; Dewdney, Tamaria G.; Reiter, Samuel J.; Brunzelle, Joseph S.; Kovari, Iulia A.; Kovari, Ladislau C.

    2013-01-08

    Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report the crystal structure of multi-drug resistant (MDR) 769 HIV-1 protease (carrying resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84 and 90) complexed with RTV and the in vitro enzymatic IC50 of RTV against MDR HIV-1 protease. The structural and functional studies demonstrate significant drug resistance of MDR HIV-1 protease against RTV, arising from reduced hydrogen bonds and Van der Waals interactions between RTV and MDR HIV-1 protease.

  2. Production of putrescine-capped stable silver nanoparticle: its characterization and antibacterial activity against multidrug-resistant bacterial strains

    NASA Astrophysics Data System (ADS)

    Saha, Saswati; Gupta, Bhaskar; Gupta, Kamala; Chaudhuri, Mahua Ghosh

    2016-04-01

    Integration of biology with nanotechnology is now becoming attention-grabbing area of research. The antimicrobial potency of silver has been eminent from antiquity. Due to the recent desire for the enhancement of antibacterial efficacy of silver, various synthesis methods of silver in their nano dimensions are being practiced using a range of capping material. The present work highlights a facile biomimetic approach for production of silver nanoparticle being capped and stabilized by putrescine, possessing a diameter of 10-25 ± 1.5 nm. The synthesized nanoparticles have been analyzed spectrally and analytically. Morphological studies are carried out by high-resolution transmission electron microscopy and crystallinity by selected area electron diffraction patterns. Moreover, the elemental composition of the capped nanoparticles was confirmed by energy-dispersive X-ray spectroscopy analysis. A comparative study (zone of inhibition and minimum inhibitory concentration) regarding the interactions and antibacterial potentiality of the capped silver nanoparticles with respect to the bare ones reveal the efficiency of the capped one over the bare one. The bacterial kinetic study was executed to monitor the interference of nanoparticles with bacterial growth rate. The results also highlight the efficacy of putrescine-capped silver nanoparticles as effective growth inhibitors against multi-drug resistant human pathogenic bacterial strains, which may, thus, potentially be applicable as an effective antibacterial control system to fight diseases.

  3. High-level expression of the bacterial opd gene in Drosophila melanogaster: improved inducible insecticide resistance.

    PubMed

    Benedict, M Q; Scott, J A; Cockburn, A F

    1994-11-01

    The bacterial parathion hydrolase gene (opd) was expressed in transformed D. melanogaster under the control of an hsp70 promoter. Transformed lines carrying chimaeric genes designed for either cytoplasmic or secretory expression exhibited high- or low-level heat-shock-inducible transient resistance to paraoxon respectively. Greatest levels of resistance occurred approximately 12-16 h after heat shock and well after periods of maximal transcription. Insecticide resistance conferred by the cytoplasmic form of opd is expressed as a semidominant trait. PMID:7704308

  4. Multi-resistant bacteria in spontaneous bacterial peritonitis: A new step in management?

    PubMed Central

    de Mattos, Angelo Alves; Costabeber, Ane Micheli; Lionço, Livia Caprara; Tovo, Cristiane Valle

    2014-01-01

    Spontaneous bacterial peritonitis (SBP) is the most typical infection observed in cirrhosis patients. SBP is responsible for an in-hospital mortality rate of approximately 32%. Recently, pattern changes in the bacterial flora of cirrhosis patients have been observed, and an increase in the prevalence of infections caused by multi-resistant bacteria has been noted. The wide-scale use of quinolones in the prophylaxis of SBP has promoted flora modifications and resulted in the development of bacterial resistance. The efficacy of traditionally recommended therapy has been low in nosocomial infections (up to 40%), and multi-resistance has been observed in up to 22% of isolated germs in nosocomial SBP. For this reason, the use of a broad empirical spectrum antibiotic has been suggested in these situations. The distinction between community-acquired infectious episodes, healthcare-associated infections, or nosocomial infections, and the identification of risk factors for multi-resistant germs can aid in the decision-making process regarding the empirical choice of antibiotic therapy. Broad-spectrum antimicrobial agents, such as carbapenems with or without glycopeptides or piperacillin-tazobactam, should be considered for the initial treatment not only of nosocomial infections but also of healthcare-associated infections when the risk factors or severity signs for multi-resistant bacteria are apparent. The use of cephalosporins should be restricted to community-acquired infections. PMID:25339797

  5. Evaluation of Fluoromycobacteriophages for Detecting Drug Resistance in Mycobacterium tuberculosis▿

    PubMed Central

    Rondón, Liliana; Piuri, Mariana; Jacobs, William R.; de Waard, Jacobus; Hatfull, Graham F.; Takiff, Howard E.

    2011-01-01

    We tested a new method for detecting drug-resistant strains of Mycobacterium tuberculosis that uses a TM4 mycobacteriophage phAE87::hsp60-EGFP (EGFP-phage) engineered to contain the gene encoding enhanced green fluorescent protein (EGFP). After promising results in preliminary studies, the EGFP-phage was used to detect isoniazid (INH), rifampin (RIF), and streptomycin (STR) resistance in 155 strains of M. tuberculosis, and the results were compared to the resazurin microplate technique, with the proportion method serving as the reference standard. The resazurin technique yielded sensitivities of 94% for INH and RIF and 98% for STR and specificities of 97% for INH, 95% for RIF, and 98% for STR. The sensitivity of EGFP-phage was 94% for all three antibiotics, with specificities of 90% for INH, 93% for RIF, and 95% for STR. The EGFP-phage results were available in 2 days for RIF and STR and in 3 days for INH, with an estimated cost of ∼2$ to test the three antibiotics. Using a more stringent criterion for resistance improved the specificity of the EGFP-phage for INH and RIF without affecting the sensitivity. In preliminary studies, the EGFP-phage could also effectively detect resistance to the fluoroquinolones. The EGFP-phage method has the potential to be a valuable rapid and economic screen for detecting drug-resistant tuberculosis if the procedure can be simplified, if it can be adapted to clinical material, and if its sensitivity can be improved. PMID:21346042

  6. Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents

    PubMed Central

    Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.

    2011-01-01

    This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences, and substance offer-response episodes. Rural youths’ resistance strategies were similar to previous findings with urban adolescents – refuse, explain, avoid, and leave (the REAL typology) – while unique features of these strategies were identified including the importance of personal narratives, the articulation of a non-user identity, and being “accountable” to self and others. PMID:21552345

  7. Recent highlights in antimalarial drug resistance and chemotherapy research

    PubMed Central

    Fidock, David A.; Eastman, Richard T.; Ward, Stephen A.; Meshnick, Steven R.

