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Sample records for multiple drug resistant

  1. 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.

  2. 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...

  3. Molecular mechanisms in multiple myeloma drug resistance

    PubMed Central

    Nikesitch, Nicholas; Ling, Silvia C W

    2016-01-01

    Multiple myeloma (MM) is predominantly an incurable malignancy despite high-dose chemotherapy, autologous stem cell transplant and novel agents. MM is a genetically heterogeneous disease and the complexity increases as the disease progresses to a more aggressive stage. MM arises from a plasma cell, which produces and secretes non-functioning immunoglobulins. Most MM cells are sensitive to proteasome inhibitors (PIs), which have become the main drug in the treatment of newly diagnosed and relapsed MM. However, not all MM is sensitive to PIs. This review summarises the literature regarding molecular biology of MM with a focus on the unfolded protein response and explores how this could affect drug sensitivity and progression of disease. PMID:26598624

  4. 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

  5. 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.

  6. 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

  7. 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, ...

  8. Multiple myeloma and persistence of drug resistance in the age of novel drugs (Review).

    PubMed

    Krishnan, Sabna Rajeev; Jaiswal, Ritu; Brown, Ross D; Luk, Frederick; Bebawy, Mary

    2016-07-01

    Multiple myeloma (MM) is a mature B cell neoplasm that results in multi-organ failure. The median age of onset, diverse clinical manifestations, heterogeneous survival rate, clonal evolution, intrinsic and acquired drug resistance have impact on the therapeutic management of the disease. Specifically, the emergence of multidrug resistance (MDR) during the course of treatment contributes significantly to treatment failure. The introduction of the immunomodulatory agents and proteasome inhibitors has seen an increase in overall patient survival, however, for the majority of patients, relapse remains inevitable with evidence that these agents, like the conventional chemotherapeutics are also subject to the development of MDR. Clinical management of patients with MM is currently compromised by lack of a suitable procedure to monitor the development of clinical drug resistance in individual patients. The current MM prognostic measures fail to pick the clonotypic tumor cells overexpressing drug efflux pumps, and invasive biopsy is insufficient in detecting sporadic tumors in the skeletal system. This review summarizes the challenges associated with treating the complex disease spectrum of myeloma, with an emphasis on the role of deleterious multidrug resistant clones orchestrating relapse. PMID:27175906

  9. Analysis of Antimicrobial Resistance Genes in Multiple Drug Resistant (MDR) Salmonella enterica Isolated from Animals and Humans

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Multiple Drug Resistant (MDR) foodborne bacteria are a concern in animal and human health. Identification of resistance genes in foodborne pathogens is necessary to determine similarities of resistance mechanisms in animal, food and human clinical isolates. This information will help us ...

  10. Epigenetic mechanisms of cell adhesion-mediated drug resistance in multiple myeloma.

    PubMed

    Furukawa, Yusuke; Kikuchi, Jiro

    2016-09-01

    Multiple myeloma cells acquire the resistance to anti-cancer drugs through physical and functional interactions with the bone marrow microenvironment via two overlapping mechanisms. First, bone marrow stromal cells (BMSCs) produce soluble factors, such as interleukin-6 and insulin-like growth factor-1, to activate signal transduction pathways leading to drug resistance (soluble factor-mediated drug resistance). Second, BMSCs up-regulate the expression of cell cycle inhibitors, anti-apoptotic members of the Bcl-2 family and ABC drug transporters in myeloma cells upon direct adhesion [cell adhesion-mediated drug resistance (CAM-DR)]. Elucidation of the mechanisms underlying drug resistance may greatly contribute to the advancement of cancer therapies. Recent investigations, including ours, have revealed the involvement of epigenetic alterations in drug resistance especially CAM-DR. For example, we found that class I histone deacetylases (HDACs) determine the sensitivity of proteasome inhibitors and the histone methyltransferase EZH2 regulates the transcription of anti-apoptotic genes during the acquisition of CAM-DR by myeloma cells. In addition, another histone methyltransferase MMSET was shown to confer drug resistance to myeloma cells by facilitating DNA repair. These findings provide a rationale for the inclusion of epigenetic drugs, such as HDAC inhibitors and histone methylation modifiers, in combination chemotherapy for MM patients to increase the therapeutic index. PMID:27411688

  11. Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

    PubMed Central

    Abdi, Jahangir; Chen, Guoan; Chang, Hong

    2013-01-01

    In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma. PMID:24327604

  12. Metabolic signature identifies novel targets for drug resistance in Multiple Myeloma

    PubMed Central

    Maiso, Patricia; Huynh, Daisy; Moschetta, Michele; Sacco, Antonio; Aljawai, Yosra; Mishima, Yuji; Asara, John M.; Roccaro, Aldo M.; Kimmelman, Alec C.; Ghobrial, Irene M.

    2015-01-01

    Drug resistance remains a major clinical challenge for cancer treatment. Multiple myeloma (MM) is an incurable plasma cell cancer selectively localized in the bone marrow (BM). The main cause of resistance in myeloma is the minimal residual disease (MRD) cells that are resistant to the original therapy including bortezomib treatment and high dose melphalan in stem cell transplant. In this study, we demonstrate that altered tumor cell metabolism is essential for the regulation of drug resistance in MM cells. We show the unprecedented role of the metabolic phenotype in inducing drug resistance through LDHA and HIF1A in MM; and that specific inhibition of LDHA and HIF1A can restore sensitivity to therapeutic agents such as bortezomib and can also inhibit tumor growth induced by altered metabolism. Knockdown of LDHA can restore sensitivity of bortezomib resistance cell lines while gain of function studies using LDHA or HIF1A induced resistance in bortezomib sensitive cell lines. Taken together, these data suggest that HIF1A and LDHA are important targets for hypoxia-driven drug resistance. Novel drugs that regulate metabolic pathways in MM, specifically targeting LDHA, can be beneficial to inhibit tumor growth and overcome drug resistance. PMID:25769724

  13. Tris DBA palladium overcomes hypoxia-mediated drug resistance in multiple myeloma.

    PubMed

    de la Puente, Pilar; Azab, Feda; Muz, Barbara; Luderer, Micah; Arbiser, Jack; Azab, Abdel Kareem

    2016-07-01

    Despite recent progress in novel and targeted therapies, multiple myeloma (MM) remains a therapeutically challenging incurable disease. The regulation of important cellular processes and its link to cancer presented Src as an attractive target for MM. We suggest a novel strategy to improve the treatment of MM and overcome the drug resistance for the current therapeutic agents by specific inhibition of Src in MM cells by Tris (Dibenzylideneacetone) dipalladium (Tris DBA). Tris DBA reduces proliferation, induces G1 arrest and apoptosis in MM cells. Tris DBA showed additive effect with proteasome inhibitors reducing proliferation, cell cycle signaling, and increasing apoptosis more than each drug alone. Tris DBA overcame hypoxia-induced effects such as enhanced chemotaxis or drug resistance to proteasome inhibitors by inhibition of HIF1α expression. Moreover, we found that Tris DBA is an effective anti-myeloma agent alone or in combination with other targeted drugs and that it reverses hypoxia-induced drug resistance in myeloma. PMID:26421357

  14. Monitoring a Nuclear Factor-κB Signature of Drug Resistance in Multiple Myeloma*

    PubMed Central

    Xiang, Yun; Remily-Wood, Elizabeth R.; Oliveira, Vasco; Yarde, Danielle; He, Lili; Cheng, Jin Q.; Mathews, Linda; Boucher, Kelly; Cubitt, Christopher; Perez, Lia; Gauthier, Ted J.; Eschrich, Steven A.; Shain, Kenneth H.; Dalton, William S.; Hazlehurst, Lori; Koomen, John M.

    2011-01-01

    The emergence of acquired drug resistance results from multiple compensatory mechanisms acting to prevent cell death. Simultaneous monitoring of proteins involved in drug resistance is a major challenge for both elucidation of the underlying biology and development of candidate biomarkers for assessment of personalized cancer therapy. Here, we have utilized an integrated analytical platform based on SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring mass spectrometry, a versatile and powerful tool for targeted quantification of proteins in complex matrices, to evaluate a well-characterized model system of melphalan resistance in multiple myeloma (MM). Quantitative assays were developed to measure protein expression related to signaling events and biological processes relevant to melphalan resistance in multiple myeloma, specifically: nuclear factor-κB subunits, members of the Bcl-2 family of apoptosis-regulating proteins, and Fanconi Anemia DNA repair components. SDS-PAGE protein fractionation prior to liquid chromatography coupled to multiple reaction monitoring methods were developed for quantification of these selected target proteins in amounts of material compatible with direct translation to clinical specimens (i.e. less than 50,000 cells). As proof of principle, both relative and absolute quantification were performed on cell line models of MM to compare protein expression before and after drug treatment in naïve cells and in drug resistant cells; these liquid chromatography-multiple reaction monitoring results are compared with existing literature and Western blots. The initial stage of a systems biology platform for examining drug resistance in MM has been implemented in cell line models and has been translated to MM cells isolated from a patient. The ultimate application of this platform could assist in clinical decision-making for individualized patient treatment. Although these specific assays have

  15. Predictive performance of microarray gene signatures: impact of tumor heterogeneity and multiple mechanisms of drug resistance

    PubMed Central

    A’Hern, Roger; Bidard, Francois-Clement; Lemetre, Christophe; Swanton, Charles; Shen, Ronglai; Reis-Filho, Jorge S.

    2014-01-01

    Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. Additionally, we explored whether sub-stratification of resistant cases could improve performance. Gene expression profiles from 1,550 breast cancers analyzed with the same microarray platform were retrieved from publicly available sources. Gene expression changes were introduced in cases defined as sensitive or resistant to a hypothetical therapy. In the resistant group, up to five different mechanisms of drug resistance causing distinct or overlapping gene expression changes were generated bioinformatically, and their impact on sensitivity, specificity and predictive values of the signatures was investigated. We found that increasing the number of resistance mechanisms corresponding to different gene expression changes weakened the performance of the predictive signatures generated, even if the resistance-induced changes in gene expression were sufficiently strong and informative. Performance was also affected by cohort composition and the proportion of sensitive versus resistant cases or resistant cases that were mechanistically distinct. It was possible to improve response prediction by sub-stratifying chemotherapy-resistant cases from actual datasets (non-bioinformatically-perturbed datasets), and by using outliers to model multiple resistance mechanisms. Our work supports the hypothesis that the presence of multiple resistance mechanisms to a given therapy in patients limits the ability of gene signatures to make clinically-useful predictions. PMID:24706696

  16. Autophagy in drug resistance of the multiple myeloma cell line RPMI8226 to doxorubicin.

    PubMed

    Pan, Y-Z; Wang, X; Bai, H; Wang, C-B; Zhang, Q; Xi, R

    2015-01-01

    We investigated the effect of autophagy on drug resistance of multiple myeloma (MM) to doxorubicin (DOX). A DOX-resistant MM cell line (RPMI8226/DOX) was developed by progressively increasing the DOX concentration gradient. The drug resistance index was determined using the MTT method. Transmission electron microscopy, anti-light chain 3-fluorescein isothiocyanate immunofluorescence, and Western blotting were used to detect autophagy of MM cells. Flow cytometry was applied to detect changes in apoptosis of RPMI8226/DOX cells (stained with annexin-V/propidium iodide) caused by inhibition by hydroxychloroquine and 3-methyladenine on autophagy. The drug resistance index of RPMI8226/DOX to DOX was 10.8, and autophagy/lysosomal was clearly observed in RPMI8226/DOX cells under transmission electron microscopy, while immunofluorescence showed granular immunofluorescence in cells. Western blot analysis showed that light chain 3-II protein expression level was higher in RPMI8226/DOX cells than in RPMI8226/S cells. The apoptosis test showed that hydroxychloroquine or 3-methyladenine partially reversed the drug resistance of RPMI8226/DOX cells by inhibiting autophagy. Activation of autophagy in MM cells may explain the drug resistance of myeloma. PMID:26125760

  17. Multiple resistance of gastrointestinal nematodes to nine different drugs in a sheep flock in southern Brazil.

    PubMed

    Cezar, Alfredo Skrebsky; Toscan, Gustavo; Camillo, Giovana; Sangioni, Luís Antônio; Ribas, Henrique Olmedo; Vogel, Fernanda Silveira Flôres

    2010-10-11

    Based on clinical observation of a flock of approximately 5000 sheep (breed Merino) from southern Brazil, the failure of anthelmintic treatments was suspected. The sensitivity of the gastrointestinal nematodes that infected these sheep to nine drugs (Levamisole, Moxidectin, Albendazole, Ivermectin, Nitroxynil, Disophenol, Trichlorphon, Closantel, and a combination of Ivermectin, Levamisole and Albendazole) was evaluated. None of the drugs reduced the count of nematode eggs per gram of feces (EPG) in the sheep to an adequate extent (defined as a 95% reduction in EPG). Therefore, we found multiple parasite resistance to all classes of anthelmintic drugs available for small ruminants in the Brazilian market. The genera Haemonchus spp., Trichostrongylus spp. and Ostertagia spp. had various degrees of resistance (or natural tolerance) to each of the drug treatments. PMID:20619543

  18. An update on molecular biology and drug resistance mechanisms of multiple myeloma.

    PubMed

    Mutlu, Pelin; Kiraz, Yağmur; Gündüz, Ufuk; Baran, Yusuf

    2015-12-01

    Multiple myeloma (MM), a neoplasm of plasma cells, is the second most common hematological malignancy. Incidance rates increase after age 40. MM is most commonly seen in men and African-American population. There are several factors to this, such as obesity, environmental factors, family history, genetic factors and monoclonal gammopathies of undetermined significance (MGUS) that have been implicated as potentially etiologic. Development of MM involves a series of complex molecular events, including chromosomal abnormalities, oncogene activation and growth factor dysregulation. Chemotherapy is the most commonly used treatment strategy in MM. However, MM is a difficult disease to treat because of its marked resistance to chemotherapy. MM has been shown to be commonly multidrug resistance (MDR)-negative at diagnosis and associated with a high incidence of MDR expression at relapse. This review deals with the molecular aspects of MM, drug resistance mechanisms during treatment and also possible new applications for overcoming drug resistance. PMID:26235594

  19. NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma

    PubMed Central

    Xia, Jiliang; Gu, Zhimin; Wendlandt, Erik; Zhan, Xin; Janz, Siegfried; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    We reported previously that increased expression of aldehyde dehydrogenase 1 (ALDH1) in multiple myeloma (MM) is a marker of tumor-initiating cells (TICs) that is further associated with chromosomal instability (CIN). Here we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, is most abundantly expressed in myeloma. Enforced expression of ALDH1A1 in myeloma cells led to increased clonogenicity, tumor formation in mice, and resistance to myeloma drugs in vitro and in vivo. The mechanism underlying these phenotypes included the ALDH1A1-dependent activation of drug-efflux pump, ABCB1, and survival proteins, AKT and BCL2. Over expression of ALDH1A1 in myeloma cells led to increased mRNA and protein levels of NIMA-related kinase 2 (NEK2), whereas shRNA-mediated knock down of NEK2 decreased drug efflux pump activity and drug resistance. The activation of NEK2 in myeloma cells relied on the ALDH1A1-dependent generation of the retinoid X receptor α (RXRα) ligand, 9-cis retinoic acid (9CRA) – not the retinoic acid receptor α (RARα) ligand, all-trans retinoic acid (ATRA). These findings implicate the ALDH1A1-RXRα-NEK2 pathway in drug resistance and disease relapse in myeloma and suggest that specific inhibitors of ALDH1A1 are worthy of consideration for clinical development of new approaches to overcome drug resistance in myeloma. PMID:25230277

  20. Phosphorylation-mediated EZH2 inactivation promotes drug resistance in multiple myeloma

    PubMed Central

    Kikuchi, Jiro; Koyama, Daisuke; Wada, Taeko; Izumi, Tohru; Hofgaard, Peter O.; Bogen, Bjarne; Furukawa, Yusuke

    2015-01-01

    Alterations in chromatin modifications, such as histone methylation, have been suggested as mediating chemotherapy resistance in several cancer types; therefore, elucidation of the epigenetic mechanisms that underlie drug resistance may greatly contribute to the advancement of cancer therapies. In the present study, we identified histone H3–lysine 27 (H3K27) as a critical residue for epigenetic modification in multiple myeloma. We determined that abrogation of drug-induced H3K27 hypermethylation is associated with cell adhesion–mediated drug resistance (CAM-DR), which is the most important form of drug resistance, using a coculture system to evaluate stroma cell adhesion–dependent alterations in multiple myeloma cells. Cell adhesion counteracted anticancer drug–induced hypermethylation of H3K27 via inactivating phosphorylation of the transcription regulator EZH2 at serine 21, leading to the sustained expression of antiapoptotic genes, including IGF1, B cell CLL/lymphoma 2 (BCL2), and hypoxia inducible factor 1, α subunit (HIF1A). Pharmacological and genetic inhibition of the IGF-1R/PI3K/AKT pathway reversed CAM-DR by promoting EZH2 dephosphorylation and H3K27 hypermethylation both in vitro and in refractory murine myeloma models. Together, our findings identify and characterize an epigenetic mechanism that underlies CAM-DR and suggest that kinase inhibitors to counteract EZH2 phosphorylation should be included in combination chemotherapy to increase therapeutic index. PMID:26517694

  1. Public Health Risks of Multiple-Drug-Resistant Enterococcus spp. in Southeast Asia

    PubMed Central

    Lee, Sui Mae; Dykes, Gary A.; Rahman, Sadequr

    2015-01-01

    Enterococci rank as one of the leading causes of nosocomial infections, such as urinary tract infections, surgical wound infections, and endocarditis, in humans. These infections can be hard to treat because of the rising incidence of antibiotic resistance. Enterococci inhabiting nonhuman reservoirs appear to play a critical role in the acquisition and dissemination of antibiotic resistance determinants. The spread of antibiotic resistance has become a major concern in both human and veterinary medicine, especially in Southeast Asia, where many developing countries have poor legislation and regulations to control the supply and excessive use of antimicrobials. This review addresses the occurrence of antibiotic-resistant enterococci in Association of Southeast Asian Nations countries and proposes infection control measures that should be applied to limit the spread of multiple-drug-resistant enterococci. PMID:26150452

  2. Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis

    PubMed Central

    Papanikolaou, Xenofon; Johnson, Sarah; Garg, Tarun; Tian, Erming; Tytarenko, Ruslana; Zhang, Qing; Stein, Caleb; Barlogie, Bart; Epstein, Joshua; Heuck, Christoph

    2014-01-01

    Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naïve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment. PMID:24948357

  3. Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future.

    PubMed Central

    Huycke, M. M.; Sahm, D. F.; Gilmore, M. S.

    1998-01-01

    Enterococci, leading causes of nosocomial bacteremia, surgical wound infection, and urinary tract infection, are becoming resistant to many and sometimes all standard therapies. New rapid surveillance methods are highlighting the importance of examining enterococcal isolates at the species level. Most enterococcal infections are caused by Enterococcus faecalis, which are more likely to express traits related to overt virulence but--for the moment--also more likely to retain sensitivity to at least one effective antibiotic. The remaining infections are mostly caused by E. faecium, a species virtually devoid of known overt pathogenic traits but more likely to be resistant to even antibiotics of last resort. Effective control of multiple-drug resistant enterococci will require 1) better understanding of the interaction between enterococci, the hospital environment, and humans, 2) prudent antibiotic use, 3) better contact isolation in hospitals and other patient care environments, and 4) improved surveillance. Equally important is renewed vigor in the search for additional drugs, accompanied by the evolution of new therapeutic paradigms less vulnerable to the cycle of drug introduction and drug resistance. PMID:9621194

  4. 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...

  5. RANK-RANKL interactions are involved in cell adhesion-mediated drug resistance in multiple myeloma cell lines.

    PubMed

    Tsubaki, Masanobu; Takeda, Tomoya; Yoshizumi, Misako; Ueda, Emi; Itoh, Tatsuki; Imano, Motohiro; Satou, Takao; Nishida, Shozo

    2016-07-01

    Interaction between multiple myeloma (MM) cells and the bone marrow microenvironment plays a critical role in MM pathogenesis and the development of drug resistance. Recently, it has been reported that MM cells express the receptor activator of nuclear factor-κB (NF-κB) (RANK). However, the role of the RANK/RANK ligand (RANKL) system in drug resistance remains unclear. In this study, we demonstrated a novel function of the RANK/RANKL system in promoting drug resistance in MM. We found that RANKL treatment induced drug resistance in RANK-expressing but not RANK-negative cell lines. RANKL stimulation of RANK-expressing cells increased multidrug resistance protein 1 (MDR1), breast cancer resistance protein (BCRP), and lung resistance protein 1 (LRP1) expression and decreased Bim expression through various signaling molecules. RNA silencing of Bim expression induced drug resistance, but the RANKL-mediated drug resistance could not be overcome through the RNA silencing of MDR1, BCRP, and LRP1 expression. These results indicate that the RANK/RANKL system induces chemoresistance through the activation of multiple signal transduction pathways and by decreasing Bim expression in RANK-positive MM cells. These findings may prove to be useful in the development of cell adhesion-mediated drug resistance inhibitors in RANK-positive MM cells. PMID:26762414

  6. An exhaustive yet simple virtual screening campaign against Sortase A from multiple drug resistant Staphylococcus aureus.

    PubMed

    Uddin, Reaz; Saeed, Kiran

    2014-08-01

    Methicillin resistant Staphylococcus aureus (MRSA) is one of the challenging bacterial pathogen due to its acquired resistance to the β lactam antibiotics. The Sortase A is an enzyme of Gram-positive bacteria including S. aureus to anchor surface proteins to the cell wall. Sortase A is well studied enzyme and considered as the drug target against MRSA. Sortase A plays active role in anchoring the virulence proteins on the cell wall of the Gram-positive bacteria. The inhibition of Sortase A activity results in the separation of S. aureus from the host cells and ultimately alleviation of the infection. Here, we adapted a structure-based virtual screening protocol which helped in identification of novel potential inhibitors of Sortase A. The protocol involved the docking of a chemical library of druglike compounds with the Sortase A binding site represented by multiple crystal structures. The compounds were ranked by multiple scoring functions and shortlisted for future experimental screening. The method resulted in shortlisting of three compounds as potential novel inhibitors of Sortase A out of a large chemical library. The high rankings of shortlisted compounds estimated by multiple scoring functions showed their binding potential with Sortase A. The results are proved to be a simple yet efficient choice of structure-based virtual screening. The identified compounds are druglike and show high rankings among all set protocols of the virtual screening. We hope that the study would eventually help to expedite the discovery of novel drug candidates against MRSA. PMID:24797540

  7. Multiple drug resistant mechanisms against darunavir, amprenavir, and nelfinavir of HIV-1 PR

    NASA Astrophysics Data System (ADS)

    Liu, Xiaoqing; Dai, Qi; Xiu, Zhilong

    2013-02-01

    Acquired immune deficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV), which is infecting more humans and is expanding faster in the world. The illness interferes with the immune system, making people with AIDS much more likely to get infections, including opportunistic infections and tumors that do not affect people with working immune systems. HIV-1 PR is one of the major targets of anti-AIDS drug discovery. It is, therefore, necessary to develop some inhibitors against HIV-1 PR. In this work, we executed molecular dynamics (MDs) simulation of HIV-1 PR with drugs darunavir (DRV), amprenavir (APV), nelfinavir (NFV), and examined the resistant mechanism of L10I, G48V, I54V, and L90M mutations of this PR, aiming at designing promising drugs. The comparative analysis suggests that the existences of dodecahydroisoquinoline ring at P1' subsite, 4-aminophenylsulfonamide at P2' subsite, and bis-tetrahydrofuranylurethane at P2 subsite are helpful for maintaining the high affinity of the inhibitor for the protease and exhibiting high potency against multiple drug resistance (MDR) mutant protease.

  8. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

    PubMed

    Franqui-Machin, Reinaldo; Wendlandt, Erik B; Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

    2015-12-01

    Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID:26415231

  9. Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction?

    PubMed Central

    Janz, Siegfried; Zhan, Fenghuang; Tricot, Guido

    2015-01-01

    Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains – just like many other cancers – a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138−, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma “stemness”, the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease. PMID:26415231

  10. Characterization of naturally acquired multiple-drug resistance of Yoshida rat ascites hepatoma AH66 cell line.

    PubMed

    Miyamoto, K; Wakabayashi, D; Minamino, T; Nomura, M; Wakusawa, S; Nakamura, S

    1996-01-01

    Characteristics of multiple-drug resistance of rat ascites hepatoma AH66, a cell line induced by dimethylaminoazobenzene and established as a transplantable tumor, were compared with those of AH66F, a drug sensitive line obtained from AH66. The AH66 cell line was resistant to vinblastine, adriamycin, SN-38 an active form of camptothesine, etoposide, and clorambucil by 10-fold or more than the AH66F cell line. The resistance of AH66 cells to vinblastine, adriamycin, and SN-38 was closely related to P-glycoprotein overexpression in the plasma membrane, because the resistance was significantly inhibited by verapamil. AH66 cells contained much glutahione and had a high activity of glutathione S-transferase P-form (GST-P), compared with AH66F cells, and resistance to clorambucil was decreased by treatment with buthionine sulfoximine, an inhibitor of glutathione synthesis. AH66 cells have a similar topoisomerase I activity, but about 6 times lower topoisomerase II activity than AH66F cells. Therefore, the resistance to etoposide and a part of the resistance to adriamycin of AH66 cells seems to depend upon this low topoisomerase II activity. These results, show that the AH66 cell line has high multiple-drug resistance compared with the AH66F cell line, by several mechanisms. Consequently, the AH66 and AH66F cell lines are useful to study naturally acquired multiple-drug resistance of hepatomas. PMID:8702243

  11. Transfer and expression of the human multiple drug resistance gene into live mice.

    PubMed Central

    Podda, S; Ward, M; Himelstein, A; Richardson, C; de la Flor-Weiss, E; Smith, L; Gottesman, M; Pastan, I; Bank, A

    1992-01-01

    The human multiple drug resistance (MDR) gene has been used as a selectable marker to increase the proportion of bone marrow cells that contain and express this gene by drug selection. By constructing retroviral vectors containing and expressing the MDR gene and a nonselectable gene such as the beta-globin gene, enrichment for cells containing both of these genes can be achieved. A retroviral construct containing MDR cDNA in a Harvey virus-based vector has been used to transfect our ecotropic 3T3 retroviral packaging line GP+E86. Clones have been isolated by exposure of the retrovirally transfected cells (MDR producer cells) to colchicine (60 ng/ml), a selective agent that kills MDR-negative cells. Flow cytometry analysis (fluorescence-activated cell sorting) with an antibody to MDR demonstrates expression of human MDR protein on the surface of these colchicine-resistant producer clones. Untransfected GP+E86 cells are negative. Colchicine-resistant clones were titered using clone supernatants and the highest titer clone (4 x 10(4) viral particles per ml) was cocultured with 10(6) donor mouse bone marrow cells for 24-48 hr. The donor cells were then injected into congenic irradiated mice, and the presence of the MDR gene was assayed by the polymerase chain reaction (PCR) analysis using MDR-specific primers. In one experiment eight of nine transduced mice were positive for MDR by PCR of peripheral blood 14 and 50 days posttransplantation; after 240 days three of nine transduced mice were positive. Bone marrow obtained from one of these positive animals was stained with the MDR monoclonal antibody and the granulocyte population was analyzed by FACS. Approximately 14% of the total granulocyte pool contain increased levels of MDR protein. In addition, the bone marrow cells of several mice initially positive for MDR gene by PCR, and subsequently negative, were exposed to taxol, a drug whose detoxification depends on MDR gene expression; a positive signal was obtained in

  12. Inhibition of MDR1 gene expression by antimessenger oligonucleotides lowers multiple drug resistance.

    PubMed

    Quattrone, A; Papucci, L; Morganti, M; Coronnello, M; Mini, E; Mazzei, T; Colonna, F P; Garbesi, A; Capaccioli, S

    1994-01-01

    The multiple drug resistance of neoplastic cells is mediated by overexpression of the human MDR1 gene, which encodes the transmembrane efflux pump P-glycoprotein. In both cell lines and human tumors the MDR phenotype closely correlates with MDR1 mRNA and P-glycoprotein levels. Reversion of the MDR phenotype was attempted in human colorectal adenocarcinoma doxorubicin (Dx)-resistant cells (Lo Vo/Dx) by long-term administration of an equimolecular mixture of three unmodified ODNs (18mer) targeted to adjacent binding sites of the MDR1 mRNA and carried by a synthetic cationic lipid (DOTAP). Three different experimental parameters were used to evaluate the antimessenger agent's effectiveness in comparison with a random sequence ODN: the level of cell resistance to Dx; the level of P-glycoprotein (determined by flow cytometry); the level of MDR1 mRNA (determined by quantitative RT-PCR). Experimental data indicate that the level of both the MDR1 mRNA and the P-glycoprotein is reduced by approximately 50% by treatment of Lo Vo/Dx cells with a 10 microM total concentration of the aODN mixture every 24 h for 15 days. In agreement with these findings, sensitivity to Dx of the antimessenger agent-treated Lo Vo/Dx cells was almost doubled in comparison with random sequence ODN-treated controls. PMID:7865906

  13. Antimicrobial (Drug) Resistance

    MedlinePlus

    ... Antimicrobial (Drug) Resistance Antibiotic-Resistant Mycobacterium tuberculosis (TB) Methicillin-Resistant Staphylococcus aureus (MRSA) Vancomycin-Resistant Enterococci (VRE) Multidrug-Resistant Neisseria ...

  14. Isolation of multiple drug-resistant enteric bacteria from feces of wild Western Lowland Gorilla (Gorilla gorilla gorilla) in Gabon.

    PubMed

    Mbehang Nguema, Pierre Philippe; Okubo, Torahiko; Tsuchida, Sayaka; Fujita, Shiho; Yamagiwa, Juichi; Tamura, Yutaka; Ushida, Kazunari

    2015-05-01

    Prevalence of drug-resistant bacteria in wildlife can reveal the actual level of anthropological burden on the wildlife. In this study, we isolated two multiple drug-resistant strains, GG6-2 and GG6-1-1, from 27 fresh feces of wild western lowland gorillas in Moukalaba-Doudou National Park, Gabon. Isolates were identified as Achromobacter xylosoxidans and Providencia sp., respectively. Minimum inhibitory concentrations of the following 12 drugs-ampicillin (ABPC), cefazolin (CEZ), cefotaxime (CTX), streptomycin (SM), gentamicin (GM), kanamycin (KM), tetracycline (TC), nalidixic acid (NA), ciprofloxacin (CPFX), colistin (CL), chloramphenicol (CP) and trimethoprim (TMP)-were determined. Isolate GG6-2 was resistant to all antimicrobials tested and highly resistant to CTX, SM, TC, NA and TMP. Isolate GG6-1-1 was resistant to ABPC, CEZ, TC, CL, CP and TMP. PMID:25649412

  15. Anthracycline Nano-Delivery Systems to Overcome Multiple Drug Resistance: A Comprehensive Review

    PubMed Central

    Ma, Ping; Mumper, Russell J.

    2013-01-01

    Anthracyclines (doxorubicin, daunorubicin, and idarubicin) are very effective chemotherapeutic drugs to treat many cancers; however, the development of multiple drug resistance (MDR) is one of the major limitations for their clinical applications. Nano-delivery systems have emerged as the novel cancer therapeutics to overcome MDR. Up until now, many anthracycline nano-delivery systems have been developed and reported to effectively circumvent MDR both in-vitro and in-vivo, and some of these systems have even advanced to clinical trials, such as the HPMA-doxorubicin (HPMA-DOX) conjugate. Doxil, a DOX PEGylated liposome formulation, was developed and approved by FDA in 1995. Unfortunately, this formulation does not address the MDR problem. In this comprehensive review, more than ten types of developed anthracycline nano-delivery systems to overcome MDR and their proposed mechanisms are covered and discussed, including liposomes; polymeric micelles, conjugate and nanoparticles; peptide/protein conjugates; solid-lipid, magnetic, gold, silica, and cyclodextrin nanoparticles; and carbon nanotubes. PMID:23888183

  16. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma

    PubMed Central

    Raninga, Prahlad V.; Di Trapani, Giovanna; Vuckovic, Slavica; Bhatia, Maneet; Tonissen, Kathryn F.

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-кβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-кβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-кβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM. PMID:25945832

  17. Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma.

    PubMed

    Raninga, Prahlad V; Di Trapani, Giovanna; Vuckovic, Slavica; Bhatia, Maneet; Tonissen, Kathryn F

    2015-06-20

    Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM. PMID:25945832

  18. HIV drug resistance interpreted by cumulative versus last genotypes in HIV-infected patients with multiple treatment failures.

    PubMed

    Punyacam, Punthiya; Iemwimangsa, Nareenart; Chantratita, Wasun; Sukasem, Chonlaphat; Sungkanuparph, Somnuek

    2012-04-01

    Genotypic resistance test has been recommended to evaluate HIV drug resistance and guide the effective regimens of antiretroviral therapy (ART) in HIV-infected patients with treatment failure. In patients with multiple treatment failures, drug resistance-associated mutations may disappear due to the loss of selective drug pressure after switching regimens. A cohort study was conducted among HIV-infected patients who had ≥2 genotypic resistance tests during 2003-2011. HIV-1 pol nucleotide sequencing of reverse transcriptase and protease region was carried out using TRUGENE HIV-1 Genotypic Assay. Sequencing data was analyzed using Stanford rule-based interpretation algorithms. Of 54 patients with mean age of 30.1 years, 46.3% were males. HIV-1 subtype A/E was observed in 88.9% of patients. At the latest failure, 55.3% were receiving protease inhibitor-based regimens. Median CD4 and HIV RNA were 167 cells/mm(3) and 22,359 copies/mL. During a median duration of ART of 38.6 months, 72.2%, 22.2%, and 5.6% had 5, 3, and 2 genotype tests, respectively. When compared between using cumulative (CG) and last genotypes (LG), CG interpreted resistance to any drug 59.3% higher than LG did. For NRTI, NNRTI, and PI drug classes, CG interpreted as resistance 42.6%, 27.8%, and 7.4% higher than LG, respectively. The most common drugs that CG interpreted resistance with the higher rate than LG were lamivudine/emtricitabine, nevirapine, efavirenz, etravirine and abacavir. In conclusion, CG interprets HIV drug resistance at a higher rate than LG and may be more accurate to use for selecting the next effective regimen of ART among HIV-infected patients with multiple treatment failures. PMID:22497699

  19. Analysis of antimicrobial resistance genes detected in multiple-drug-resistant Escherichia coli isolates from broiler chicken carcasses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Multi-drug resistant (MDR) bacteria in food animals are a potential problem in both animal and human health. In this study, MDR commensal Escherichia coli isolates from poultry were examined. Thirty-two E. coli isolates from broiler carcass rinses were selected based on resistance to aminoglycosid...