    2009-01-01

    This review summarizes recent investigations into antimalarial drug resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of antimalarial chemotherapy and priorities moving forward. PMID:18938106

  8. Global Phenotypic Characterization of Effects of Fluoroquinolone Resistance Selection on the Metabolic Activities and Drug Susceptibilities of Clostridium perfringens Strains

    PubMed Central

    Park, Miseon

    2014-01-01

    Fluoroquinolone resistance affects toxin production of Clostridium perfringens strains differently. To investigate the effect of fluoroquinolone resistance selection on global changes in metabolic activities and drug susceptibilities, four C. perfringens strains and their norfloxacin-, ciprofloxacin-, and gatifloxacin-resistant mutants were compared in nearly 2000 assays, using phenotype microarray plates. Variations among mutant strains resulting from resistance selection were observed in all aspects of metabolism. Carbon utilization, pH range, osmotic tolerance, and chemical sensitivity of resistant strains were affected differently in the resistant mutants depending on both the bacterial genotype and the fluoroquinolone to which the bacterium was resistant. The susceptibilities to gentamicin and erythromycin of all resistant mutants except one increased, but some resistant strains were less susceptible to amoxicillin, cefoxitin, ceftriaxone, chloramphenicol, and metronidazole than their wild types. Sensitivity to ethidium bromide decreased in some resistant mutants and increased in others. Microarray analysis of two gatifloxacin-resistant mutants showed changes in metabolic activities that were correlated with altered expression of various genes. Both the chemical structures of fluoroquinolones and the genomic makeup of the wild types influenced the changes found in resistant mutants, which may explain some inconsistent reports of the effects of therapeutic use of fluoroquinolones on clinical isolates of bacteria. PMID:25587280

  9. Global Phenotypic Characterization of Effects of Fluoroquinolone Resistance Selection on the Metabolic Activities and Drug Susceptibilities of Clostridium perfringens Strains.

    PubMed

    Park, Miseon; Rafii, Fatemeh

    2014-01-01

    Fluoroquinolone resistance affects toxin production of Clostridium perfringens strains differently. To investigate the effect of fluoroquinolone resistance selection on global changes in metabolic activities and drug susceptibilities, four C. perfringens strains and their norfloxacin-, ciprofloxacin-, and gatifloxacin-resistant mutants were compared in nearly 2000 assays, using phenotype microarray plates. Variations among mutant strains resulting from resistance selection were observed in all aspects of metabolism. Carbon utilization, pH range, osmotic tolerance, and chemical sensitivity of resistant strains were affected differently in the resistant mutants depending on both the bacterial genotype and the fluoroquinolone to which the bacterium was resistant. The susceptibilities to gentamicin and erythromycin of all resistant mutants except one increased, but some resistant strains were less susceptible to amoxicillin, cefoxitin, ceftriaxone, chloramphenicol, and metronidazole than their wild types. Sensitivity to ethidium bromide decreased in some resistant mutants and increased in others. Microarray analysis of two gatifloxacin-resistant mutants showed changes in metabolic activities that were correlated with altered expression of various genes. Both the chemical structures of fluoroquinolones and the genomic makeup of the wild types influenced the changes found in resistant mutants, which may explain some inconsistent reports of the effects of therapeutic use of fluoroquinolones on clinical isolates of bacteria. PMID:25587280

  10. Resistance, resilience and recovery: aquatic bacterial dynamics after water column disturbance.

    PubMed

    Shade, Ashley; Read, Jordan S; Welkie, David G; Kratz, Timothy K; Wu, Chin H; McMahon, Katherine D

    2011-10-01

    For lake microbes, water column mixing acts as a disturbance because it homogenizes thermal and chemical gradients known to define the distributions of microbial taxa. Our first objective was to isolate hypothesized drivers of lake bacterial response to water column mixing. To accomplish this, we designed an enclosure experiment with three treatments to independently test key biogeochemical changes induced by mixing: oxygen addition to the hypolimnion, nutrient addition to the epilimnion, and full water column mixing. We used molecular fingerprinting to observe bacterial community dynamics in the treatment and control enclosures, and in ambient lake water. We found that oxygen and nutrient amendments simulated the physical-chemical water column environment following mixing and resulted in similar bacterial communities to the mixing treatment, affirming that these were important drivers of community change. These results demonstrate that specific environmental changes can replicate broad disturbance effects on microbial communities. Our second objective was to characterize bacterial community stability by quantifying community resistance, recovery and resilience to an episodic disturbance. The communities in the nutrient and oxygen amendments changed quickly (had low resistance), but generally matched the control composition by the 10th day after treatment, exhibiting resilience. These results imply that aquatic bacterial assemblages are generally stable in the face of disturbance. PMID:21883795

  11. Engineering serendipity: High-throughput discovery of materials that resist bacterial attachment☆

    PubMed Central

    Magennis, E.P.; Hook, A.L.; Davies, M.C.; Alexander, C.; Williams, P.; Alexander, M.R.

    2016-01-01

    Controlling the colonisation of materials by microorganisms is important in a wide range of industries and clinical settings. To date, the underlying mechanisms that govern the interactions of bacteria with material surfaces remain poorly understood, limiting the ab initio design and engineering of biomaterials to control bacterial attachment. Combinatorial approaches involving high-throughput screening have emerged as key tools for identifying materials to control bacterial attachment. The hundreds of different materials assessed using these methods can be carried out with the aid of computational modelling. This approach can develop an understanding of the rules used to predict bacterial attachment to surfaces of non-toxic synthetic materials. Here we outline our view on the state of this field and the challenges and opportunities in this area for the coming years. Statement of significance This opinion article on high throughput screening methods reflects one aspect of how the field of biomaterials research has developed and progressed. The piece takes the reader through key developments in biomaterials discovery, particularly focusing on need to reduce bacterial colonisation of surfaces. Such bacterial resistant surfaces are increasingly required in this age of antibiotic resistance. The influence and origin of high-throughput methods are discussed with insights into the future of biomaterials development where computational methods may drive materials development into new fertile areas of discovery. New biomaterials will exhibit responsiveness to adapt to the biological environment and promote better integration and reduced rejection or infection. PMID:26577984

  12. Risk practices associated with bacterial infections among injection drug users in Denver, CO

    PubMed Central

    Phillips, Kristina T.; Stein, Michael D.

    2016-01-01

    Background There has been limited research on bacterial infections (e.g., skin and soft tissue abscesses, endocarditis) among injection drug users (IDUs), despite these infections often resulting in serious morbidity and costly medical care. Although high-risk practices that contribute to bacterial infections are not entirely clear, certain injection practices have been found to increase risk in past studies. Objectives To examine rates of bacterial infections among IDUs in Denver, CO and high-risk practices that predict skin infections. Methods Structured interviews were conducted with 51 active heroin, cocaine and methamphetamine IDUs (over 18 years). Results Among all participants, 55% reported a lifetime history of at least one skin infection and 29% reported having an infection in the last year. Those with a skin infection in the last year were significantly more likely to inject intramuscularly (OR = 1.57) and to report greater heroin injection frequency (OR = 1.08) compared to IDUs with no history of skin infections. Heroin and speedball injectors reported a higher number of past abscesses compared to methamphetamine and cocaine injectors. Conclusion Intervention strategies to reduce bacterial infections should focus on high-risk injection practices. Scientific Significance Learning about rates of bacterial infections and high-risk practices associated with these infections can benefit researchers developing risk reduction interventions for IDUs. PMID:20337504

  13. Mechanisms of acquired resistance to androgen receptor targeting drugs in castration resistant prostate cancer

    PubMed Central

    Chism, David D.; De Silva, Dinuka; Whang, Young E.

    2014-01-01

    After initial response to androgen receptor targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer (CRPC) remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand binding domain of androgen receptor may confer resistance to enzalutamide. Emergence of androgen receptor splice variants lacking the ligand binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for androgen receptor. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of CRPC. PMID:24927631

  14. Treatment of chloroquine-resistant malaria in monkeys with a drug combination that reverses resistance in vitro.

    PubMed

    Williams, H L; Johnson, D J; Okoye, V C; Martin, S K

    1992-10-01

    Compounds that inhibit the P-glycoprotein-related efflux mechanism of multidrug-resistant cells reverse chloroquine resistance in vitro. Hence, the co-administration of chloroquine and an efflux-blocking drug could potentially treat chloroquine-resistant malaria infections. We administered a drug combination (chloroquine and a tiapamil analogue), that has been shown to reverse chloroquine resistance in vitro, to Aotus monkeys but failed to safely clear experimentally-induced chloroquine-resistant Plasmodium falciparum parasitaemias. PMID:1288427

  15. Antibiotic resistance among cultured bacterial isolates from bioethanol fermentation facilities across the United States.

    PubMed

    Murphree, Colin A; Heist, E Patrick; Moe, Luke A

    2014-09-01

    Bacterial contamination of fuel ethanol fermentations by lactic acid bacteria (LAB) can have crippling effects on bioethanol production. Producers have had success controlling bacterial growth through prophylactic addition of antibiotics to fermentors, yet concerns have arisen about antibiotic resistance among the LAB. Here, we report on mechanisms used by 32 LAB isolates from eight different US bioethanol facilities to persist under conditions of antibiotic stress. Minimum inhibitory concentration assays with penicillin, erythromycin, and virginiamycin revealed broad resistance to each of the antibiotics as well as high levels of resistance to individual antibiotics. Phenotypic assays revealed that antibiotic inactivation mechanisms contributed to the high levels of individual resistances among the isolates, especially to erythromycin and virginiamycin, yet none of the isolates appeared to use a β-lactamase. Biofilm formation was noted among the majority of the isolates and may contribute to persistence under low levels of antibiotics. Nearly all of the isolates carried at least one canonical antibiotic resistance gene and many carried more than one. The erythromycin ribosomal methyltransferase (erm) gene class was found in 19 of 32 isolates, yet a number of these isolates exhibit little to no resistance to erythromycin. The erm genes were present in 15 isolates that encoded more than one antibiotic resistance mechanism, suggestive of potential genetic linkages. PMID:24748439

  16. Antibiotic resistance differentiates Echinacea purpurea endophytic bacterial communities with respect to plant organs.

    PubMed

    Mengoni, Alessio; Maida, Isabel; Chiellini, Carolina; Emiliani, Giovanni; Mocali, Stefano; Fabiani, Arturo; Fondi, Marco; Firenzuoli, Fabio; Fani, Renato

    2014-10-01

    Recent findings have shown that antibiotic resistance is widespread in multiple environments and multicellular organisms, as plants, harboring rich and complex bacterial communities, could be hot spot for emergence of antibiotic resistances as a response to bioactive molecules production by members of the same community. Here, we investigated a panel of 137 bacterial isolates present in different organs of the medicinal plant Echinacea purpurea, aiming to evaluate if different plant organs harbor strains with different antibiotic resistance profiles, implying then the presence of different biological interactions in the communities inhabiting different plant organs. Data obtained showed a large antibiotic resistance variability among strains, which was strongly related to the different plant organs (26% of total variance, P < 0.0001). Interestingly this uneven antibiotic resistance pattern was present also when a single genus (Pseudomonas), ubiquitous in all organs, was analyzed and no correlation of antibiotic resistance pattern with genomic relatedness among strains was found. In conclusion, we speculate that antibiotic resistance patterns are tightly linked to the type of plant organ under investigation, suggesting the presence of differential forms of biological interaction in stem/leaves, roots and rhizosphere. PMID:25283726

  17. Cultivable Bacterial Microbiota of Northern Bobwhite (Colinus virginianus): A New Reservoir of Antimicrobial Resistance?

    PubMed Central

    Su, Hongwen; McKelvey, Jessica; Rollins, Dale; Zhang, Michael; Brightsmith, Donald J.; Derr, James; Zhang, Shuping

    2014-01-01

    The northern bobwhite (Colinus virginianus) is an ecologically and economically important avian species. At the present time, little is known about the microbial communities associated with these birds. As the first step to create a quail microbiology knowledge base, the current study conducted an inventory of cultivable quail tracheal, crop, cecal, and cloacal microbiota and associated antimicrobial resistance using a combined bacteriology and DNA sequencing approach. A total of 414 morphologically unique bacterial colonies were selected from nonselective aerobic and anaerobic cultures, as well as selective and enrichment cultures. Analysis of the first 500-bp 16S rRNA gene sequences in conjunction with biochemical identifications revealed 190 non-redundant species-level taxonomic units, representing 160 known bacterial species and 30 novel species. The bacterial species were classified into 4 phyla, 14 orders, 37 families, and 59 or more genera. Firmicutes was the most commonly encountered phylum (57%) followed by Actinobacteria (24%), Proteobacteria (17%) and Bacteroidetes (0.02%). Extensive diversity in the species composition of quail microbiota was observed among individual birds and anatomical locations. Quail microbiota harbored several opportunistic pathogens, such as E. coli and Ps. aeruginosa, as well as human commensal organisms, including Neisseria species. Phenotypic characterization of selected bacterial species demonstrated a high prevalence of resistance to the following classes of antimicrobials: phenicol, macrolide, lincosamide, quinolone, and sulphate. Data from the current investigation warrant further investigation on the source, transmission, pathology, and control of antimicrobial resistance in wild quail populations. PMID:24937705

  18. Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance

    PubMed Central

    Nichol, Daniel; Jeavons, Peter; Fletcher, Alexander G.; Bonomo, Robert A.; Maini, Philip K.; Paul, Jerome L.; Gatenby, Robert A.; Anderson, Alexander R.A.; Scott, Jacob G.