  20. Isolation of multiple drug-resistant enteric bacteria from feces of wild Western Lowland Gorilla (Gorilla gorilla gorilla) in Gabon

    PubMed Central

    MBEHANG NGUEMA, Pierre Philippe; OKUBO, Torahiko; TSUCHIDA, Sayaka; FUJITA, Shiho; YAMAGIWA, Juichi; TAMURA, Yutaka; USHIDA, Kazunari

    2015-01-01

    Prevalence of drug-resistant bacteria in wildlife can reveal the actual level of anthropological burden on the wildlife. In this study, we isolated two multiple drug-resistant strains, GG6-2 and GG6-1-1, from 27 fresh feces of wild western lowland gorillas in Moukalaba-Doudou National Park, Gabon. Isolates were identified as Achromobacter xylosoxidans and Providencia sp., respectively. Minimum inhibitory concentrations of the following 12 drugs—ampicillin (ABPC), cefazolin (CEZ), cefotaxime (CTX), streptomycin (SM), gentamicin (GM), kanamycin (KM), tetracycline (TC), nalidixic acid (NA), ciprofloxacin (CPFX), colistin (CL), chloramphenicol (CP) and trimethoprim (TMP)—were determined. Isolate GG6-2 was resistant to all antimicrobials tested and highly resistant to CTX, SM, TC, NA and TMP. Isolate GG6-1-1 was resistant to ABPC, CEZ, TC, CL, CP and TMP. PMID:25649412

  1. Measurement of multiple drug resistance transporter activity in putative cancer stem/progenitor cells.

    PubMed

    Donnenberg, Vera S; Meyer, E Michael; Donnenberg, Albert D

    2009-01-01

    Multiple drug resistance, mediated by the expression and activity of ABC-transporters, is a major obstacle to antineoplastic therapy. Normal tissue stem cells and their malignant counterparts share MDR transporter activity as a major mechanism of self-protection. Although MDR activity is upregulated in response to substrate chemotherapeutic agents, it is also constitutively expressed on both normal tissue stem cells and a subset of tumor cells prior to the initiation of therapy, representing a built-in obstacle to therapeutic ratio. Constitutive and induced MDR activity can be detected in cellular subsets of disaggregated tissues, using the fluorescent substrates Rhodamine 123 and Hoechst 33342 for ABCB1 (also known as P-gp and MDR1) and ABCG2 (BCRP1). In this chapter, we will describe the complete procedure for the detection of MDR activity, including: (1) Preparing single-cell suspensions from tumor and normal tissue specimens; (2) An efficient method to perform cell surface marker staining on large numbers of cells; (3) Flow cytometer setup and controls; (4) Simultaneous measurement of Hoechst 33342 and Rhodamine123 transport; and (5) Data acquisition and analysis. PMID:19582433

  2. Steps toward discovering the function and expression of multiple drug resistance genes in "Arabidopsis thaliana"

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ATP-binding cassette (ABC) superfamily is the largest protein family identified in all organisms. It is a highly conserved domain responsible for the ATP-dependent transport of substances including ions, carbohydrates, xenobiotics, drugs, and peptides. Also, the subfamily, multidrug resistance...

  3. Improving cancer treatment with cyclotron produced radionuclides. [Multiple Drug Resistance (MDR)

    SciTech Connect

    Larson, S.M.; Finn, R.D.

    1990-10-15

    The overall objective of this work was to promote nuclear medicine applications in oncology. This is being done by improving the scientific basis of diagnosis, treatment and treatment follow-up with cyclotron-produced tracers. For diagnostic use, positron-emitting isotopes such as Ga-66 and I-124 are being used. Initial studies on the characterization of He-4 particle energies required for Ga-66 production have been completed. Parameters for I-124 radiolabelling of monoclonal antibodies have been determined; the labelled antibodies have been used in animal studies using positron emission tomography (PET) to quantify antibody concentration within tumors in vivo. Imaging physics studies have demonstrated that I-124 can be quantitatively imaged by PET, even in the presence of 100-told greater concentrations of I-131. Measurement of concentrations of label in vivo has been accomplished in nuclei mice bearing neuroblastoma tumors and nude rats bearing human ovarian cancer cells. These studies have major implications for both the quantification of dosimetry and quantification kinetic assessment of anti-tumor antibody localization in vivo. For treatment of tumors, F-18 has been incorporated in 2-fluoro-2-deoxy glucose and 5-fluoro uridine, and O-15 labelled water has been produced. Reagents incorporating C-11 and N-13 are under development. In a related area, C-14 labelled colchicine is being studied as a means of assaying cells for multiple drug resistance (MDR). Cells expressing MDR are shown to retain significantly less C-14 colchiene. This suggest that colchiene retention may be of useful probe in modelling and studying MDR development in human tumors. The precursor required for producing C-11 colchicine has also been synthesized. 11 refs. (MHB)

  4. Whole genome sequencing of multiple Leishmania donovani clinical isolates provides insights into population structure and mechanisms of drug resistance.

    PubMed

    Downing, Tim; Imamura, Hideo; Decuypere, Saskia; Clark, Taane G; Coombs, Graham H; Cotton, James A; Hilley, James D; de Doncker, Simonne; Maes, Ilse; Mottram, Jeremy C; Quail, Mike A; Rijal, Suman; Sanders, Mandy; Schönian, Gabriele; Stark, Olivia; Sundar, Shyam; Vanaerschot, Manu; Hertz-Fowler, Christiane; Dujardin, Jean-Claude; Berriman, Matthew

    2011-12-01

    Visceral leishmaniasis is a potentially fatal disease endemic to large parts of Asia and Africa, primarily caused by the protozoan parasite Leishmania donovani. Here, we report a high-quality reference genome sequence for a strain of L. donovani from Nepal, and use this sequence to study variation in a set of 16 related clinical lines, isolated from visceral leishmaniasis patients from the same region, which also differ in their response to in vitro drug susceptibility. We show that whole-genome sequence data reveals genetic structure within these lines not shown by multilocus typing, and suggests that drug resistance has emerged multiple times in this closely related set of lines. Sequence comparisons with other Leishmania species and analysis of single-nucleotide diversity within our sample showed evidence of selection acting in a range of surface- and transport-related genes, including genes associated with drug resistance. Against a background of relative genetic homogeneity, we found extensive variation in chromosome copy number between our lines. Other forms of structural variation were significantly associated with drug resistance, notably including gene dosage and the copy number of an experimentally verified circular episome present in all lines and described here for the first time. This study provides a basis for more powerful molecular profiling of visceral leishmaniasis, providing additional power to track the drug resistance and epidemiology of an important human pathogen. PMID:22038251

  5. Incidence and Characterization of Integrons, Genetic Elements Mediating Multiple-Drug Resistance, in Avian Escherichia coli

    PubMed Central

    Bass, Lydia; Liebert, Cynthia A.; Lee, Margie D.; Summers, Anne O.; White, David G.; Thayer, Stephan G.; Maurer, John J.

    1999-01-01

    Antibiotic resistance among avian bacterial isolates is common and is of great concern to the poultry industry. Approximately 36% (n = 100) of avian, pathogenic Escherichia coli isolates obtained from diseased poultry exhibited multiple-antibiotic resistance to tetracycline, oxytetracycline, streptomycin, sulfonamides, and gentamicin. Clinical avian E. coli isolates were further screened for the presence of markers for class 1 integrons, the integron recombinase intI1 and the quaternary ammonium resistance gene qacEΔ1, in order to determine the contribution of integrons to the observed multiple-antibiotic resistance phenotypes. Sixty-three percent of the clinical isolates were positive for the class 1 integron markers intI1 and qacEΔ1. PCR analysis with the conserved class 1 integron primers yielded amplicons of approximately 1 kb from E. coli isolates positive for intI1 and qacEΔ1. These PCR amplicons contained the spectinomycin-streptomycin resistance gene aadA1. Further characterization of the identified integrons revealed that many were part of the transposon Tn21, a genetic element that encodes both antibiotic resistance and heavy-metal resistance to mercuric compounds. Fifty percent of the clinical isolates positive for the integron marker gene intI1 as well as for the qacEΔ1 and aadA1 cassettes also contained the mercury reductase gene merA. The correlation between the presence of the merA gene with that of the integrase and antibiotic resistance genes suggests that these integrons are located in Tn21. The presence of these elements among avian E. coli isolates of diverse genetic makeup as well as in Salmonella suggests the mobility of Tn21 among pathogens in humans as well as poultry. PMID:10582884

  6. Multiple drugs compete for transport via the Plasmodium falciparum chloroquine resistance transporter at distinct but interdependent sites.

    PubMed

    Bellanca, Sebastiano; Summers, Robert L; Meyrath, Max; Dave, Anurag; Nash, Megan N; Dittmer, Martin; Sanchez, Cecilia P; Stein, Wilfred D; Martin, Rowena E; Lanzer, Michael

    2014-12-26

    Mutations in the "chloroquine resistance transporter" (PfCRT) are a major determinant of drug resistance in the malaria parasite Plasmodium falciparum. We have previously shown that mutant PfCRT transports the antimalarial drug chloroquine away from its target, whereas the wild-type form of PfCRT does not. However, little is understood about the transport of other drugs via PfCRT or the mechanism by which PfCRT recognizes different substrates. Here we show that mutant PfCRT also transports quinine, quinidine, and verapamil, indicating that the protein behaves as a multidrug resistance carrier. Detailed kinetic analyses revealed that chloroquine and quinine compete for transport via PfCRT in a manner that is consistent with mixed-type inhibition. Moreover, our analyses suggest that PfCRT accepts chloroquine and quinine at distinct but antagonistically interacting sites. We also found verapamil to be a partial mixed-type inhibitor of chloroquine transport via PfCRT, further supporting the idea that PfCRT possesses multiple substrate-binding sites. Our findings provide new mechanistic insights into the workings of PfCRT, which could be exploited to design potent inhibitors of this key mediator of drug resistance. PMID:25378409

  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. Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1α

    PubMed Central

    Arnason, Terra; Harkness, Troy

    2015-01-01

    Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds. Our recent work suggests the anticoagulant protein Tissue Factor Pathway Inhibitor 1α (TFPI1α) plays a role in driving the development of multiple drug resistance (MDR); but not maintenance; of the MDR state. Other factors; such as the ABC transporter drug efflux pumps MDR-1/P-gp (ABCB1) and BCRP (ABCG2); are required for MDR maintenance; as well as development. The patient population struggling with therapeutic resistance specifically requires novel treatment options to resensitize these tumor cells to therapy. In this review we discuss the development, maintenance, and reversal of MDR as three distinct phases of cancer biology. Possible means to exploit these stages to reverse MDR will be explored. Early molecular detection of MDR cancers before clinical failure has the potential to offer new approaches to fighting MDR cancer. PMID:26501324

  9. The oncogenic PIM kinase family regulates drug resistance through multiple mechanisms.

    PubMed

    Isaac, Methvin; Siu, Allan; Jongstra, Jan

    2011-01-01

    Resistance to chemotherapeutic drugs is a significant clinical problem for the treatment of cancer patients and has been linked to the activation of survival pathways and expression of multidrug efflux transporters. Thus inhibition of these survival pathways or efflux transporter expression may increase the efficacy of drug treatment. Here we review the role of the oncogenic PIM kinase family in regulating important proliferation and survival pathways in cancer cells and the involvement of PIM kinases in the expression and activity of MDR-1 and BCRP, two of the most important drug efflux transporters. PIM kinases are over expressed in various types of tumors and regulate the activation of signaling pathways that are important for tumor cell proliferation, survival and expression of drug efflux proteins. This makes PIM kinases attractive targets for the development of anti-cancer chemotherapeutic drugs. Focussing mainly on solid tumors, we provide an update on the literature describing the tumorigenic functions of PIM kinases. Also we provide an overview of the development of selective small molecule PIM kinase inhibitors. Because of the intense effort by pharmaceutical companies and academia it is reasonable to expect that PIM kinase inhibitors will enter the clinic in the foreseeable future. We therefore finish this review with a discussion on the most efficient application of these PIM inhibitors. This includes a consideration of which tumor type is the most appropriate target for treatment, how to select the patient population that stands to gain the most from treatment with PIM inhibitors, which molecular markers are suitable to follow the course of treatment and whether PIM kinase inhibitors should be used as monotherapy or in combination with other cytotoxic agents. PMID:21601509

  10. Trastuzumab-deBouganin Conjugate Overcomes Multiple Mechanisms of T-DM1 Drug Resistance.

    PubMed

    Dillon, Rachelle L; Chooniedass, Shilpa; Premsukh, Arjune; Adams, Gregory P; Entwistle, Joycelyn; MacDonald, Glen C; Cizeau, Jeannick

    2016-04-01

    The development of antibody drug conjugates has provided enhanced potency to tumor-targeting antibodies by the addition of highly potent payloads. In the case of trastuzumab-DM1 (T-DM1), approved for the treatment of metastatic breast cancer, the addition of mertansine (DM1) to trastuzumab substantially increased progression-free survival. Despite these improvements, most patients eventually relapse due to complex mechanisms of resistance often associated with small molecule chemotherapeutics. Therefore, identifying payloads with different mechanisms of action (MOA) is critical for increasing the efficacy of targeted therapeutics and ultimately improving patient outcomes. To evaluate payloads with different MOA, deBouganin, a deimmunized plant toxin that inhibits protein synthesis, was conjugated to trastuzumab and compared with T-DM1 both in vitro and in vivo. The trastuzumab-deBouganin conjugate (T-deB) demonstrated greater potency in vitro against most cells lines with high levels of Her2 expression. In addition, T-deB, unlike T-DM1, was unaffected by inhibitors of multidrug resistance, Bcl-2-mediated resistance, or Her2-Her3 dimerization. Contrary to T-DM1 that showed only minimal cytotoxicity, T-deB was highly potent in vitro against tumor cells with cancer stem cell properties. Overall, the results demonstrate the potency and efficacy of deBouganin and emphasize the importance of using payloads with different MOAs. The data suggest that deBouganin could be a highly effective against tumor cell phenotypes not being addressed by current antibody drug conjugate formats and thereby provide prolonged clinical benefit. PMID:26938945

  11. Hemibody irradiation. An effective second-line therapy in drug-resistance multiple myeloma

    SciTech Connect

    Singer, C.R.; Tobias, J.S.; Giles, F.; Rudd, G.N.; Blackman, G.M.; Richards, J.D.

    1989-06-15

    The authors report the results of treatment of 41 patients with melphalan-resistant multiple myeloma using single half-body irradiation (HBI) or double half-body irradiation (DHBI). Patients were grouped using prognostic classification reported by the Medical Research Council. Patients in group I and II showed the best response to therapy with reduction in serum of urinary paraprotein and improvement in symptoms, most notably a marked reduction in bone pain. In these groups five patients have survived over 2 years after therapy. The therapeutic response appeared better in those patients who received DHBI as opposed to those whom treated with single HBI. Patients in group III did not achieve prolonged survival but effective relief of bone pain was a consistent finding in these patients also. Thus HBI represents an alternative to combination chemotherapy as second-line treatment of patients with melphalan-resistant multiple myeloma. A comparative study of HBI versus combination chemotherapy is now indicated to establish which therapeutic approach is most effective.

  12. Emergence of Staphylococcus aureus carrying multiple drug resistance genes on a plasmid encoding exfoliative toxin B.

    PubMed

    Hisatsune, Junzo; Hirakawa, Hideki; Yamaguchi, Takayuki; Fudaba, Yasuyuki; Oshima, Kenshiro; Hattori, Masahira; Kato, Fuminori; Kayama, Shizuo; Sugai, Motoyuki

    2013-12-01

    We report the complete nucleotide sequence and analysis of pETBTY825, a Staphylococcus aureus TY825 plasmid encoding exfoliative toxin B (ETB). S. aureus TY825 is a clinical isolate obtained from an impetigo patient in 2002. The size of pETBTY825, 60.6 kbp, was unexpectedly larger than that of the archetype pETBTY4 (∼30 kbp). Genomic comparison of the plasmids shows that pETBTY825 has the archetype pETBTY4 as the backbone and has a single large extra DNA region of 22.4 kbp. The extra DNA region contains genes for resistance to aminoglycoside [aac(6')/aph(2″)], macrolide (msrA), and penicillin (blaZ). A plasmid deletion experiment indicated that these three resistance elements were functionally active. We retrospectively examined the resistance profile of the clinical ETB-producing S. aureus strains isolated in 1977 to 2007 using a MIC determination with gentamicin (GM), arbekacin (ABK), and erythromycin (EM) and by PCR analyses for aac(6')/aph(2″) and msrA using purified plasmid preparations. The ETB-producing S. aureus strains began to display high resistance to GM, which was parallel with the detection of aac(6')/aph(2″) and mecA, after 1990. Conversely, there was no significant change in the ABK MIC during the testing period, although it had a tendency to slightly increase. After 2001, isolates resistant to EM significantly increased; however, msrA was hardly detected in ETB-producing S. aureus strains, and only five isolates were positive for both aac(6')/aph(2″) and msrA. In this study, we report the emergence of a fusion plasmid carrying the toxin gene etb and drug resistance genes. Prevalence of the pETBTY825 carrier may further increase the clinical threat, since ETB-producing S. aureus is closely related to more severe impetigo or staphylococcal scalded-skin syndrome (SSSS), which requires a general antimicrobial treatment. PMID:24080652

  13. Ursodeoxycholic acid pretreatment reduces oral bioavailability of the multiple drug resistance-associated protein 2 substrate baicalin in rats.