    2015-01-01

    The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2–4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically ‘steer’ the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic–resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy. PMID:26360300

  19. Steering Evolution with Sequential Therapy to Prevent the Emergence of Bacterial Antibiotic Resistance.

    PubMed

    Nichol, Daniel; Jeavons, Peter; Fletcher, Alexander G; Bonomo, Robert A; Maini, Philip K; Paul, Jerome L; Gatenby, Robert A; Anderson, Alexander R A; Scott, Jacob G

    2015-09-01

    The increasing rate of antibiotic resistance and slowing discovery of novel antibiotic treatments presents a growing threat to public health. Here, we consider a simple model of evolution in asexually reproducing populations which considers adaptation as a biased random walk on a fitness landscape. This model associates the global properties of the fitness landscape with the algebraic properties of a Markov chain transition matrix and allows us to derive general results on the non-commutativity and irreversibility of natural selection as well as antibiotic cycling strategies. Using this formalism, we analyze 15 empirical fitness landscapes of E. coli under selection by different β-lactam antibiotics and demonstrate that the emergence of resistance to a given antibiotic can be either hindered or promoted by different sequences of drug application. Specifically, we demonstrate that the majority, approximately 70%, of sequential drug treatments with 2-4 drugs promote resistance to the final antibiotic. Further, we derive optimal drug application sequences with which we can probabilistically 'steer' the population through genotype space to avoid the emergence of resistance. This suggests a new strategy in the war against antibiotic-resistant organisms: drug sequencing to shepherd evolution through genotype space to states from which resistance cannot emerge and by which to maximize the chance of successful therapy. PMID:26360300

  20. Mathematical models of tumor heterogeneity and drug resistance

    NASA Astrophysics Data System (ADS)

    Greene, James

    In this dissertation we develop mathematical models of tumor heterogeneity and drug resistance in cancer chemotherapy. Resistance to chemotherapy is one of the major causes of the failure of cancer treatment. Furthermore, recent experimental evidence suggests that drug resistance is a complex biological phenomena, with many influences that interact nonlinearly. Here we study the influence of such heterogeneity on treatment outcomes, both in general frameworks and under specific mechanisms. We begin by developing a mathematical framework for describing multi-drug resistance to cancer. Heterogeneity is reflected by a continuous parameter, which can either describe a single resistance mechanism (such as the expression of P-gp in the cellular membrane) or can account for the cumulative effect of several mechanisms and factors. The model is written as a system of integro-differential equations, structured by the continuous "trait," and includes density effects as well as mutations. We study the limiting behavior of the model, both analytically and numerically, and apply it to study treatment protocols. We next study a specific mechanism of tumor heterogeneity and its influence on cell growth: the cell-cycle. We derive two novel mathematical models, a stochastic agent-based model and an integro-differential equation model, each of which describes the growth of cancer cells as a dynamic transition between proliferative and quiescent states. By examining the role all parameters play in the evolution of intrinsic tumor heterogeneity, and the sensitivity of the population growth to parameter values, we show that the cell-cycle length has the most significant effect on the growth dynamics. In addition, we demonstrate that the agent-based model can be approximated well by the more computationally efficient integro-differential equations, when the number of cells is large. The model is closely tied to experimental data of cell growth, and includes a novel implementation of transition rates as a function of global density. Finally, we extend the model of cell-cycle heterogeneity to include spatial variables. Cells are modeled as soft spheres and exhibit attraction/repulsion/random forces. A fundamental hypothesis is that cell-cycle length increases with local density, thus producing a distribution of observed division lengths. Apoptosis occurs primarily through an extended period of unsuccessful proliferation, and the explicit mechanism of the drug (Paclitaxel) is modeled as an increase in cell-cycle duration. We show that the distribution of cell-cycle lengths is highly time-dependent, with close time-averaged agreement with the distribution used in the previous work. Furthermore, survival curves are calculated and shown to qualitatively agree with experimental data in different densities and geometries, thus relating the cellular microenvironment to drug resistance.

  1. Assessing transmissibility of HIV-1 drug resistance mutations from treated and from drug-naive individuals

    PubMed Central

    Winand, Raf; Theys, Kristof; Eusébio, Mónica; Aerts, Jan; Camacho, Ricardo J.; Gomes, Perpetua; Suchard, Marc A.; Vandamme, Anne-Mieke; Abecasis, Ana B.

    2015-01-01

    Objectives: Surveillance drug resistance mutations (SDRMs) in drug-naive patients are typically used to survey HIV-1-transmitted drug resistance (TDR). We test here how SDRMs in patients failing treatment, the original source of TDR, contribute to assessing TDR, transmissibility and transmission source of SDRMs. Design: This is a retrospective observational study analyzing a Portuguese cohort of HIV-1-infected patients. Methods: The prevalence of SDRMs to protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) in drug-naive and treatment-failing patients was measured for 3554 HIV-1 subtype B patients. Transmission ratio (prevalence in drug-naive/prevalence in treatment-failing patients), average viral load and robust linear regression with outlier detection (prevalence in drug-naive versus in treatment-failing patients) were analyzed and used to interpret transmissibility. Results: Prevalence of SDRMs in drug-naive and treatment-failing patients were linearly correlated, but some SDRMs were classified as outliers – above (PRO: D30N, N88D/S, L90 M, RT: G190A/S/E) or below (RT: M184I/V) expectations. The normalized regression slope was 0.073 for protease inhibitors, 0.084 for NRTIs and 0.116 for NNRTIs. Differences between SDRMs transmission ratios were not associated with differences in viral loads. Conclusion: The significant linear correlation between prevalence of SDRMs in drug-naive and in treatment-failing patients indicates that the prevalence in treatment-failing patients can be useful to predict levels of TDR. The slope is a cohort-dependent estimate of rate of TDR per drug class and outlier detection reveals comparative persistence of SDRMs. Outlier SDRMs with higher transmissibility are more persistent and more likely to have been acquired from drug-naive patients. Those with lower transmissibility have faster reversion dynamics after transmission and are associated with acquisition from treatment-failing patients. PMID:26355575

  2. Steroidal regulation of uterine resistance to bacterial infection in livestock.

    PubMed

    Lewis, Gregory S

    2003-11-28

    Postpartum uterine infections reduce reproductive efficiency and have significant animal welfare and economic consequences. Postpartum uterine infections are classified as nonspecific, but Arcanobacterium pyogenes and Escherichia coli are usually associated with them in cattle and sheep. Pyometra is the most common type of uterine infection in dairy cattle, and it is detected almost exclusively in cows with active corpora lutea. Luteal progesterone typically down-regulates uterine immune functions and prevents the uterus from resisting infections. Progesterone also can down-regulate uterine eicosanoid synthesis. This seems to be a critical event in the onset of uterine infections, because eicosanoids can up-regulate immune cell functions in vitro. In addition, exogenous prostaglandin F2 alpha stimulates uterine secretion of prostaglandin F2 alpha and enhances immune functions in vivo. Thus, one may hypothesize that eicosanoids can override the negative effects of progesterone and that the up-regulatory effects of exogenous prostaglandin F2 alpha allow the uterus to resolve an infection, regardless of progesterone concentrations. Based on the results of studies to test that hypothesis, cows, sheep, and pigs in various physiological statuses are resistant to intrauterine infusions of Arcanobacterium pyogenes and Escherichia coli, unless progesterone concentrations are increased. In sheep and pigs, exogenous prostaglandin F2 alpha stimulates uterine production of prostaglandin F2 alpha and allows the uterus to resolve Arcanobacterium pyogenes-Escherichia coli-induced infections, even when progesterone is maintained at luteal phase concentrations before and after treatment. Prostaglandin F2 alpha is a proinflammatory molecule that stimulates the production of various proinflammatory cytokines, and it may enhance uterine production of leukotriene B4. Proinflammatory cytokines and leukotriene B4 enhance phagocytosis and lymphocyte functions. Even though there are clear associations among prostaglandin F2 alpha, leukotriene B4, proinflammatory cytokines, phagocytosis, and lymphocyte functions, the mechanism of action of exogenous prostaglandin F2 alpha in overriding the down-regulatory effects of progesterone and resolving uterine infections has not been elucidated. Defining this mechanism should yield new prevention and treatment strategies for uterine infections that do not rely on antibiotic and antimicrobial compounds. PMID:14641941

  3. Collateral Resistance and Sensitivity Modulate Evolution of High-Level Resistance to Drug Combination Treatment in Staphylococcus aureus.

    PubMed

    Rodriguez de Evgrafov, Mari; Gumpert, Heidi; Munck, Christian; Thomsen, Thomas T; Sommer, Morten O A

    2015-05-01

    As drug-resistant pathogens continue to emerge, combination therapy will increasingly be relied upon to treat infections and to help combat further development of multidrug resistance. At present a dichotomy exists between clinical practice, which favors therapeutically synergistic combinations, and the scientific model emerging from in vitro experimental work, which maintains that this interaction provides greater selective pressure toward resistance development than other interaction types. We sought to extend the current paradigm, based on work below or near minimum inhibitory concentration levels, to reflect drug concentrations more likely to be encountered during treatment. We performed a series of adaptive evolution experiments using Staphylococcus aureus. Interestingly, no relationship between drug interaction type and resistance evolution was found as resistance increased significantly beyond wild-type levels. All drug combinations, irrespective of interaction types, effectively limited resistance evolution compared with monotreatment. Cross-resistance and collateral sensitivity were found to be important factors in the extent of resistance evolution toward a combination. Comparative genomic analyses revealed that resistance to drug combinations was mediated largely by mutations in the same genes as single-drug-evolved lineages highlighting the importance of the component drugs in determining the rate of resistance evolution. Results of this work suggest that the mechanisms of resistance to constituent drugs should be the focus of future resistance evolution work. PMID:25618457

  4. Antiretroviral (ARV) drug resistance in the developing world.

    PubMed Central

    Shekelle, Paul; Maglione, Margaret; Geotz, Matthew Bidwell; Wagner, Glenn; Wang, Zhen; Hilton, Lara; Carter, Jason; Chen, Susan; Tringle, Carlo; Mojica, Walter; Newberry, Synde

    2007-01-01

    OBJECTIVES To describe the overall prevalence of ARV resistance in the developing world, focusing on: (1) treatment naïve populations, (2) the resistance consequences of prevention of mother to child transmission (pMTCT) drug regimens, and (3) the relationship of medication adherence to resistance. DATA SOURCES We searched PubMed(R), EMBASE, the Cochrane Controlled Clinical Trials Register Database, and the Cochrane Database of Reviews of Effectiveness (DARE). Additional sources of evidence included the Stanford University HIV Drug Resistance Database; reports of WATCH: Worldwide Analysis of Resistance Transmission over Time of Chronically and Acute Infected HIV-1 infected persons; a recent unpublished pMTCT overview; and various conference proceedings. Studies that did not report original research, that reported data already reported in another article, and case studies of fewer than 20 individuals were excluded. Of 1,122 titles identified, 117 journal articles and presentations were included. REVIEW METHODS We abstracted data on geographic region, number of participants, subject demographics, HIV viral clade, medications taken (if any), years of data collection, how people were selected for resistance testing, and how and when resistance was assessed. Because of study heterogeneity, pooling was not possible; thus, the data are summarized qualitatively. Differences by region, population group, and HIV viral clade are described. RESULTS The patterns of ARV resistance among treatment naïve populations worldwide appear to reflect geographic trends in use of ARV medications. A worldwide surveillance program (WATCH) found the rate of resistance (to any drug) among treatment naïve individuals was 5.5 percent in Africa, 7.4 percent in East Asia, 5.7 percent in Southeast Asia, and 6.4 percent in Latin America, lower than in North America (11.4 percent) and Europe (10.6 percent). Resistance data on HIV clades other than A, B, C, and D were too scarce to permit reliable conclusions. We also identified very few studies designed to assess the effect of health services delivery factors or medication adherence on the development of resistance in patients in developing countries. Evidence provided by longitudinal analyses suggests that, among women taking intrapartum single dose nevirapine (SD-NVP) to prevent mother-to-child transmission of HIV, both the overall prevalence of NNRTI resistance as well as the frequency of mutant virus in the overall viral population decreases with time since SD-NVP prophylaxis was received. CONCLUSIONS In future resistance studies, rare HIV clades should be over-sampled in order to provide statistically meaningful data. Resistance surveillance programs should be maintained throughout the developing world, and data should be reported and analyzed in a consistent and timely manner. Where resources permit, studies of adherence in developing regions should conduct resistance testing. PMID:18088163