    PubMed

    Wu, Tao; Li, Xi-Ping; Xu, Yan-Jiao; Du, Guang; Liu, Dong

    2013-11-01

    Baicalin is a major bioactive component of Scutellaria baicalensis and a substrate of multiple drug resistance-associated protein 2. Expression of multiple drug resistance-associated protein 2 is regulated by NF-E2-related factor 2. The aim of this study was to explore whether ursodeoxycholic acid, an NF-E2-related factor 2 activator, could influence the oral bioavailability of baicalin. A single dose of baicalin (200 mg/kg) was given orally to rats pretreated with ursodeoxycholic acid (75 mg/kg and 150 mg/kg, per day, intragastrically) or normal saline (per day, intragastrically) for six consecutive days. The plasma concentration of baicalin was measured with the HPLC method. The result indicated that the oral bioavailability of baicalin was significantly and dose-dependently reduced in rats pretreated with ursodeoxycholic acid. Compared with control rats, the mean area under concentration-time curve of baicalin was reduced from 13.25 ± 0.24 mg/L h to 7.62 ± 0.15 mg/L h and 4.97 ± 0.21 mg/L h, and the C(max) value was decreased from 1.31 ± 0.03 mg/L to 0.62 ± 0.05 mg/L and 0.36 ± 0.04 mg/L in rats pretreated with ursodeoxycholic acid at doses of 75 mg/kg and 150 mg/kg, respectively, for six consecutive days. Hence, ursodeoxycholic acid treatment reduced the oral bioavailability of baicalin in rats, probably due to the enhanced efflux of baicalin from the intestine and liver by multiple drug resistance-associated protein 2. PMID:24135887

  14. SerpinE2 promotes multiple cell proliferation and drug resistance in osteosarcoma.

    PubMed

    Mao, Minzhi; Wang, Wanchun

    2016-07-01

    SerpinE2 is a member of the Serpins family, which could inhibit serine protease and promote tumor progression, particularly in tumor metastasis. However, at present, its role in the progression of osteosarcoma has not been determined. The present study analyzed the expression profiles of SerpinE2 in cancer tissues, including tissues from osteosarcoma of different stages. Higher expression of SerpinE2 was shown in osteosarcoma tissues, particularly in tissue from patients with metastasis and a tumor-node-metastasis stage II‑III. Following chemotherapy, the SerpinE2 expression levels were shown to be higher than those at diagnosis. Cell proliferation and colony formation were increased after transfection with SerpinE2 over‑expression vector. Additionally, drug resistance to bortezomib and doxorubicin treatment following SerpinE2 transfection was analyzed. MG‑63 and SAOS‑2 cells showed less sensitivity following transfection with SerpinE2. The cell cycle‑related genes, cyclin‑dependent kinase (CDK)4 and cyclin D1 were positively correlated with SerpinE2 expression in patient‑derived tissue and in osteosarcoma cells. Finally, the high expression of SerpinE2 contributes to poor survival rates in patients with osteosarcoma. In conclusion, high expression of SerpinE2 in osteosarcoma stimulates cell proliferation, promotes drug‑resistance, and results in poor survival by regulating CDK4 and cyclin D1. Thus, SerpinE2 could be a potential target for treatment of patients with osteosarcoma. PMID:27221371

  15. Bedaquiline versus placebo for management of multiple drug-resistant tuberculosis: A systematic review

    PubMed Central

    Charan, Jaykaran; Reljic, Tea; Kumar, Ambuj

    2016-01-01

    Background: Multidrug-resistant tuberculosis (MDR-TB) is associated with significant morbidity and mortality. Bedaquiline is the first drug approved for treating MDR-TB. Objectives: We performed a systematic review and meta-analysis to summarize the totality of all available evidence on the efficacy of bedaquiline for the management of MDR-TB. Materials and Methods: We searched the following PubMed and Cochrane Registry of Clinical Trials. Randomized controlled trials (RCTs) with a parallel design comparing bedaquiline versus any treatment for the management of MDR-TB in adults were eligible for inclusion. Data were pooled under a random effects model. Results: Two trials published as three manuscripts with a total of 207 patients were included. As per the Cochrane risk of bias tool, majority of parameter were labeled as high or unclear risk of bias. Bedaquiline compared with placebo was associated with a statistically significant decrease in time to conversion of positive sputum culture to negative at 8 and 24 weeks with a significant increase in mortality on long-term follow-up. There was no difference in completion rates between bedaquiline and placebo. Conclusion: Bedaquiline is an effective treatment modality for MDR-TB but needs to be balanced against significant mortality. Future Phase 3 RCTs are needed to make a conclusive recommendation. PMID:27127322

  16. Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.

    PubMed

    Chakravarty, Geetika; Mathur, Aditi; Mallade, Pallavi; Gerlach, Samantha; Willis, Joniece; Datta, Amrita; Srivastav, Sudesh; Abdel-Mageed, Asim B; Mondal, Debasis

    2016-05-01

    Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus

  17. Detection of multiple drug-resistant Trypanosoma congolense populations in village cattle of south-east Mali

    PubMed Central

    2012-01-01

    responded positively to DIM treatment. Conclusions The overreliance on trypanocides in the control of trypanosomosis will ultimately lead to multiple drug-resistant trypanosome populations as detected in villages in south-east Mali rendering the use of drugs doubtful. Effective alternative methods for trypanosomosis control ought to substitute chemotherapy to ensure sustainable cattle production in these villages. Since there is no single strategy for containing trypanocidal drug resistance, promotion of an integrated approach combining proven trypanosomosis control approaches in high trypanosomosis risk areas is most desirous. The best-bet strategy this study recommended for areas with multiple drug resistance included area-wide community tsetse control, control of co-infections to exploit self-cure against resistant trypanosome populations and the rational use of trypanocidal drugs which should be urgently promoted at all levels as a way of containing or reversing resistance. PMID:22852796

  18. Molecular diagnostics of a single drug-resistant multiple myeloma case using targeted next-generation sequencing

    PubMed Central

    Ikeda, Hiroshi; Ishiguro, Kazuya; Igarashi, Tetsuyuki; Aoki, Yuka; Hayashi, Toshiaki; Ishida, Tadao; Sasaki, Yasushi; Tokino, Takashi; Shinomura, Yasuhisa

    2015-01-01

    A 69-year-old man was diagnosed with IgG λ-type multiple myeloma (MM), Stage II in October 2010. He was treated with one cycle of high-dose dexamethasone. After three cycles of bortezomib, the patient exhibited slow elevations in the free light-chain levels and developed a significant new increase of serum M protein. Bone marrow cytogenetic analysis revealed a complex karyotype characteristic of malignant plasma cells. To better understand the molecular pathogenesis of this patient, we sequenced for mutations in the entire coding regions of 409 cancer-related genes using a semiconductor-based sequencing platform. Sequencing analysis revealed eight nonsynonymous somatic mutations in addition to several copy number variants, including CCND1 and RB1. These alterations may play roles in the pathobiology of this disease. This targeted next-generation sequencing can allow for the prediction of drug resistance and facilitate improvements in the treatment of MM patients. PMID:26491355

  19. The Transmission and Antibiotic Resistance Variation in a Multiple Drug Resistance Clade of Vibrio cholerae Circulating in Multiple Countries in Asia

    PubMed Central

    Zhou, Zhemin; Diao, Baowei; Cui, Zhigang; Zhou, Haijian; Kan, Biao

    2016-01-01

    Vibrio cholerae has caused massive outbreaks and even trans-continental epidemics. In 2008 and 2010, at least 3 remarkable cholera outbreaks occurred in Hainan, Anhui and Jiangsu provinces of China. To address the possible transmissions and the relationships to the 7th pandemic strains of those 3 outbreaks, we sequenced the whole genomes of the outbreak isolates and compared with the global isolates from the 7th pandemic. The three outbreaks in this study were caused by a cluster of V. cholerae in clade 3.B which is parallel to the clade 3.C that was transmitted from Nepal to Haiti and caused an outbreak in 2010. Pan-genome analysis provided additional evolution information on the mobile element and acquired multiple antibiotic resistance genes. We suggested that clade 3.B should be monitored because the multiple antibiotic resistant characteristics of this clade and the ‘amplifier’ function of China in the global transmission of current Cholera pandemic. We also show that dedicated whole genome sequencing analysis provided more information than the previous techniques and should be applied in the disease surveillance networks. PMID:26930352

  20. The Transmission and Antibiotic Resistance Variation in a Multiple Drug Resistance Clade of Vibrio cholerae Circulating in Multiple Countries in Asia.

    PubMed

    Pang, Bo; Du, Pengcheng; Zhou, Zhemin; Diao, Baowei; Cui, Zhigang; Zhou, Haijian; Kan, Biao

    2016-01-01

    Vibrio cholerae has caused massive outbreaks and even trans-continental epidemics. In 2008 and 2010, at least 3 remarkable cholera outbreaks occurred in Hainan, Anhui and Jiangsu provinces of China. To address the possible transmissions and the relationships to the 7th pandemic strains of those 3 outbreaks, we sequenced the whole genomes of the outbreak isolates and compared with the global isolates from the 7th pandemic. The three outbreaks in this study were caused by a cluster of V. cholerae in clade 3.B which is parallel to the clade 3.C that was transmitted from Nepal to Haiti and caused an outbreak in 2010. Pan-genome analysis provided additional evolution information on the mobile element and acquired multiple antibiotic resistance genes. We suggested that clade 3.B should be monitored because the multiple antibiotic resistant characteristics of this clade and the 'amplifier' function of China in the global transmission of current Cholera pandemic. We also show that dedicated whole genome sequencing analysis provided more information than the previous techniques and should be applied in the disease surveillance networks. PMID:26930352

  1. Drug Resistance in Leishmaniasis

    PubMed Central

    Chakravarty, Jaya; Sundar, Shyam

    2010-01-01

    The treatment options of leishmaniasis are limited and far from satisfactory. For more than 60 years, treatment of leishmaniasis has centered around pentavalent antimonials (Sbv). Widespread misuse has led to the emergence of Sbv resistance in the hyperendemic areas of North Bihar. Other antileishmanials could also face the same fate, especially in the anthroponotic cycle. The HIV/ visceral leishmaniasis (VL) coinfected patients are another potential source for the emergence of drug resistance. At present no molecular markers of resistance are available and the only reliable method for monitoring resistance of isolates is the technically demanding in vitro amastigote-macrophage model. As the armametrium of drugs for leishmaniasis is limited, it is important that effective monitoring of drug use and response should be done to prevent the spread of resistance. Regimens of simultaneous or sequential combinations should be seriously considered to limit the emergence of resistance. PMID:20606973

  2. Multiple antibiotic resistance in Rhizobium japonicum.

    PubMed

    Cole, M A; Elkan, G H

    1979-05-01

    A total of 48 strains of the soil bacterium Rhizobium japonicum were screened for their response to several widely used antibiotics. Over 60% of the strains were resistant to chloramphenicol, polymyxin B, and erythromycin, and 47% or more of the strains were resistant to neomycin and penicillin G, when tested by disk assay procedures. The most common grouping of resistances in strains was simultaneous resistance to tetracycline, penicillin G, neomycin, chloramphenicol, and streptomycin (25% of all strains tested). The occurrence of multiple drug resistance in a soil bacterium that is not a vertebrate pathogen suggests that chemotherapeutic use of antibiotics is not required for the development of multiple drug resistance. PMID:485137

  3. Analysis of Antimicrobial Resistance Genes in Multiple Drug Resistant (MDR) Escherichia coli Isolated from Broiler Chicken Carcasses

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: MDR food-borne bacteria are a concern in both animal and human health. To understand the mechanisms driving this problem, the genetic elements responsible for resistance need to be determined and analyzed. Methods: From 2000-2007, 16,912 Escherichia coli were isolated from broiler carcas...

  4. Antibiotic Resistance, RAPD- PCR Typing of Multiple Drug Resistant Strains of Escherichia Coli From Urinary Tract Infection (UTI)

    PubMed Central

    Marialouis, Xavier Alexander

    2016-01-01

    Introduction Global spreading of multidrug resistant strains of Escherichia coli is responsible for Urinary Tract Infection (UTI) which is a major health problem in of concern. Among the gram negative bacteria, the major contributors for UTI belongs to the family Enterobacteriaceae, which includes E. coli, Klebsiella, Citrobacter and Proteus. However, E. coli accounts for the major cause of Urinary tract infections (UTIs) and accounts for 75% to 90% of UTI isolates. Aim The main aim of this study is to analyse the phylogenetic grouping of clinical isolates of UTI E. coli. Materials and Methods In this study nearly 58 E. coli strains were isolated and confirmed through microbiological, biochemical characterization. The urine samples were collected from outpatients having symptoms of UTI, irrespective of age and sex in Tamil Nadu, India. The isolates were subjected to analyse for ESBL and AmpC β-lactamase production. To understand its genetic correlation, molecular typing was carried out using RAPD-PCR method. Results Here we noted phenotypically twenty seven isolates were positive for ESBL and seven for AmpC β-lactamase production. However, among the ESBL isolates higher sensitivity was noted for Nitrofurantoin and Cefoxitin. It is worth to note that the prevalence of UTIs was more common among female and elderly male. Phylogenetic grouping revealed the presence of 24 isolates belonged to B2 group followed by 19 isolates to group A, eight isolates to group B1 and Seven isolates to group D. Conclusion Phenotypically most of the strains were positive for ESBL and showed high sensitivity for Nitrofurantoin and cefoxitin. PMID:27134870

  5. 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

  6. Drug resistance in leishmaniasis.

    PubMed

    Croft, Simon L; Sundar, Shyam; Fairlamb, Alan H

    2006-01-01

    Leishmaniasis is a complex disease, with visceral and cutaneous manifestations, and is caused by over 15 different species of the protozoan parasite genus Leishmania. There are significant differences in the sensitivity of these species both to the standard drugs, for example, pentavalent antimonials and miltefosine, and those on clinical trial, for example, paromomycin. Over 60% of patients with visceral leishmaniasis in Bihar State, India, do not respond to treatment with pentavalent antimonials. This is now considered to be due to acquired resistance. Although this class of drugs has been used for over 60 years for leishmaniasis treatment, it is only in the past 2 years that the mechanisms of action and resistance have been identified, related to drug metabolism, thiol metabolism, and drug efflux. With the introduction of new therapies, including miltefosine in 2002 and paromomycin in 2005-2006, it is essential that there be a strategy to prevent the emergence of resistance to new drugs; combination therapy, monitoring of therapy, and improved diagnostics could play an essential role in this strategy. PMID:16418526

  7. Drugs Approved for Multiple Myeloma

    Cancer.gov

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for multiple myeloma and other plasma cell neoplasms. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters. The drug names link to NCI's Cancer Drug Information summaries.

  8. A treatment plant receiving waste water from multiple bulk drug manufacturers is a reservoir for highly multi-drug resistant integron-bearing bacteria.

    PubMed

    Marathe, Nachiket P; Regina, Viduthalai R; Walujkar, Sandeep A; Charan, Shakti Singh; Moore, Edward R B; Larsson, D G Joakim; Shouche, Yogesh S

    2013-01-01

    The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into

  9. A Treatment Plant Receiving Waste Water from Multiple Bulk Drug Manufacturers Is a Reservoir for Highly Multi-Drug Resistant Integron-Bearing Bacteria

    PubMed Central

    Walujkar, Sandeep A.; Charan, Shakti Singh; Moore, Edward R. B.; Larsson, D. G. Joakim; Shouche, Yogesh S.

    2013-01-01

    The arenas and detailed mechanisms for transfer of antibiotic resistance genes between environmental bacteria and pathogens are largely unclear. Selection pressures from antibiotics in situations where environmental bacteria and human pathogens meet are expected to increase the risks for such gene transfer events. We hypothesize that waste-water treatment plants (WWTPs) serving antibiotic manufacturing industries may provide such spawning grounds, given the high bacterial densities present there together with exceptionally strong and persistent selection pressures from the antibiotic-contaminated waste. Previous analyses of effluent from an Indian industrial WWTP that processes waste from bulk drug production revealed the presence of a range of drugs, including broad spectrum antibiotics at extremely high concentrations (mg/L range). In this study, we have characterized the antibiotic resistance profiles of 93 bacterial strains sampled at different stages of the treatment process from the WWTP against 39 antibiotics belonging to 12 different classes. A large majority (86%) of the strains were resistant to 20 or more antibiotics. Although there were no classically-recognized human pathogens among the 93 isolated strains, opportunistic pathogens such as Ochrobactrum intermedium, Providencia rettgeri, vancomycin resistant Enterococci (VRE), Aerococcus sp. and Citrobacter freundii were found to be highly resistant. One of the O. intermedium strains (ER1) was resistant to 36 antibiotics, while P. rettgeri (OSR3) was resistant to 35 antibiotics. Class 1 and 2 integrons were detected in 74/93 (80%) strains each, and 88/93 (95%) strains harbored at least one type of integron. The qPCR analysis of community DNA also showed an unprecedented high prevalence of integrons, suggesting that the bacteria living under such high selective pressure have an appreciable potential for genetic exchange of resistance genes via mobile gene cassettes. The present study provides insight into

  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. CD44hiCD24lo mammosphere-forming cells from primary breast cancer display resistance to multiple chemotherapeutic drugs.