  5. Peptide IDR-1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections.

    PubMed

    Mansour, Sarah C; de la Fuente-Núñez, César; Hancock, Robert E W

    2015-05-01

    Host defense (antimicrobial) peptides, produced by all complex organisms, typically contain an abundance of positively charged and hydrophobic amino acid residues. A small synthetic peptide termed innate defense regulator (IDR-)1018 was derived by substantial modification of the bovine neutrophil host defense peptide bactenecin. Here, we review its intriguing properties that include anti-infective, anti-inflammatory, wound healing, and anti-biofilm activities. It was initially developed as an immune modulator with an ability to selectively enhance chemokine production and polarize cellular differentiation while suppressing/balancing the pro-inflammatory response. In this regard, it has demonstrated in vivo activity in murine models including enhancement of wound healing and an ability to protect against Staphylococcus aureus, multidrug resistant Mycobacterium tuberculosis, herpes virus, and inflammatory disorders, including cerebral malaria and neuronal damage in a pre-term birth model. More recently, IDR-1018 was shown, in a broad-spectrum fashion, to selectively target bacterial biofilms, which are adaptively resistant to many antibiotics and represent the most common growth state of bacteria in human infections. Furthermore, IDR-1018 demonstrated synergy with conventional antibiotics to both prevent biofilm formation and treat pre-existing biofilms. These data are consistent with a strong potential as an adjunctive therapy against antibiotic-resistant infections. PMID:25358509

  6. Bottlenecks in the Transferability of Antibiotic Resistance from Natural Ecosystems to Human Bacterial Pathogens

    PubMed Central

    Martínez, José L.

    2011-01-01

    It is generally accepted that resistance genes acquired by human pathogens through horizontal gene transfer originated in environmental, non-pathogenic bacteria. As a consequence, there is increasing concern on the roles that natural, non-clinical ecosystems, may play in the evolution of resistance. Recent studies have shown that the variability of determinants that can provide antibiotic resistance on their expression in a heterologous host is much larger than what is actually found in human pathogens, which implies the existence of bottlenecks modulating the transfer, spread, and stability of antibiotic resistance genes. In this review, the role that different factors such as founder effects, ecological connectivity, fitness costs, or second-order selection may have on the establishment of a specific resistance determinant in a population of bacterial pathogens is analyzed. PMID:22319513

  7. Breakthroughs in bacterial resistance mechanisms and the potential ways to combat them.

    PubMed

    Khameneh, Bahman; Diab, Roudayna; Ghazvini, Kiarash; Fazly Bazzaz, Bibi Sedigheh

    2016-06-01

    Multidrug-resistant (MDR) bacteria have increased at an alarming rate over recent decades and cause serious problems. The emergence of resistant infections caused by these bacteria has led to mortality and morbidity; consequently there is an urgent need to find solution for combating bacterial resistance. In the present paper, first, some mechanisms of antibiotic resistance such as changing the antibacterial agent's uptake and biofilm formation are discussed. Following, for removing the antibacterial resistance, a wide range of approaches like developing new generations of antibiotics, combination therapy, natural antibacterial substances and applying nanoparticulate systems have been explained. Among them, antibiotic delivery via nanoparticles, has been attracted more attention recently, so discussed in present review, separately. PMID:26911646

  8. Discussion on research methods of bacterial resistant mutation mechanisms under selective culture--uncertainty analysis of data from the Luria-Delbrück fluctuation experiment.

    PubMed

    Jin, Jianling; Wei, Gang; Yang, Weiqiang; Zhang, Huaiqiang; Gao, Peiji

    2012-11-01

    Whether bacterial drug-resistance is drug-induced or results from rapid propagation of random spontaneous mutations in the flora prior to exposure, remains a long-term key issue concerned and debated in both genetics and medicinal fields. In a pioneering study, Luria and Delbrück exposed E. coli to T1 phage, to investigate whether the number of resistant colonies followed the Poisson distribution. They deduced that the development of resistant colonies is independent of phage presence. Similar results have since been obtained on solid medium containing antibacterial agents. Luria and Delbrück's conclusions were long considered a gold standard for analyzing drug resistance mutations. More recently, the concept of adaptive mutation has triggered controversy over this approach. Microbiological observation shows that, following exposure to drugs of various concentrations, drug-resistant cells emerge and multiply depending on the time course, and show a process function, inconsistent with the definition of Poisson distribution (which assumes not only that resistance is independent of drug quantity but follows no specific time course). At the same time, since cells tend to aggregate after division rather than separating, colonies growing on drug plates arise from the multiplication of resistant bacteria cells of various initial population sizes. Thus, statistical analysis based on equivalence of initial populations will yield erroneous results. In this paper, 310 data from the Luria-Delbrück fluctuation experiment were reanalyzed from this perspective. In most cases, a high-end abnormal value, resulting from the non-synchronous variation of the two above-mentioned time variables, was observed. Therefore, the mean value cannot be regarded as an unbiased expectation estimate. The ratio between mean value and variance was similarly incomparable, because two different sampling methods were used. In fact, the Luria-Delbrück data appear to follow an aggregated, rather than Poisson distribution. In summary, the statistical analysis of Luria and Delbrück is insufficient to describe rules of resistant mutant development and multiplication. Correction of this historical misunderstanding will enable new insight into bacterial resistance mechanisms. PMID:23160830

  9. Overcoming Drug Resistance and Treating Advanced Prostate Cancer

    PubMed Central

    Semenas, Julius; Allegrucci, Cinzia; Boorjian, Stephen A; Mongan, Nigel P; Persson, Jenny Liao