    PubMed

    Ji, Ping; Zhang, Yong; Wang, Shu-Jun; Ge, Hai-Liang; Zhao, Guo-Ping; Xu, Ying-Chun; Wang, Ying

    2016-06-01

    -like properties together with multiple drug resistance. Determination of the sensitivity of these primary cancer-derived mammosphere-forming cells to chemotherapeutic drugs may thus provide useful instructions for individualized therapy against the recurrence of breast cancer in the future. PMID:27109463

  12. Old drugs, novel ways out: Drug resistance toward cytotoxic chemotherapeutics.

    PubMed

    Wijdeven, Ruud H; Pang, Baoxu; Assaraf, Yehuda G; Neefjes, Jacques

    2016-09-01

    Efficacy of chemotherapy in the treatment of distinct malignancies is often hampered by drug resistance arising in the tumor. Understanding the molecular basis of drug resistance and translating this knowledge into personalized treatment decisions can enhance therapeutic efficacy and even curative outcome. Over the years, multiple drug resistance mechanisms have been identified that enable tumors to cope with the damage instigated by a specific drug or group of anti-tumor agents. Here we provide an overview of the molecular pathways leading to resistance against conventional anti-cancer drugs, with emphasis on the utility of these pathways for rational selection of treatments for individual cancer patients. We further complement the review by discussing the pitfalls and difficulties in translating these findings into novel treatment strategies for cancer patients. PMID:27620955

  13. Antimalarial drug resistance: An overview.

    PubMed

    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

  14. 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

  15. Multiple Introduction and Naturally Occuring Drug Resistance of HCV among HIV-Infected Intravenous Drug Users in Yunnan: An Origin of China’s HIV/HCV Epidemics

    PubMed Central

    Chen, Min; Ma, Yanling; Chen, Huichao; Luo, Hongbing; Dai, Jie; Song, Lijun; Yang, Chaojun; Mei, Jingyuan; Yang, Li; Dong, Lijuan; Jia, Manhong; Lu, Lin

    2015-01-01

    Background The human immunodeficiency virus 1 (HIV-1) epidemic in China historically stemmed from intravenous drug users (IDUs) in Yunnan. Due to a shared transmission route, hepatitis C virus (HCV)/HIV-1 co-infection is common. Here, we investigated HCV genetic characteristics and baseline drug resistance among HIV-infected IDUs in Yunnan. Methods Blood samples of 432 HIV-1/HCV co-infected IDUs were collected from January to June 2014 in six prefectures of Yunnan Province. Partial E1E2 and NS5B genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed. Results Among the 293 specimens successfully genotyped, seven subtypes were identified, including subtypes 3b (37.9%, 111/293), 3a (21.8%, 64/293), 6n (14.0%, 41/293), 1b (10.6%, 31/293), 1a (8.2%, 24/293), 6a (5.1%, 15/293) and 6u (2.4%, 7/293). The distribution of HCV subtypes was mostly related to geographic location. Subtypes 3b, 3a, and 6n were detected in all six prefectures, however, the other four subtypes were detected only in parts of the six prefectures. Phylogeographic analyses indicated that 6n, 1a and 6u originated in the western prefecture (Dehong) and spread eastward and showed genetic relatedness with those detected in Burmese. However, 6a originated in the southeast prefectures (Honghe and Wenshan) bordering Vietnam and was transmitted westward. These subtypes exhibited different evolutionary rates (between 4.35×10−4 and 2.38×10−3 substitutions site-1 year-1) and times of most recent common ancestor (tMRCA, between 1790.3 and 1994.6), suggesting that HCV was multiply introduced into Yunnan. Naturally occurring resistance-associated mutations (C316N, A421V, C445F, I482L, V494A, and V499A) to NS5B polymerase inhibitors were detected in direct-acting antivirals (DAAs)-naïve IDUs. Conclusion This work reveals the temporal-spatial distribution of HCV subtypes and baseline HCV drug resistance among HIV-infected IDUs in Yunnan. The findings enhance our

  16. Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid

    PubMed Central

    Ro, Dae-Kyun; Ouellet, Mario; Paradise, Eric M; Burd, Helcio; Eng, Diana; Paddon, Chris J; Newman, Jack D; Keasling, Jay D

    2008-01-01

    Background Due to the global occurrence of multi-drug-resistant malarial parasites (Plasmodium falciparum), the anti-malarial drug most effective against malaria is artemisinin, a natural product (sesquiterpene lactone endoperoxide) extracted from sweet wormwood (Artemisia annua). However, artemisinin is in short supply and unaffordable to most malaria patients. Artemisinin can be semi-synthesized from its precursor artemisinic acid, which can be synthesized from simple sugars using microorganisms genetically engineered with genes from A. annua. In order to develop an industrially competent yeast strain, detailed analyses of microbial physiology and development of gene expression strategies are required. Results Three plant genes coding for amorphadiene synthase, amorphadiene oxidase (AMO or CYP71AV1), and cytochrome P450 reductase, which in concert divert carbon flux from farnesyl diphosphate to artemisinic acid, were expressed from a single plasmid. The artemisinic acid production in the engineered yeast reached 250 μg mL-1 in shake-flask cultures and 1 g L-1 in bio-reactors with the use of Leu2d selection marker and appropriate medium formulation. When plasmid stability was measured, the yeast strain synthesizing amorphadiene alone maintained the plasmid in 84% of the cells, whereas the yeast strain synthesizing artemisinic acid showed poor plasmid stability. Inactivation of AMO by a point-mutation restored the high plasmid stability, indicating that the low plasmid stability is not caused by production of the AMO protein but by artemisinic acid synthesis or accumulation. Semi-quantitative reverse-transcriptase (RT)-PCR and quantitative real time-PCR consistently showed that pleiotropic drug resistance (PDR) genes, belonging to the family of ATP-Binding Cassette (ABC) transporter, were massively induced in the yeast strain producing artemisinic acid, relative to the yeast strain producing the hydrocarbon amorphadiene alone. Global transcriptional analysis by

  17. Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3

    PubMed Central

    Lv, Meng; Liang, Xiaodong; Dai, Hui; Qin, Xiaodan; Zhang, Yan; Hao, Jie; Sun, Xiuyuan; Yin, Yanhui; Huang, Xiaojun; Zhang, Jun; Lu, Jin; Ge, Qing

    2016-01-01

    Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis. PMID:26848618

  18. Nosocomial outbreak of septicaemia in neonatal intensive care unit due to extended spectrum β-lactamase producing Klebsiella pneumoniae showing multiple mechanisms of drug resistance.

    PubMed

    Rastogi, V; Nirwan, P S; Jain, S; Kapil, A

    2010-01-01

    A total of 14 phenotypically similar clinical isolates of Klebsiella pneumoniae, resistant to multiple drugs including cefotaxime and ceftazidime, were isolated from blood of neonates admitted to neonatal intensive care unit (NICU) within a short span of 10 days. Alarmed at the possibility of occurrence of outbreak, a thorough investigation was done. Microbiological sampling of the NICU and labour room (LR) environment yielded 12 K. pneumoniae isolates. The presence of extended spectrum β-lactamase (ESBL) in the clinical and environmental strains was detected by double-disk synergy test (DDST), CLSI phenotypic confirmatory disk diffusion test (PCDDT) and E-test ESBL strips. Amp-C screen (disk) test was done to determine Amp-C β-lactamase production. 100% clinical strains, 57% NICU strains and 80% LR strains were ESBL positive. 57% clinical, 43% NICU and 20% LR strains were Amp-C screen positive. Polymerase chain reaction (PCR) of representative ESBL positive (10 clinical and 5 environmental) strains showed CTX gene and TEM and/or SHV gene in all. K. pneumoniae showing multiple mechanisms of drug resistance was responsible for the outbreak. PMID:20966575

  19. Mechanisms of drug resistance: quinolone resistance

    PubMed Central

    Hooper, David C.; Jacoby, George A.

    2015-01-01

    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

  20. 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

  1. Relationship between multiple drug resistance and biofilm formation in Staphylococcus aureus isolated from medical and non-medical personnel in Yaounde, Cameroon

    PubMed Central

    Eyoh, Agnes Bedie; Toukam, Michel; Atashili, Julius; Fokunang, Charles; Gonsu, Hortense; Lyonga, Emilia Enjema; Mandi, Henshaw; Ikomey, George; Mukwele, Bertha; Mesembe, Martha; Assoumou, Marie Claire Okomo

    2014-01-01

    Introduction Monitoring the prevalence of nasal carriage of multiple drug resistance (MDR) Staphylococcus aureus (SA) strains in hospital personnel is essential. These strains when transmitted from hospital personnel to patients with already weakened immune states or in-built medical devices, may limit the latter's treatment options. This study aimed at assessing the potential exposure of patients to these MDR SA in a resource-limited hospital setting by assessing the prevalence and relationship between antimicrobial susceptibility and biofilm forming capacity of SA isolates from hospital personnel. Methods A total of 59 bacteria isolates phenotypically identified as Staphylococcus aureus obtained from medical (39) and non-medical personnel (20) in Yaounde were used in the study. Multiple drug resistance defined as resistance to four or more of twelve locally used antibiotics were determined by Kirby Bauer disc diffusion technique whereas quantification of biofilm production was by the microtitre plate method. Results Among the 59 SA isolates, the prevalence of MDR was 50.9%. Among medical personnel 48.7% had MDR as against 55.9% for non-medical personnel (p-value=0.648). The overall percentage of weak biofilm producers was 35.6%. Although the prevalence of weak biofilm formers was higher in isolates from non-medical personnel (40%) than medical personnel (33.3%) the difference was not statistically significant (p-value= 0.246). Slightly less than half (42.9%) of the weak biofilm producers were MDR. Conclusion Considering the high rates of MDR and that slightly less than half of biofilm formers were MDR, these trends need to be monitored regularly among hospital personnel in Yaounde. PMID:25396012

  2. Fosfomycin, interesting alternative drug for treatment of urinary tract infections created by multiple drug resistant and extended spectrum β-lactamase producing strains

    PubMed Central

    Yeganeh-Sefidan, Fatemeh; Ghotaslou, Reza; Akhi, Mohammad Taghi; Sadeghi, Mohammad Reza; Mohammadzadeh-Asl, Yalda; Bannazadeh Baghi, Hussein

    2016-01-01

    Background and Objectives: The emergence and spread of multidrug resistant (MDR) and extended spectrum β-lactamase (ESBL) producing strains reduces the number of effective drugs that can be used for treatment. The aim of this study was to evaluate the susceptibility profile of Enterobacteriaceae isolated from UTIs, specifically MDR and ESBL producing strains, to fosfomycin and other antibiotics. Materials and Methods: The study was performed during a 6 month period (February 2014 to August 2015). A total of 219 non-duplicate urinary isolates of Enterobacteriaceae were collected. Identification and susceptibility testing was done according to standard microbiological procedures and the Kirby-Bauer test, respectively. Based on the results obtained from susceptibility testing, MDR bacteria were recovered and identification of ESBL production was done according to CLSI recommendation. Results: Isolates of E. coli and Klebsiella spp. were responsible for 80.8% and 12.8% of patients with UTIs respectively. The rates of resistance to ampicillin, cefazolin, nalidixic acid, trimethoprim-sulfamethoxazole were 86.3%, 79.4%, 68.5% and 63.9% respectively. In contrast, high sensitivity rates were detected to fosfomycin, amikacin and amoxicillin-clavulanic acid with 97.3%, 91.8% and 80.8%, respectively. Of all isolates, 167 (76.3%) were detected as MDR and 75 (34.2%) as ESBL producing strains. Conclusion: The rate of antibiotic resistance among uropathogens Enterobacteriaceae is remarkably high. The most effective antibiotic was fosfomycin. Moreover, susceptibility to fosfomycin is over 90% for MDR and ESBL producer isolates. Therefore, fosfomycin can be a good option for treating UTIs. PMID:27307978

  3. [Resistance to the antimalarial drugs].

    PubMed

    Venanzi, E; López-Vélez, R

    2016-09-01

    Malaria is one of the most widespread infectious diseases around the world with 214 million cases and 438,000 deaths in 2015. In the early twentieth century it was described for the first time the resistance to quinine and, since then, drug resistance to antimalarial drugs has spread up to represent a global challenge in the fight and control of malaria. Understanding the mechanisms, geography and monitoring tools that we can act against resistance to antimalarial drugs is critical to prevent its expansion. PMID:27608319

  4. Cbl-b inhibits P-gp transporter function by preventing its translocation into caveolae in multiple drug-resistant gastric and breast cancers

    PubMed Central

    Zhang, Ye; Qu, Xiujuan; Teng, Yuee; Li, Zhi; Xu, Ling; Liu, Jing; Ma, Yanju; Fan, Yibo; Li, Ce; Liu, Shizhou; Wang, Zhenning; Hu, Xuejun; Zhang, Jingdong; Liu, Yunpeng

    2015-01-01

    The transport function of P-glycoprotein (P-gp) requires its efficient localization to caveolae, a subset of lipid rafts, and disruption of caveolae suppresses P-gp transport function. However, the regulatory molecules involved in the translocation of P-gp into caveolae remain unknown. In the present study, we showed that c-Src dependent Caveolin-1 phosphorylation promoted the translocation of P-gp into caveolae, resulting in multidrug resistance in adriamycin resistant gastric cancer SGC7901/Adr and breast cancer MCF-7/Adr cells. In a negative feedback loop, the translocation of Cbl-b from the nucleus to the cytoplasm prevented the localization of P-gp to caveolae resulting in the reversal of MDR through the ubiquitination and degradation of c-Src. Clinical data showed a significant positive relationship between Cbl-b expression and survival in P-gp positive breast cancer patients who received anthracycline-based chemotherapy. Our findings identified a new regulatory mechanism of P-gp transport function in multiple drug-resistant gastric and breast cancers. PMID:25788263

  5. Dissemination of Multiple Drug Resistance Genes by Class 1 Integrons in Klebsiella pneumoniae Isolates from Four Countries: a Comparative Study ▿

    PubMed Central

    Roy Chowdhury, Piklu; Ingold, Ana; Vanegas, Natasha; Martínez, Elena; Merlino, John; Merkier, Andrea Karina; Castro, Mercedes; González Rocha, Gerardo; Borthagaray, Graciela; Centrón, Daniela; Bello Toledo, Helia; Márquez, Carolina M.; Stokes, H. W.

    2011-01-01

    A comparative genetic analysis of 42 clinical Klebsiella pneumoniae isolates, resistant to two or more antibiotics belonging to the broad-spectrum β-lactam group, sourced from Sydney, Australia, and three South American countries is presented. The study focuses on the genetic contexts of class 1 integrons, mobilizable genetic elements best known for their role in the rapid evolution of antibiotic resistance among Gram-negative pathogens. It was found that the class 1 integrons in this cohort were located in a number of different genetic contexts with clear regional differences. In Sydney, IS26-associated Tn21-like transposons on IncL/M plasmids contribute greatly to the dispersal of integron-associated multiple-drug-resistant (MDR) loci. In contrast, in the South American countries, Tn1696-like transposons on an IncA/C plasmid(s) appeared to be disseminating a characteristic MDR region. A range of mobile genetic elements is clearly being recruited by clinically important mobile class 1 integrons, and these elements appear to be becoming more common with time. This in turn is driving the evolution of complex and laterally mobile MDR units and may further complicate antibiotic therapy. PMID:21518841

  6. 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

  7. A nano ultra-performance liquid chromatography-high resolution mass spectrometry approach for global metabolomic profiling and case study on drug-resistant multiple myeloma.

    PubMed

    Jones, Drew R; Wu, Zhiping; Chauhan, Dharminder; Anderson, Kenneth C; Peng, Junmin

    2014-04-01

    Global metabolomics relies on highly reproducible and sensitive detection of a wide range of metabolites in biological samples. Here we report the optimization of metabolome analysis by nanoflow ultraperformance liquid chromatography coupled to high-resolution orbitrap mass spectrometry. Reliable peak features were extracted from the LC-MS runs based on mandatory detection in duplicates and additional noise filtering according to blank injections. The run-to-run variation in peak area showed a median of 14%, and the false discovery rate during a mock comparison was evaluated. To maximize the number of peak features identified, we systematically characterized the effect of sample loading amount, gradient length, and MS resolution. The number of features initially rose and later reached a plateau as a function of sample amount, fitting a hyperbolic curve. Longer gradients improved unique feature detection in part by time-resolving isobaric species. Increasing the MS resolution up to 120000 also aided in the differentiation of near isobaric metabolites, but higher MS resolution reduced the data acquisition rate and conferred no benefits, as predicted from a theoretical simulation of possible metabolites. Moreover, a biphasic LC gradient allowed even distribution of peak features across the elution, yielding markedly more peak features than the linear gradient. Using this robust nUPLC-HRMS platform, we were able to consistently analyze ~6500 metabolite features in a single 60 min gradient from 2 mg of yeast, equivalent to ~50 million cells. We applied this optimized method in a case study of drug (bortezomib) resistant and drug-sensitive multiple myeloma cells. Overall, 18% of metabolite features were matched to KEGG identifiers, enabling pathway enrichment analysis. Principal component analysis and heat map data correctly clustered isogenic phenotypes, highlighting the potential for hundreds of small molecule biomarkers of cancer drug resistance. PMID:24611431

  8. [Drug resistant epilepsy. Clinical and neurobiological concepts].

    PubMed

    Espinosa-Jovel, Camilo A; Sobrino-Mejía, Fidel E

    2015-08-16

    Drug-resistant epilepsy, is a condition defined by the International League Against Epilepsy as persistent seizures despite having used at least two appropriate and adequate antiepileptic drug treatments. Approximately 20-30% of patients with epilepsy are going to be resistant to antiepileptic drugs, with different patterns of clinical presentation, which are related to the biological basis of this disease (de novo resistance, relapsing-remitting and progressive). Drug resistant epilepsy, impacts negatively the quality of life and significantly increases the risk of premature death. From the neurobiological point of view, this medical condition is the result of the interaction of multiple variables related to the underlying disease, drug interactions and proper genetic aspects of each patient. Thanks to advances in pharmacogenetics and molecular biology research, currently some hypotheses may explain the cause of this condition and promote the study of new therapeutic options. Currently, overexpression of membrane transporters such as P-glycoprotein, appears to be one of the most important mechanisms in the development of drug resistant epilepsy. The objective of this review is to deepen the general aspects of this clinical condition, addressing the definition, epidemiology, differential diagnosis and the pathophysiological bases. PMID:26204087

  9. Drug resistance in eukaryotic microorganisms.

    PubMed

    Fairlamb, Alan H; Gow, Neil A R; Matthews, Keith R; Waters, Andrew P

    2016-01-01

    Eukaryotic microbial pathogens are major contributors to illness and death globally. Although much of their impact can be controlled by drug therapy as with prokaryotic microorganisms, the emergence of drug resistance has threatened these treatment efforts. Here, we discuss the challenges posed by eukaryotic microbial pathogens and how these are similar to, or differ from, the challenges of prokaryotic antibiotic resistance. The therapies used for several major eukaryotic microorganisms are then detailed, and the mechanisms that they have evolved to overcome these therapies are described. The rapid emergence of resistance and the restricted pipeline of new drug therapies pose considerable risks to global health and are particularly acute in the developing world. Nonetheless, we detail how the integration of new technology, biological understanding, epidemiology and evolutionary analysis can help sustain existing therapies, anticipate the emergence of resistance or optimize the deployment of new therapies. PMID:27572976

  10. Overexpression of PDZK1 within the 1q12-q22 Amplicon Is Likely To Be Associated with Drug-Resistance Phenotype in Multiple Myeloma

    PubMed Central

    Inoue, Jun; Otsuki, Takemi; Hirasawa, Akira; Imoto, Issei; Matsuo, Yoshinobu; Shimizu, Shiroh; Taniwaki, Masafumi; Inazawa, Johji

    2004-01-01

    We investigated DNA copy number aberrations in 37 cell lines derived from multiple myelomas (MMs) using comparative genomic hybridization, and 11 (29.7%) showed high-level gain indicative of gene amplification at 1q12-q22. A corresponding transcriptional mapping using oligonucleotide arrays extracted three up-regulated genes (IRTA2, PDZK1, and S100A6) within the smallest region of overlapping in amplifications. Among them PDZK1 showed amplification and consequent overexpression in the MM cell lines. Amplification of PDZK1 was observed in primary cases of MM as well. MM cell lines with amplification of PDZK1 exhibited the resistance to melphalan-, cis-platin-, and vincristin-induced cell death compared with MM cell lines without its amplifications. Furthermore, down-regulation of PDZK1 with an anti-sense oligonucleotide sensitized a cell line KMS-11 to melphalan, cis-platin, and vincristin. Taken together, our results indicate that PDZK1 is likely to be one of targets for 1q12-q22 amplification in MM and may be associated with the malignant phenotype, including drug resistance, in this type of tumor. PMID:15215163

  11. [Infection caused by Mycobacterium tuberculosis with primary resistance to multiple drugs: a case report of a patient with AIDS].

    PubMed

    Grinbaum, R S; Daher, M; Medeiros, E A; de Mendonça, J S; Beu, M F; Kusano, E; Telles, M A; Ueki, S Y

    1995-01-01

    Primary multidrug-resistant Mycobacterium tuberculosis is an important problem in the United States. There is no report in formal literature of this pathogen in Brazilian patients. CASE REPORT--We report a case of ganglionar tuberculosis diagnosed by acid-fast smears in a male, HIV positive patient. Mode of acquisition of HIV was not determined. Treatment was started, and isoniazid, rifampicin and pyrazinamide were prescribed. The patient and his family reported strict adherence to therapy, but no improvement was observed. After 75 days, the patient was admitted in our hospital because of clinical worsening. Clinical features were the presence of large submandibular and axillar lymph nodes, respiratory insufficiency and complains of abdominal pain. He died six days after admission. Culture obtained from the ganglionar aspirate disclosed M. tuberculosis susceptible to ethambutol, but resistant to isoniazid, rifampicin, pyrazinamide, ethionamide and streptomycin. DISCUSSION--Although this was a case of extrapulmonary tuberculosis, there is a concern about multidrug-resistant tuberculosis, that has been poorly evaluated in Brazil. Since high lethality and intrahospital transmission have been reported, we discuss the need of performing culture and antibiogram in suspected cases, and the prevention of the spread of M. tuberculosis to patients and health-care workers through the strict adherence to the isolation practices. PMID:8574241

  12. 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

  13. Antimicrobial (Drug) Resistance Prevention

    MedlinePlus

    ... Action Plan for Combating Antibiotic-Resistant Bacteria (PDF) ​​​​​​ Javascript Error Your browser JavaScript is turned off causing certain features of the ... incorrectly. Please visit your browser settings and turn JavaScript on. Read more information on enabling JavaScript. Skip ...

  14. 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

  15. Multiple Disease Resistance in Plants.

    PubMed

    Wiesner-Hanks, Tyr; Nelson, Rebecca

    2016-08-01

    Many plants, both in nature and in agriculture, are resistant to multiple diseases. Although much of the plant innate immunity system provides highly specific resistance, there is emerging evidence to support the hypothesis that some components of plant defense are relatively nonspecific, providing multiple disease resistance (MDR). Understanding MDR is of fundamental and practical interest to plant biologists, pathologists, and breeders. This review takes stock of the available evidence related to the MDR hypothesis. Questions about MDR are considered primarily through the lens of forward genetics, starting at the organismal level and proceeding to the locus level and, finally, to the gene level. At the organismal level, MDR may be controlled by clusters of R genes that evolve under diversifying selection, by dispersed, pathogen-specific genes, and/or by individual genes providing MDR. Based on the few MDR loci that are well-understood, MDR is conditioned by diverse mechanisms at the locus and gene levels. PMID:27296142

  16. In Vitro Resistance Selections for Plasmodium falciparum Dihydroorotate Dehydrogenase Inhibitors Give Mutants with Multiple Point Mutations in the Drug-binding Site and Altered Growth*

    PubMed Central

    Ross, Leila S.; Gamo, Francisco Javier; Lafuente-Monasterio, Maria José; Singh, Onkar M. P.; Rowland, Paul; Wiegand, Roger C.; Wirth, Dyann F.

    2014-01-01

    Malaria is a preventable and treatable disease; yet half of the world's population lives at risk of infection, and an estimated 660,000 people die of malaria-related causes every year. Rising drug resistance threatens to make malaria untreatable, necessitating both the discovery of new antimalarial agents and the development of strategies to identify and suppress the emergence and spread of drug resistance. We focused on in-development dihydroorotate dehydrogenase (DHODH) inhibitors. Characterizing resistance pathways for antimalarial agents not yet in clinical use will increase our understanding of the potential for resistance. We identified resistance mechanisms of Plasmodium falciparum (Pf) DHODH inhibitors via in vitro resistance selections. We found 11 point mutations in the PfDHODH target. Target gene amplification and unknown mechanisms also contributed to resistance, albeit to a lesser extent. These mutant parasites were often hypersensitive to other PfDHODH inhibitors, which immediately suggested a novel combination therapy approach to preventing resistance. Indeed, a combination of wild-type and mutant-type selective inhibitors led to resistance far less often than either drug alone. The effects of point mutations in PfDHODH were corroborated with purified recombinant wild-type and mutant-type PfDHODH proteins, which showed the same trends in drug response as the cognate cell lines. Comparative growth assays demonstrated that two mutant parasites grew less robustly than their wild-type parent, and the purified protein of those mutants showed a decrease in catalytic efficiency, thereby suggesting a reason for the diminished growth rate. Co-crystallography of PfDHODH with three inhibitors suggested that hydrophobic interactions are important for drug binding and selectivity. PMID:24782313

  17. Extensively drug-resistant tuberculosis.

    PubMed

    Jassal, Mandeep; Bishai, William R

    2009-01-01

    Extensively drug-resistant (XDR) tuberculosis is defined as disease caused by Mycobacterium tuberculosis with resistance to at least isoniazid and rifampicin, any fluoroquinolone, and at least one of three injectable second-line drugs (amikacin, capreomycin, or kanamycin). The definition has applicable clinical value and has allowed for more uniform surveillance in varied international settings. Recent surveillance data have indicated that the prevalence of tuberculosis drug resistance has risen to the highest rate ever recorded. The gold standard for drug-susceptibility testing has been the agar proportion method; however, this technique requires several weeks for results to be determined. More sensitive and specific diagnostic tests are still unavailable in resource-limited settings. Clinical manifestations, although variable in different settings and among different strains, have in general shown that XDR tuberculosis is associated with greater morbidity and mortality than non-XDR tuberculosis. The treatment of XDR tuberculosis should include agents to which the organism is susceptible, and should continue for a minimum of 18-24 months. However, treatment continues to be limited in tuberculosis-endemic countries largely because of weaknesses in national tuberculosis health-care models. The ultimate strategy to control drug-resistant tuberculosis is one that implements a comprehensive approach incorporating innovation from the political, social, economic, and scientific realms. PMID:18990610

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

    PubMed

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

    2016-09-01

    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

  19. 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

  20. Antiviral Drug Resistance: Mechanisms and Clinical Implications

    PubMed Central

    Chou, Sunwen

    2010-01-01

    Summary Antiviral drug resistance is an increasing concern in immunocompromised patient populations, where ongoing viral replication and prolonged drug exposure lead to the selection of resistant strains. Rapid diagnosis of resistance can be made by associating characteristic viral mutations with resistance to various drugs as determined by phenotypic assays. Management of drug resistance includes optimization of host factors and drug delivery, selection of alternative therapies based on knowledge of mechanisms of resistance, and the development of new antivirals. This article discusses drug resistance in herpesviruses and hepatitis B. PMID:20466277

  1. Overcoming drug resistance in multi-drug resistant cancers and microorganisms: a conceptual framework.

    PubMed

    Avner, Benjamin S; Fialho, Arsenio M; Chakrabarty, Ananda M

    2012-01-01

    Resistance development against multiple drugs is a common feature among many pathogens--including bacteria such as Pseudomonas aeruginosa, viruses, and parasites--and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their

  2. Transformation of cinnamic acid from trans- to cis-form raises a notable bactericidal and synergistic activity against multiple-drug resistant Mycobacterium tuberculosis.

    PubMed

    Chen, Yen-Ling; Huang, Shao-Tsung; Sun, Fang-Ming; Chiang, Yu-Ling; Chiang, Chia-Jung; Tsai, Chiung-Man; Weng, Chia-Jui

    2011-06-14

    Tuberculosis (TB) is a contagious disease caused by Mycobacterium tuberculosis. The long course of treatments on TB with a combination of antibiotics leads unfavorable side effects and poor patient compliance which contributes to sustaining multiple-drug resistant tuberculosis (MDR-TB). Therefore, the development of a new effective drug or synergist to reduce the prevalence of MDR-TB is urgent to date. Cinnamic acid (CA) is a natural occurring phenolic compound with anti-microbial activity. Both trans- and cis-isoforms of CA exist in planta, and cis-cinnamic acid (c-CA) can be transformed from trans-cinnamic acid (t-CA) under sunlight. Due to the unavailability of c-CA, the literature regarding the biological functions of c-CA is still limited. We had previously developed a practicable method for the transformation of c-CA from t-CA and the isolation of c-CA. Using the techniques, sufficient c-CA was obtained to evaluate its antituberculosis activity against a MDR M. tuberculosis strain. Moreover, the synergistic effects of c-CA and t-CA with two first-line anti-TB antibiotics, isoniazid (INH) and rifampicin (RIF), were also determined. Although both of c-CA and t-CA decreased the viability of MDR-TB bacilli in a dose-dependent manner, the antituberculosis activity of c-CA was approximately 120-fold of t-CA. Furthermore, the c-CA exhibited higher synergistic effect with INH or RIF against tuberculosis than t-CA. The micrographs of scanning electron microscope (SEM) display that c-CA caused an injury on the out-layer of MDR-TB bacilli. The c-CA might be a potential anti-mycobacterial or synergistic agent that can be developed to against tuberculosis. PMID:21536127

  3. Resistant multiple sparse canonical correlation.

    PubMed

    Coleman, Jacob; Replogle, Joseph; Chandler, Gabriel; Hardin, Johanna

    2016-04-01

    Canonical correlation analysis (CCA) is a multivariate technique that takes two datasets and forms the most highly correlated possible pairs of linear combinations between them. Each subsequent pair of linear combinations is orthogonal to the preceding pair, meaning that new information is gleaned from each pair. By looking at the magnitude of coefficient values, we can find out which variables can be grouped together, thus better understanding multiple interactions that are otherwise difficult to compute or grasp intuitively. CCA appears to have quite powerful applications to high-throughput data, as we can use it to discover, for example, relationships between gene expression and gene copy number variation. One of the biggest problems of CCA is that the number of variables (often upwards of 10,000) makes biological interpretation of linear combinations nearly impossible. To limit variable output, we have employed a method known as sparse canonical correlation analysis (SCCA), while adding estimation which is resistant to extreme observations or other types of deviant data. In this paper, we have demonstrated the success of resistant estimation in variable selection using SCCA. Additionally, we have used SCCA to find multiple canonical pairs for extended knowledge about the datasets at hand. Again, using resistant estimators provided more accurate estimates than standard estimators in the multiple canonical correlation setting. R code is available and documented at https://github.com/hardin47/rmscca. PMID:26963062

  4. Cytokines in cancer drug resistance: Cues to new therapeutic strategies.

    PubMed

    Jones, Valerie Sloane; Huang, Ren-Yu; Chen, Li-Pai; Chen, Zhe-Sheng; Fu, Liwu; Huang, Ruo-Pan

    2016-04-01

    The development of oncoprotein-targeted anticancer drugs is an invaluable weapon in the war against cancer. However, cancers do not give up without a fight. They may develop multiple mechanisms of drug resistance, including apoptosis inhibition, drug expulsion, and increased proliferation that reduce the effectiveness of the drug. The collective work of researchers has highlighted the role of cytokines in the mechanisms of cancer drug resistance, as well as in cancer cell progression. Furthermore, recent studies have described how specific cytokines secreted by cancer stromal cells confer resistance to chemotherapeutic treatments. In order to gain a better understanding of mechanism of cancer drug resistance and a prediction of treatment outcome, it is imperative that correlations are established between global cytokine profiles and cancer drug resistance. Here we discuss the recent discoveries in this field of research and discuss their implications for the future development of effective anti-cancer medicines. PMID:26993403

  5. Nanomedicine therapeutic approaches to overcome cancer drug resistance.

    PubMed

    Markman, Janet L; Rekechenetskiy, Arthur; Holler, Eggehard; Ljubimova, Julia Y

    2013-11-01

    Nanomedicine is an emerging form of therapy that focuses on alternative drug delivery and improvement of the treatment efficacy while reducing detrimental side effects to normal tissues. Cancer drug resistance is a complicated process that involves multiple mechanisms. Here we discuss the major forms of drug resistance and the new possibilities that nanomedicines offer to overcome these treatment obstacles. Novel nanomedicines that have a high ability for flexible, fast drug design and production based on tumor genetic profiles can be created making drug selection for personal patient treatment much more intensive and effective. This review aims to demonstrate the advantage of the young medical science field, nanomedicine, for overcoming cancer drug resistance. With the advanced design and alternative mechanisms of drug delivery known for different nanodrugs including liposomes, polymer conjugates, micelles, dendrimers, carbon-based, and metallic nanoparticles, overcoming various forms of multi-drug resistance looks promising and opens new horizons for cancer treatment. PMID:24120656

  6. 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.

  7. 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

  8. Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis

    PubMed Central

    Mitnick, Carole D.; Shin, Sonya S.; Seung, Kwonjune J.; Rich, Michael L.; Atwood, Sidney S.; Furin, Jennifer J.; Fitzmaurice, Garrett M.; Alcantara Viru, Felix A.; Appleton, Sasha C.; Bayona, Jaime N.; Bonilla, Cesar A.; Chalco, Katiuska; Choi, Sharon; Franke, Molly F.; Fraser, Hamish S.F.; Guerra, Dalia; Hurtado, Rocio M.; Jazayeri, Darius; Joseph, Keith; Llaro, Karim; Mestanza, Lorena; Mukherjee, Joia S.; Muñoz, Maribel; Palacios, Eda; Sanchez, Epifanio; Sloutsky, Alexander; Becerra, Mercedes C.