    2012-01-01

    Most of the prostate cancers (PCa) in advanced stage will progress to castration-resistant prostate cancer (CRPC). Within CRPC group, 50-70% of the patients will develop bone metastasis in axial and other regions of the skeleton. Once PCa cells spread to the bone, currently, no treatment regimens are available to eradicate the metastasis, and cancer-related death becomes inevitable. In 2012, it is estimated that there will be 28,170 PCa deaths in the United States. Thus, PCa bone metastasis-associated clinical complications and treatment resistance pose major clinical challenges. In this review, we will present recent findings on the molecular and cellular pathways that are responsible for bone metastasis of PCa. We will address several novel mechanisms with a focus on the role of bone and bone marrow microenvironment in promoting PCa metastasis, and will further discuss why prostate cancer cells preferentially metastasize to the bone. Additionally, we will discuss novel roles of several key pathways, including angiogenesis and extracellular matrix remodeling in bone marrow and stem cell niches with their relationship to PCa bone metastasis and poor treatment response. We will evaluate how various chemotherapeutic drugs and radiation therapies may allow aggressive PCa cells to gain advantageous mutations leading to increased survival and rendering the cancer cells to become resistant to treatment. The novel concept relating several key survival and invasion signaling pathways to stem cell niches and treatment resistance will be reviewed. Lastly, we will provide an update of several recently developed novel drug candidates that target metastatic cancer microenvironments or niches, and discuss the advantages and significance provided by such therapeutic approaches in pursuit of overcoming drug resistance and treating advanced PCa. PMID:22746994

  10. Stochastic model of an influenza epidemic with drug resistance.

    PubMed

    Xu, Yaji; Allen, Linda J S; Perelson, Alan S

    2007-09-01

    A continuous-time Markov chain (CTMC) model is formulated for an influenza epidemic with drug resistance. This stochastic model is based on an influenza epidemic model, expressed in terms of a system of ordinary differential equations (ODE), developed by Stilianakis, N.I., Perelson, A.S., Hayden, F.G., [1998. Emergence of drug resistance during an influenza epidemic: insights from a mathematical model. J. Inf. Dis. 177, 863-873]. Three different treatments-chemoprophylaxis, treatment after exposure but before symptoms, and treatment after symptoms appear, are considered. The basic reproduction number, R(0), is calculated for the deterministic-model under different treatment strategies. It is shown that chemoprophylaxis always reduces the basic reproduction number. In addition, numerical simulations illustrate that the basic reproduction number is generally reduced with realistic treatment rates. Comparisons are made among the different models and the different treatment strategies with respect to the number of infected individuals during an outbreak. The final size distribution is computed for the CTMC model and, in some cases, it is shown to have a bimodal distribution corresponding to two situations: when there is no outbreak and when an outbreak occurs. Given an outbreak occurs, the total number of cases for the CTMC model is in good agreement with the ODE model. The greatest number of drug resistant cases occurs if treatment is delayed or if only symptomatic individuals are treated. PMID:17582443

  11. Delamanid expanded access novel treatment of drug resistant tuberculosis

    PubMed Central

    Rustomjee, Roxana; Zumla, Alimuddin

    2015-01-01

    Tuberculosis (TB) remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683) is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary TB. Delamanid kills Mycobacterium tuberculosis by inhibiting the synthesis of mycolic acids required for cell wall synthesis. Whilst delamanid has been included in the WHO Model List of Essential Medicine by the World Health Organization Expert Committee on Selection and Use of Essential Medicines and in international guidance for the treatment of multi-drug resistant TB since April 2014, its access in countries with the greatest need, has proven challenging. This review provides an update on currently available clinical safety and efficacy data on delamanid and offers a discussion on research priorities and recommendations for expedited, expanded access. PMID:26604805

  12. Delamanid expanded access novel treatment of drug resistant tuberculosis.

    PubMed

    Rustomjee, Roxana; Zumla, Alimuddin

    2015-01-01

    Tuberculosis (TB) remains a global emergency and is one of the most common infectious disease causes of death in developing countries. Current treatment regimens for multi-drug resistant TB are associated with low treatment success rates, are toxic, and require long duration of treatment. The need for shorter and more effective treatment regimens is urgent. Delamanid (Deltyba, or formerly known as OPC-67683) is a new dihydro-imidazooxazole anti-TB drug active against resistant forms of pulmonary TB. Delamanid kills Mycobacterium tuberculosis by inhibiting the synthesis of mycolic acids required for cell wall synthesis. Whilst delamanid has been included in the WHO Model List of Essential Medicine by the World Health Organization Expert Committee on Selection and Use of Essential Medicines and in international guidance for the treatment of multi-drug resistant TB since April 2014, its access in countries with the greatest need, has proven challenging. This review provides an update on currently available clinical safety and efficacy data on delamanid and offers a discussion on research priorities and recommendations for expedited, expanded access. PMID:26604805

  13. Facultative bacterial symbionts in aphids confer resistance to parasitic wasps.

    PubMed

    Oliver, Kerry M; Russell, Jacob A; Moran, Nancy A; Hunter, Martha S

    2003-02-18

    Symbiotic relationships between animals and microorganisms are common in nature, yet the factors controlling the abundance and distributions of symbionts are mostly unknown. Aphids have an obligate association with the bacterium Buchnera aphidicola (the primary symbiont) that has been shown to contribute directly to aphid fitness. In addition, aphids sometimes harbor other vertically transmitted bacteria (secondary symbionts), for which few benefits of infection have been previously documented. We carried out experiments to determine the consequences of these facultative symbioses in Acyrthosiphon pisum (the pea aphid) for vulnerability of the aphid host to a hymenopteran parasitoid, Aphidius ervi, a major natural enemy in field populations. Our results show that, in a controlled genetic background, infection confers resistance to parasitoid attack by causing high mortality of developing parasitoid larvae. Compared with uninfected controls, experimentally infected aphids were as likely to be attacked by ovipositing parasitoids but less likely to support parasitoid development. This strong interaction between a symbiotic bacterium and a host natural enemy provides a mechanism for the persistence and spread of symbiotic bacteria. PMID:12563031

  14. Surfactant-based drug delivery systems for treating drug-resistant lung cancer.

    PubMed

    Kaur, Prabhjot; Garg, Tarun; Rath, Goutam; Murthy, R S R; Goyal, Amit K

    2016-03-01

    Among all cancers, lung cancer is the major cause of deaths. Lung cancer can be categorized into two classes for prognostic and treatment purposes: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Both categories of cancer are resistant to certain drugs. Various mechanisms behind drug resistance are over-expression of superficial membrane proteins [glycoprotein (P-gp)], lung resistance-associated proteins, aberration of the intracellular enzyme system, enhancement of the cell repair system and deregulation of cell apoptosis. Structure-performance relationships and chemical compatibility are consequently major fundamentals in surfactant-based formulations, with the intention that a great deal investigation is committed to this region. With the purpose to understand the potential of P-gp in transportation of anti-tumor drugs to cancer cells with much effectiveness and specificity, several surfactant-based delivery systems have been developed which may include microspheres, nanosized drug carriers (nanoparticles, nanoemulsions, stealth liposomes, nanogels, polymer-drug conjugates), novel powders, hydrogels and mixed micellar systems intended for systemic and/or localized delivery. PMID:25013959