    2009-01-01

    BACKGROUND Extensively drug-resistant tuberculosis has been reported in 45 countries, including countries with limited resources and a high burden of tuberculosis. We describe the management of extensively drug-resistant tuberculosis and treatment outcomes among patients who were referred for individualized outpatient therapy in Peru. METHODS A total of 810 patients were referred for free individualized therapy, including drug treatment, resective surgery, adverse-event management, and nutritional and psychosocial support. We tested isolates from 651 patients for extensively drug-resistant tuberculosis and developed regimens that included five or more drugs to which the infecting isolate was not resistant. RESULTS Of the 651 patients tested, 48 (7.4%) had extensively drug-resistant tuberculosis; the remaining 603 patients had multidrug-resistant tuberculosis. The patients with extensively drug-resistant tuberculosis had undergone more treatment than the other patients (mean [±SD] number of regimens, 4.2±1.9 vs. 3.2±1.6; P<0.001) and had isolates that were resistant to more drugs (number of drugs, 8.4±1.1 vs. 5.3±1.5; P<0.001). None of the patients with extensively drug-resistant tuberculosis were coinfected with the human immunodeficiency virus (HIV). Patients with extensively drug-resistant tuberculosis received daily, supervised therapy with an average of 5.3±1.3 drugs, including cycloserine, an injectable drug, and a fluoroquinolone. Twenty-nine of these patients (60.4%) completed treatment or were cured, as compared with 400 patients (66.3%) with multidrug-resistant tuberculosis (P=0.36). CONCLUSIONS Extensively drug-resistant tuberculosis can be cured in HIV-negative patients through outpatient treatment, even in those who have received multiple prior courses of therapy for tuberculosis. PMID:18687637

  9. 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

  10. 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

  11. 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

  12. Contemporary drug therapies for multiple myeloma.

    PubMed

    de la Puente, P; Azab, A K

    2013-09-01

    Multiple myeloma (MM) is an incurable disease characterized by the proliferation of plasma cells. The survival in MM patients has improved significantly in the past decade due to the introduction of novel agents. In this review, we focus on novel agents used in MM, including immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide), proteasome inhibitors (bortezomib, carfilzomib, marizomib and ixazomib citrate), monoclonal antibodies (elotuzumab, siltuximab, daratumumab and BT-062), and drugs affecting an interaction with the tumor microenvironment (anti-VLA4 monoclonal antibody, chemokine CXCR4 inhibitor AMD-3100 and selectin inhibitor GMI-1070). We discuss their mechanism of action, preclinical and clinical outcome in the treatment of MM. Although the development of novel agents has improved the outcomes of MM treatment, most of the patients will still relapse and become refractory to therapy due to development of drug resistance. A better understanding of the biological mechanisms of MM progression, including cellular and molecular events in the MM cells and in their bone marrow microenvironment, is warranted to provide new therapeutic targets and develop new drugs and therapeutic strategies to treat MM. PMID:24086952

  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. 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

  15. 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

  16. Extensively Drug-Resistant Tuberculosis: A New Face to an Old Pathogen

    PubMed Central

    Shenoi, Sheela; Friedland, Gerald

    2009-01-01

    The presence and consequences of resistance to drugs used for the treatment of tuberculosis have long been neglected. The recent detection and recognition of widespread multiple-drug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis have raised interest and concern among clinicians and public health authorities globally. In this article, we describe the current global status of drug-resistant tuberculosis. We discuss the development of resistance, current management, and strategies for control. PMID:19630575

  17. Superinfection and the evolution of resistance to antimalarial drugs

    PubMed Central

    Klein, Eili Y.; Smith, David L.; Laxminarayan, Ramanan; Levin, Simon

    2012-01-01

    A major issue in the control of malaria is the evolution of drug resistance. Ecological theory has demonstrated that pathogen superinfection and the resulting within-host competition influences the evolution of specific traits. Individuals infected with Plasmodium falciparum are consistently infected by multiple parasites; however, while this probably alters the dynamics of resistance evolution, there are few robust mathematical models examining this issue. We developed a general theory for modelling the evolution of resistance with host superinfection and examine: (i) the effect of transmission intensity on the rate of resistance evolution; (ii) the importance of different biological costs of resistance; and (iii) the best measure of the frequency of resistance. We find that within-host competition retards the ability and slows the rate at which drug-resistant parasites invade, particularly as the transmission rate increases. We also find that biological costs of resistance that reduce transmission are less important than reductions in the duration of drug-resistant infections. Lastly, we find that random sampling of the population for resistant parasites is likely to significantly underestimate the frequency of resistance. Considering superinfection in mathematical models of antimalarial drug resistance may thus be important for generating accurate predictions of interventions to contain resistance. PMID:22787024

  18. Mathematical models of the epidemiology and control of drug-resistant TB.

    PubMed

    Cohen, Ted; Dye, Christopher; Colijn, Caroline; Williams, Brian; Murray, Megan

    2009-02-01

    Recent reports of extensively drug-resistant TB in South Africa have renewed concerns that antibiotic resistance may undermine progress in TB control. We review three major questions for which mathematical models elucidate the epidemiology and control of drug-resistant TB. How is multiple drug-resistant Mycobacterium tuberculosis selected for in individuals exposed to combination chemotherapy? What factors determine the prevalence of drug-resistant TB? Which interventions to prevent the spread of drug-resistant TB are effective and feasible? Models offer insight into the acquisition and amplification of drug resistance, reveal the importance of distinguishing the intrinsic and extrinsic determinants of the reproductive capacity of drug-resistant M. tuberculosis, and demonstrate the cost effectiveness of interventions for drug-resistant TB. These models also highlight knowledge gaps for which new research will improve our ability to project trends of drug resistance and develop more effective policies for its control. PMID:20477283

  19. Amplification of a Gene Related to Mammalian mdr Genes in Drug-Resistant Plasmodium falciparum

    NASA Astrophysics Data System (ADS)

    Wilson, Craig M.; Serrano, Adelfa E.; Wasley, Annemarie; Bogenschutz, Michael P.; Shankar, Anuraj H.; Wirth, Dyann F.

    1989-06-01

    The malaria parasite Plasmodium falciparum contains at least two genes related to the mammalian multiple drug resistance genes, and at least one of the P. falciparum genes is expressed at a higher level and is present in higher copy number in a strain that is resistant to multiple drugs than in a strain that is sensitive to the drugs.

  20. 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

  1. Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance.

    PubMed

    Valle, Demetrio L; Cabrera, Esperanza C; Puzon, Juliana Janet M; Rivera, Windell L

    2016-01-01

    Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria. PMID

  2. Antimicrobial Activities of Methanol, Ethanol and Supercritical CO2 Extracts of Philippine Piper betle L. on Clinical Isolates of Gram Positive and Gram Negative Bacteria with Transferable Multiple Drug Resistance

    PubMed Central

    Valle, Demetrio L.; Cabrera, Esperanza C.; Puzon, Juliana Janet M.; Rivera, Windell L.

    2016-01-01

    Piper betle L. has traditionally been used in alternative medicine in different countries for various therapeutic purposes, including as an anti-infective agent. However, studies reported in the literature are mainly on its activities on drug susceptible bacterial strains. This study determined the antimicrobial activities of its ethanol, methanol, and supercritical CO2 extracts on clinical isolates of multiple drug resistant bacteria which have been identified by the Infectious Disease Society of America as among the currently more challenging strains in clinical management. Assay methods included the standard disc diffusion method and the broth microdilution method for the determination of the minimum inhibitory concentration (MIC) and the minimum bactericidal concentrations (MBC) of the extracts for the test microorganisms. This study revealed the bactericidal activities of all the P. betle leaf crude extracts on methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE), extended spectrum β-lactamase-producing Enterobacteriaceae, carbapenem-resistant Enterobacteriaceae, and metallo-β-lactamase-producing Pseudomonas aeruginosa and Acinetobacter baumannii, with minimum bactericidal concentrations that ranged from 19μg/ml to 1250 μg/ml. The extracts proved to be more potent against the Gram positive MRSA and VRE than for the Gram negative test bacteria. VRE isolates were more susceptible to all the extracts than the MRSA isolates. Generally, the ethanol extracts proved to be more potent than the methanol extracts and supercritical CO2 extracts as shown by their lower MICs for both the Gram positive and Gram negative MDRs. MTT cytotoxicity assay showed that the highest concentration (100 μg/ml) of P. betle ethanol extract tested was not toxic to normal human dermal fibroblasts (HDFn). Data from the study firmly established P. betle as an alternative source of anti-infectives against multiple drug resistant bacteria. PMID

  3. Clinical Management of HIV Drug Resistance

    PubMed Central

    Cortez, Karoll J.; Maldarelli, Frank

    2011-01-01

    Combination antiretroviral therapy for HIV-1 infection has resulted in profound reductions in viremia and is associated with marked improvements in morbidity and mortality. Therapy is not curative, however, and prolonged therapy is complicated by drug toxicity and the emergence of drug resistance. Management of clinical drug resistance requires in depth evaluation, and includes extensive history, physical examination and laboratory studies. Appropriate use of resistance testing provides valuable information useful in constructing regimens for treatment-experienced individuals with viremia during therapy. This review outlines the emergence of drug resistance in vivo, and describes clinical evaluation and therapeutic options of the individual with rebound viremia during therapy. PMID:21994737

  4. 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

  5. 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

  6. A functional variomics tool for discovering drug resistance genes and drug targets

    PubMed Central

    Huang, Zhiwei; Chen, Kaifu; Zhang, Jianhuai; Li, Yongxiang; Wang, Hui; Cui, Dandan; Tang, Jiangwu; Liu, Yong; Shi, Xiaomin; Li, Wei; Liu, Dan; Chen, Rui; Sucgang, Richard S.; Pan, Xuewen

    2013-01-01

    Comprehensive discovery of genetic mechanisms of drug resistance and identification of in vivo drug targets represent significant challenges. Here we present a functional variomics technology in the model organism Saccharomyces cerevisiae. This tool analyzes numerous genetic variants and effectively tackles both problems simultaneously. Using this tool, we discovered almost all genes that, due to mutations or modest overexpression, confer resistance to rapamycin, cycloheximide, and amphotericin B. Most significant among the resistance genes were drug targets, including multiple targets of a given drug. With amphotericin B, we discovered the highly conserved membrane protein Pmp3 as a potent resistance factor and a possible novel target. Widespread application of this tool should allow rapid identification of conserved resistance mechanisms and targets of many more compounds. New genes and alleles that confer resistance to other stresses can also be discovered. Similar tools in other systems such as human cell lines will also be useful. PMID:23416056

  7. Medical Management of Drug-Resistant Tuberculosis

    PubMed Central

    2015-01-01

    Drug-resistant tuberculosis (TB) is still a major threat worldwide. However, recent scientific advances in diagnostic and therapeutic tools have improved the management of drug-resistant TB. The development of rapid molecular testing methods allows for the early detection of drug resistance and prompt initiation of an appropriate treatment. In addition, there has been growing supportive evidence for shorter treatment regimens in multidrug-resistant TB; and for the first time in over 50 years, new anti-TB drugs have been developed. The World Health Organization has recently revised their guidelines, primarily based on evidence from a meta-analysis of individual patient data (n=9,153) derived from 32 observational studies, and outlined the recommended combination and correct use of available anti-TB drugs. This review summarizes the updated guidelines with a focus on the medical management of drug-resistant TB. PMID:26175768

  8. 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.

  9. Emergence of therapy resistance in multiple myeloma in heterogeneous microenvironment

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

    Cancer chemotherapy resistance is always a problem that is not clear considering spatial heterogeneity in the tumor microenvironment. We culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region in a microfluidic device which mimics the tumor microenvironment with a chemotherapy drug gradient and microhabitats. Resistance of the multiple myeloma cells to doxorubicin emerged within two weeks. For the resistant cells evolved from the devices, the doxorubicin concentration that inhibits 50% of the controlled population increased by 16-fold than the parental cells. Whole transcriptome sequencing revealed that 39% of newly acquired mutational hotspots (the genes with more than 3 non-synonymous point mutation) of the resistant cells are involved in apoptosis and DNA repair. On the other hand, 40% of the non-mutated genes that are abnormally regulated in the resistant cells, are involved in metabolism, biosynthesis, and biomolecular transport. Among them, metabolic drug efflux pumps and oxidative stress scavengers are up-regulated to reduce the cytotoxicity of doxorubicin and further result in the resistance. The roles of the spatial drug gradients and microhabitats in rapid emergence of cancer resistance will be discussed. The project described was supported by the National Science Foundation and the National Cancer Institute.

  10. Anticipating designer drug-resistant cancer cells.

    PubMed

    Frangione, Mark L; Lockhart, John H; Morton, Daniel T; Pava, Libia M; Blanck, George

    2015-07-01

    Successful use of anticancer designer drugs is likely to depend on simultaneous combinations of these drugs to minimize the development of resistant cancer cells. Considering the knowledge base of cancer signaling pathways, mechanisms of designer drug resistance should be anticipated, and early clinical trials could be designed to include arms that combine new drugs specifically with currently US Food and Drug Administration (FDA)-approved drugs expected to blunt alternative signaling pathways. In this review, we indicate examples of alternative signal pathways for recent anticancer drugs, and the use of original, Python-based software to systematically identify signaling pathways that could facilitate resistance to drugs targeting a particular protein. Pathway alternatives can be assessed at http://www.alternativesignalingpathways.com, developed with this review article. PMID:25697478

  11. Drug-Resistant Candida glabrata Infection in Cancer Patients

    PubMed Central

    Farmakiotis, Dimitrios; Tarrand, Jeffrey J.

    2014-01-01

    Cancer patients are at risk for candidemia, and increasing Candida spp. resistance poses an emerging threat. We determined rates of antifungal drug resistance, identified factors associated with resistance, and investigated the correlation between resistance and all-cause mortality rates among cancer patients with ≥1 C. glabrata–positive blood culture at MD Anderson Cancer Center, Houston, Texas, USA, during March 2005–September 2013. Of 146 isolates, 30 (20.5%) were resistant to fluconazole, 15 (10.3%) to caspofungin, and 10 (6.8%) to multiple drugs (9 caspofungin-resistant isolates were also resistant to fluconazole, 1 to amphotericin B). Independently associated with fluconazole resistance were azole preexposure, hematologic malignancy, and mechanical ventilation. Independently associated with caspofungin resistance were echinocandin preexposure, monocytopenia, and total parenteral nutrition. Fluconazole resistance was highly associated with caspofungin resistance, independent of prior azole or echinocandin use. Caspofungin resistance was associated with increased 28-day all-cause mortality rates. These findings highlight the need for good stewardship of antifungal drugs. PMID:25340258

  12. 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

  13. Effects of the W153L Substitution in HIV Reverse Transcriptase on Viral Replication and Drug Resistance to Multiple Categories of Reverse Transcriptase Inhibitors

    PubMed Central

    Xu, Hong-Tao; Colby-Germinario, Susan P.; Oliveira, Maureen; Rajotte, Daniel; Bethell, Richard

    2014-01-01

    A W153L substitution in HIV-1 reverse transcriptase (RT) was recently identified by selection with a novel nucleotide-competing RT inhibitor (NcRTI) termed compound A that is a member of the benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI family of drugs. To investigate the impact of W153L, alone or in combination with the clinically relevant RT resistance substitutions K65R (change of Lys to Arg at position 65), M184I, K101E, K103N, E138K, and Y181C, on HIV-1 phenotypic susceptibility, viral replication, and RT enzymatic function, we generated recombinant RT enzymes and viruses containing each of these substitutions or various combinations of them. We found that W153L-containing viruses were impaired in viral replicative capacity and were hypersusceptible to tenofovir (TFV) while retaining susceptibility to most nonnucleoside RT inhibitors. The nucleoside 3TC retained potency against W153L-containing viruses but not when the M184I substitution was also present. W153L was also able to reverse the effects of the K65R substitution on resistance to TFV, and K65R conferred hypersusceptibility to compound A. Biochemical assays demonstrated that W153L alone or in combination with K65R, M184I, K101E, K103N, E138K, and Y181C impaired enzyme processivity and polymerization efficiency but did not diminish RNase H activity, providing mechanistic insights into the low replicative fitness associated with these substitutions. We show that the mechanism of the TFV hypersusceptibility conferred by W153L is mainly due to increased efficiency of TFV-diphosphate incorporation. These results demonstrate that compound A and/or derivatives thereof have the potential to be important antiretroviral agents that may be combined with tenofovir to achieve synergistic results. PMID:24867966

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

    PubMed

    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

    2015-09-01

    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

  15. 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

  16. 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

  17. Mechanisms of Drug Resistance: Daptomycin Resistance

    PubMed Central

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

    2016-01-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction in clinical practice in 2003, DAP has become an important key front-line antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP-resistance (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 resistance 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 offered 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

  18. A novel asymmetric-loop molecular beacon-based two-phase hybridization assay for accurate and high-throughput detection of multiple drug resistance-conferring point mutations in Mycobacterium tuberculosis

    PubMed Central

    Chen, Qinghai; Wu, Nan; Xie, Meng; Zhang, Bo; Chen, Ming; Li, Jianjun; Zhuo, Lisha; Kuang, Hong; Fu, Weiling

    2012-01-01

    Summary The accurate and high-throughput detection of drug resistance-related multiple point mutations remains a challenge. Although the combination of molecular beacons with bio-immobilization technology, such as microarray, is promising, its application is difficult due to the ineffective immobilization of molecular beacons on the chip surface. Here, we propose a novel asymmetric-loop molecular beacon in which the loop consists of 2 parts. One is complementary to a target, while the other is complementary to an oligonucleotide probe immobilized on the chip surface. With this novel probe, a two-phase hybridization assay can be used for simultaneously detecting multiple point mutations. This assay will have advantages, such as easy probe availability, multiplex detection, low background, and high-efficiency hybridization, and may provide a new avenue for the immobilization of molecular beacons and high-throughput detection of point mutations. PMID:22460100

  19. Sphingolipids in neuroblastoma: their role in drug resistance mechanisms.

    PubMed

    Sietsma, Hannie; Dijkhuis, Anne Jan; Kamps, Willem; Kok, Jan Willem

    2002-08-01

    Disseminated neuroblastoma usually calls for chemotherapy as the primary approach for treatment. Treatment failure is often attributable to drug resistance. This involves a variety of cellular mechanisms, including increased drug efflux through expression of ATP-binding cassette transporters (e.g., P-glycoprotein) and the inability of tumor cells to activate or propagate the apoptotic response. In recent years it has become apparent that sphingolipid metabolism and the generation of sphingolipid species, such as ceramide, also play a role in drug resistance. This may involve an autonomous mechanism, related to direct effects of sphingolipids on the apoptotic response, but also a subtle interplay between sphingolipids and ATP-binding cassette transporters. Here, we present an overview of the current understanding of the multiple levels at which sphingolipids function in drug resistance, with an emphasis on sphingolipid function in neuroblastoma and how modulation of sphingolipid metabolism may be used as a novel treatment paradigm. PMID:12374201

  20. 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.