  15. No role for bacterially produced salicylic Acid in rhizobacterial induction of systemic resistance in Arabidopsis.

    PubMed

    Ran, L X; van Loon, L C; Bakker, P A H M

    2005-11-01

    ABSTRACT The role of bacterially produced salicylic acid (SA) in the induction of systemic resistance in plants by rhizobacteria is far from clear. The strong SA producer Pseudomonas fluorescens WCS374r induces resistance in radish but not in Arabidopsis thaliana, whereas application of SA leads to induction of resistance in both plant species. In this study, we compared P. fluorescens WCS374r with three other SA-producing fluorescent Pseudomonas strains, P. fluorescens WCS417r and CHA0r, and P. aeruginosa 7NSK2 for their abilities to produce SA under different growth conditions and to induce systemic resistance in A. thaliana against bacterial speck, caused by P. syringae pv. tomato. All strains produced SA in vitro, varying from 5 fg cell(-1) for WCS417r to >25 fg cell(-1) for WCS374r. Addition of 200 muM FeCl(3) to standard succinate medium abolished SA production in all strains. Whereas the incubation temperature did not affect SA production by WCS417r and 7NSK2, strains WCS374r and CHA0r produced more SA when grown at 33 instead of 28 degrees C. WCS417r, CHA0r, and 7NSK2 induced systemic resistance apparently associated with their ability to produce SA, but WCS374r did not. Conversely, a mutant of 7NSK2 unable to produce SA still triggered induced systemic resistance (ISR). The possible involvement of SA in the induction of resistance was evaluated using SA-nonaccumulating transgenic NahG plants. Strains WCS417r, CHA0r, and 7NSK2 induced resistance in NahG Arabidopsis. Also, WCS374r, when grown at 33 or 36 degrees C, triggered ISR in these plants, but not in ethylene-insensitive ein2 or in non-plant pathogenesis- related protein-expressing npr1 mutant plants, irrespective of the growth temperature of the bacteria. These results demonstrate that, whereas WCS374r can be manipulated to trigger ISR in Arabidopsis, SA is not the primary determinant for the induction of systemic resistance against bacterial speck disease by this bacterium. Also, for the other SAproducing strains used in this study, bacterial determinants other than SA must be responsible for inducing resistance. PMID:18943367

  16. Exosomes in development, metastasis and drug resistance of breast cancer

    PubMed Central

    Yu, Dan-dan; Wu, Ying; Shen, Hong-yu; Lv, Meng-meng; Chen, Wei-xian; Zhang, Xiao-hui; Zhong, Shan-liang; Tang, Jin-hai; Zhao, Jian-hua

    2015-01-01

    Transport through the cell membrane can be divided into active, passive and vesicular types (exosomes). Exosomes are nano-sized vesicles released by a variety of cells. Emerging evidence shows that exosomes play a critical role in cancers. Exosomes mediate communication between stroma and cancer cells through the transfer of nucleic acid and proteins. It is demonstrated that the contents and the quantity of exosomes will change after occurrence of cancers. Over the last decade, growing attention has been paid to the role of exosomes in the development of breast cancer, the most life-threatening cancer in women. Breast cancer could induce salivary glands to secret specific exosomes, which could be used as biomarkers in the diagnosis of early breast cancer. Exosome-delivered nucleic acid and proteins partly facilitate the tumorigenesis, metastasis and resistance of breast cancer. Exosomes could also transmit anti-cancer drugs outside breast cancer cells, therefore leading to drug resistance. However, exosomes are effective tools for transportation of anti-cancer drugs with lower immunogenicity and toxicity. This is a promising way to establish a drug delivery system. PMID:26052865

  17. Drug Resistance and the Kinetics of Metastatic Cancer

    NASA Astrophysics Data System (ADS)

    Blagoev, Krastan B.

    2012-02-01

    Most metastatic cancers after initial response to current drug therapies develop resistance to the treatment. We present cancer data and a theory that explains the observed kinetics of tumor growth in cancer patients and using a stochastic model based on this theory we relate the kinetics of tumor growth to Kaplan-Meyer survival curves. The theory points to the tumor growth rate as the most important parameter determining the outcome of a drug treatment. The overall tumor growth or decay rate is a reflection of the balance between cell division, senescence and apoptosis and we propose that the deviation of the decay rate from exponential is a measure of the emergence of drug resistance. In clinical trials the progression free survival, the overall survival, and the shape of the Kaplan-Meyer plots are determined by the tumor growth rate probability distribution among the patients in the trial. How drug treatments modify this distribution will also be described. At the end of the talk we will discuss the connection between the theory described here and the age related cancer mortality rates in the United States.

  18. Oscyp71Z2 involves diterpenoid phytoalexin biosynthesis that contributes to bacterial blight resistance in rice.

    PubMed

    Li, Wenqi; Shao, Min; Yang, Jie; Zhong, Weigong; Okada, Kazunori; Yamane, Hisakazu; Qian, Guoliang; Liu, Fengquan

    2013-06-01

    Bacterial blight is one of the most destructive rice diseases, which caused by Xoo, and results in yield losses, endangering worldwide food security. Diterpenoid phytoalexins, a type of antimicrobials produced in rice, are critical for resistance to fungal and bacterial pathogens. This article reports the characterization of the cytochrome P450 gene Oscyp71Z2, which belongs to the CYP71Z subfamily. Overexpression of Oscyp71Z2 in rice enhanced resistance to Xoo at the booting stage. The accumulation of phytoalexins was rapidly and strongly induced in Oscyp71Z2-overexpressing plants, and the transcript levels of genes related to the phytoalexin biosynthesis pathway were elevated. The H₂O₂ concentration in Oscyp71Z2-overexpressing plants was reduced in accordance with the increase in ROS-scavenging ability due to the induction of SOD as well as POD and CAT activation. We also showed that suppression of Oscyp71Z2 had no significantly effect on disease resistance to Xoo in rice. These results demonstrated that Oscyp71Z2 plays an important role in bacterial blight resistance by regulating the diterpenoid phytoalexin biosynthesis and H₂O₂ generation. PMID:23602104