  1. [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

  2. Facing multi-drug resistant tuberculosis.

    PubMed

    Sotgiu, Giovanni; Migliori, Giovanni Battista

    2015-06-01

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

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

    MedlinePlus

    ... NIAID invests in basic research to understand the biology of microbes, their behavior, and how drug resistance ... Nucleotide Polymorphism Phylogenetics & Ontology Proteomics & Protein Analysis Systems Biology Data Portals Software Applications BCBB Mobyle Interface Designer ( ...

  4. Impact of treatment heterogeneity on drug resistance and supply chain costs☆

    PubMed Central

    Spiliotopoulou, Eirini; Boni, Maciej F.; Yadav, Prashant

    2013-01-01

    The efficacy of scarce drugs for many infectious diseases is threatened by the emergence and spread of resistance. Multiple studies show that available drugs should be used in a socially optimal way to contain drug resistance. This paper studies the tradeoff between risk of drug resistance and operational costs when using multiple drugs for a specific disease. Using a model for disease transmission and resistance spread, we show that treatment with multiple drugs, on a population level, results in better resistance-related health outcomes, but more interestingly, the marginal benefit decreases as the number of drugs used increases. We compare this benefit with the corresponding change in procurement and safety stock holding costs that result from higher drug variety in the supply chain. Using a large-scale simulation based on malaria transmission dynamics, we show that disease prevalence seems to be a less important factor when deciding the optimal width of drug assortment, compared to the duration of one episode of the disease and the price of the drug(s) used. Our analysis shows that under a wide variety of scenarios for disease prevalence and drug cost, it is optimal to simultaneously deploy multiple drugs in the population. If the drug price is high, large volume purchasing discounts are available, and disease prevalence is high, it may be optimal to use only one drug. Our model lends insights to policy makers into the socially optimal size of drug assortment for a given context. PMID:25843982

  5. Mechanisms of echinocandin antifungal drug resistance

    PubMed Central

    Perlin, David S.

    2015-01-01

    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 are 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 promote 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 promote more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  6. Antiretroviral drug resistance and routine therapy, Cameroon.

    PubMed

    Laurent, Christian; Kouanfack, Charles; Vergne, Laurence; Tardy, Michèle; Zekeng, Léopold; Noumsi, Nathalie; Butel, Christelle; Bourgeois, Anke; Mpoudi-Ngolé, Eitel; Koulla-Shiro, Sinata; Peeters, Martine; Delaporte, Eric

    2006-06-01

    Among 128 patients routinely receiving highly active antiretroviral therapy in an HIV/AIDS outpatient clinic in Cameroon, 16.4% had drug resistance after a median of 10 months. Of these, 12.5% had resistance to nucleoside reverse transcriptase inhibitors (NRTIs), 10.2% to non-NRTIs, and 2.3% to protease inhibitors. PMID:16707062

  7. Evolution of Drug Resistance in Bacteria.

    PubMed

    Waclaw, B

    2016-01-01

    Resistance to antibiotics is an important and timely problem of contemporary medicine. Rapid evolution of resistant bacteria calls for new preventive measures to slow down this process, and a longer-term progress cannot be achieved without a good understanding of the mechanisms through which drug resistance is acquired and spreads in microbial populations. Here, we discuss recent experimental and theoretical advances in our knowledge how the dynamics of microbial populations affects the evolution of antibiotic resistance . We focus on the role of spatial and temporal drug gradients and show that in certain situations bacteria can evolve de novo resistance within hours. We identify factors that lead to such rapid onset of resistance and discuss their relevance for bacterial infections. PMID:27193537

  8. Antimicrobial (Drug) Resistance: Vancomycin-Resistant Enterococci (VRE) Frequently Asked Questions

    MedlinePlus

    ... Understanding Antimicrobial (Drug) Resistance Examples of Antimicrobial Resistance Methicillin-Resistant Staphylococcus aureus (MRSA) Vancomycin-Resistant Enterococci (VRE) Overview Transmission Diagnosis ...

  9. 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

  10. Does multiple paternity influence offspring disease resistance?

    PubMed

    Thonhauser, K E; Raveh, S; Thoß, M; Penn, D J

    2016-06-01

    It has been suggested that polyandry allows females to increase offspring genetic diversity and reduce the prevalence and susceptibility of their offspring to infectious diseases. We tested this hypothesis in wild-derived house mice (Mus musculus) by experimentally infecting the offspring from 15 single- and 15 multiple-sired litters with two different strains of a mouse pathogen (Salmonella Typhimurium) and compared their ability to control infection. We found a high variation in individual infection resistance (measured with pathogen loads) and significant differences among families, suggesting genetic effects on Salmonella resistance, but we found no difference in prevalence or infection resistance between single- vs. multiple-sired litters. We found a significant sex difference in infection resistance, but surprisingly, males were more resistant to infection than females. Also, infection resistance was correlated with weight loss during infection, although only for females, indicating that susceptibility to infection had more harmful health consequences for females than for males. To our knowledge, our findings provide the first evidence for sex-dependent resistance to Salmonella infection in house mice. Our results do not support the hypothesis that multiple-sired litters are more likely to survive infection than single-sired litters; however, as we explain, additional studies are required before ruling out this hypothesis. PMID:26949230

  11. 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

  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. Coinfection and the evolution of drug resistance.

    PubMed

    Hansen, J; Day, T

    2014-12-01

    Recent experimental work in the rodent malaria model has shown that when two or more strains share a host, there is competitive release of drug-resistant strains upon treatment. In other words, the propagule output of a particular strain is repressed when competing with other strains and increases upon the removal of this competition. This within-host effect is predicted to have an important impact on the evolution and growth of resistant strains. However, how this effect translates to epidemiological parameters at the between-host level, the level at which disease and resistance spread, has yet to be determined. Here we present a general, between-host epidemiological model that explicitly takes into account the effect of coinfection and competitive release. Although our model does show that when there is coinfection competitive release may contribute to the emergence of resistance, it also highlights an additional between-host effect. It is the combination of these two effects, the between-host effect and the within-host effect, that determines the overall influence of coinfection on the emergence of resistance. Therefore, even when competitive release of drug-resistant strains occurs, within an infected individual, it is not necessarily true that coinfection will result in the increased emergence of resistance. These results have important implications for the control of the emergence and spread of drug resistance. PMID:25417787

  14. First Report of blaIMP-14 on a Plasmid Harboring Multiple Drug Resistance Genes in Escherichia coli Sequence Type 131.

    PubMed

    Stoesser, Nicole; Sheppard, Anna E; Peirano, Gisele; Sebra, Robert P; Lynch, Tarah; Anson, Luke W; Kasarskis, Andrew; Motyl, Mary R; Crook, Derrick W; Pitout, Johann D

    2016-08-01

    The blaIMP-14 carbapenem resistance gene has largely previously been observed in Pseudomonas aeruginosa and Acinetobacter spp. As part of global surveillance and sequencing of carbapenem-resistant Escherichia coli, we identified a sequence type 131 strain harboring blaIMP-14 within a class 1 integron, itself nested within an ∼54-kb multidrug resistance region on an epidemic IncA/C2 plasmid. The emergence of blaIMP-14 in this context in the ST131 lineage is of potential clinical concern. PMID:27246777

  15. First Report of blaIMP-14 on a Plasmid Harboring Multiple Drug Resistance Genes in Escherichia coli Sequence Type 131

    PubMed Central

    Sheppard, Anna E.; Peirano, Gisele; Sebra, Robert P.; Lynch, Tarah; Anson, Luke W.; Kasarskis, Andrew; Motyl, Mary R.; Crook, Derrick W.; Pitout, Johann D.

    2016-01-01

    The blaIMP-14 carbapenem resistance gene has largely previously been observed in Pseudomonas aeruginosa and Acinetobacter spp. As part of global surveillance and sequencing of carbapenem-resistant Escherichia coli, we identified a sequence type 131 strain harboring blaIMP-14 within a class 1 integron, itself nested within an ∼54-kb multidrug resistance region on an epidemic IncA/C2 plasmid. The emergence of blaIMP-14 in this context in the ST131 lineage is of potential clinical concern. PMID:27246777

  16. 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

  17. 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

  18. Drug resistance genomics of the antimalarial drug artemisinin.

    PubMed

    Winzeler, Elizabeth A; Manary, Micah J

    2014-01-01

    Across the globe, over 200 million annual malaria infections result in up to 660,000 deaths, 77% of which occur in children under the age of five years. Although prevention is important, malaria deaths are typically prevented by using antimalarial drugs that eliminate symptoms and clear parasites from the blood. Artemisinins are one of the few remaining compound classes that can be used to cure multidrug-resistant Plasmodium falciparum infections. Unfortunately, clinical trials from Southeast Asia are showing that artemisinin-based treatments are beginning to lose their effectiveness, adding renewed urgency to the search for the genetic determinants of parasite resistance to this important drug class. We review the genetic and genomic approaches that have led to an improved understanding of artemisinin resistance, including the identification of resistance-conferring mutations in the P. falciparum kelch13 gene. PMID:25470531

  19. 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

  20. Drug-resistant Neisseria gonorrhoeae in Michigan

    PubMed Central

    Boehme, Martha S.; Rudrik, James T.; Ganoczy, Dara; Crandell-Alden, Erin; Schneider, William A.; Somsel, Patricia A.

    2005-01-01

    The increasing prevalence of quinolone-resistant Neisseria gonorrhoeae (QRNG) in the United States is a cause for concern. Detecting resistance is complicated by the widespread use of molecular tests that do not provide isolates for susceptibility testing. The Michigan Department of Community Health developed a sentinel surveillance program to detect antimicrobial drug resistance in N. gonorrhoeae. Sentinel surveillance from 11 laboratories submitted 1,122 isolates for antimicrobial drug susceptibility testing and detected 2 clusters of QRNG from January 2003 to September 2004. These clusters were epidemiologically distinct: one involved young, heterosexual youth, and the other involved older men who have sex with men. This finding led to changes in local treatment recommendations that limited spread of resistant strains. Development of the sentinel program, collection of data, and epidemiologic analysis of the clusters are discussed. PMID:16022773

  1. Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants

    PubMed Central

    Larson, Alyssa M.; Chen, Jianzhu; Klibanov, Alexander M.

    2013-01-01

    By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-L-glutamate resulted in some of the most potent inhibitors for 2′s conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective. PMID:23832466

  2. Conjugation to polymeric chains of influenza drugs targeting M2 ion channels partially restores inhibition of drug-resistant mutants.

    PubMed

    Larson, Alyssa M; Chen, Jianzhu; Klibanov, Alexander M

    2013-08-01

    By attaching multiple copies of the influenza M2 ion channel inhibitors amantadine (1) and rimantadine (2) to polymeric chains, we endeavored to recover their potency in inhibiting drug-resistant influenza viruses. Depending on loading densities, as well as the nature of the drug, the polymer, and the spacer arm, polymer-conjugated drugs were up to 30-fold more potent inhibitors of drug-resistant strains than their monomeric parents. In particular, a 20% loading density and a short linker group on the negatively charged poly-l-glutamate resulted in one of the most potent inhibitors for 2's conjugates against drug-resistant influenza strains. Although full recovery of the inhibitory action against drug-resistant strains was not achieved, this study may be a step toward salvaging anti-influenza drugs that are no longer effective. PMID:23832466

  3. 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

  4. Vaults: a ribonucleoprotein particle involved in drug resistance?

    PubMed

    Mossink, Marieke H; van Zon, Arend; Scheper, Rik J; Sonneveld, Pieter; Wiemer, Erik A C

    2003-10-20

    Vaults are ribonucleoprotein particles found in the cytoplasm of eucaryotic cells. The 13 MDa particles are composed of multiple copies of three proteins: an M(r) 100 000 major vault protein (MVP) and two minor vault proteins of M(r) 193 000 (vault poly-(ADP-ribose) polymerase) and M(r) 240 000 (telomerase-associated protein 1), as well as small untranslated RNA molecules of approximately 100 bases. Although the existence of vaults was first reported in the mid-1980s no function has yet been attributed to this organelle. The notion that vaults might play a role in drug resistance was suggested by the molecular identification of the lung resistance-related (LRP) protein as the human MVP. MVP/LRP was found to be overexpressed in many chemoresistant cancer cell lines and primary tumor samples of different histogenetic origin. Several, but not all, clinico-pathological studies showed that MVP expression at diagnosis was an independent adverse prognostic factor for response to chemotherapy. The hollow barrel-shaped structure of the vault complex and its subcellular localization indicate a function in intracellular transport. It was therefore postulated that vaults contributed to drug resistance by transporting drugs away from their intracellular targets and/or the sequestration of drugs. Here, we review the current knowledge on the vault complex and critically discuss the evidence that links vaults to drug resistance. PMID:14576851

  5. Suspect aggression and victim resistance in multiple perpetrator rapes.

    PubMed

    Woodhams, Jessica; Cooke, Claire

    2013-11-01

    Several research studies have reported an elevated level of aggression in rapes committed by multiple perpetrators compared to rapes committed by lone suspects. Several factors that have been linked to elevated aggression in generic samples of rape were examined for the first time with a sample of multiple perpetrator rapes. Factors that might be associated with victim resistance were also investigated. Victim and offender characteristics, as well as the behaviors displayed by victims and offenders, were extracted from the police files of 89 multiple perpetrator stranger rapes perpetrated against female victims in the United Kingdom. These behaviors were rated for their level of suspect (non-sexual) aggression and victim resistance, respectively. Degree of victim resistance was significantly and positively associated with suspect aggression. Older victims were the recipients of significantly higher levels of suspect aggression. Victims who were incapacitated from drugs and/or alcohol were less likely to be the recipients of suspect aggression. Group leaders displayed more aggression towards the victim than the followers in the groups. The number of perpetrators was significantly related to the degree of resistance displayed by the victim with offences perpetrated by fewer suspects being characterized by more victim resistance. Research regarding cognitive appraisal during criminal interactions and the respective roles of offenders is referred to in considering these relationships. PMID:23740469

  6. Repurposing salicylanilide anthelmintic drugs to combat drug resistant Staphylococcus aureus.

    PubMed

    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

  7. 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

  8. Malaria drug resistance: new observations and developments

    PubMed Central

    Sá, Juliana M.; Chong, Jason L.; Wellems, Thomas E.

    2012-01-01

    Drug-resistant micro-organisms became widespread in the 20th Century, often with devastating consequences, in response to widespread use of natural and synthetic drugs against infectious diseases. Antimalarial resistance provides one of the earliest examples, following the introduction of new medicines that filled important needs for prophylaxis and treatment around the globe. In the present chapter, we offer a brief synopsis of major antimalarial developments from two natural remedies, the qinghaosu and cinchona bark infusions, and of synthetic drugs inspired by the active components of these remedies. We review some contributions that early efficacy studies of antimalarial treatment brought to clinical pharmacology, including convincing documentation of atebrine-resistant malaria in the 1940s, prior to the launching of what soon became first-choice antimalarials, chloroquine and amodiaquine. Finally, we discuss some new observations on the molecular genetics of drug resistance, including delayed parasite clearances that have been increasingly observed in response to artemisinin derivatives in regions of South-East Asia. PMID:22023447

  9. Drugs Approved for Multiple Myeloma and Other Plasma Cell Neoplasms

    MedlinePlus

    ... Professionals Questions to Ask about Your Treatment Research Drugs Approved for Multiple Myeloma and Other Plasma Cell ... plasma cell neoplasms that are not listed here. Drugs Approved for Multiple Myeloma and Other Plasma Cell ...

  10. Targeting mitochondrial biogenesis to overcome drug resistance to MAPK inhibitors

    PubMed Central

    Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; 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; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon B.; Altieri, Dario C.; Flaherty, Keith T.

    2016-01-01

    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

  11. 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

  12. Multiple-anion nonvolatile acetal (MANA) resists

    NASA Astrophysics Data System (ADS)

    Guevremont, Jeffrey M.; Brainard, Robert L.; Reeves, Scott D.; Zhou, Xin; Nguyen, Thinh B.; Mackevich, Joseph F.; Anderson, Erik H.; Taylor, Gary N.

    2001-08-01

    New acetal or ketal blocking reagents were investigated for use in e-beam lithography and compared with the performance of ethyl vinyl either (EVE). Three blocking groups, (alpha) -Angelicalactone (AL), 6-methylene-5,6-benzo-1,4- dioxane (MBD), and MANA50 (an undisclosed blocking group used to show the potential of this chemistry) were reacted with poly(p-hydroxystyrene) (PHS) under acid catalyzed conditions to form AL-PHS, MBD-PHS, MANA50-PHS. The performance objectives pursued in the design of these new materials was to use acetal (ketal) chemistry to deliver wide process latitudes (e.g. good PED performance and minimal PEB sensitivity), use high molecular weight blocking groups to eliminate outgassing, and use the novel concept of multiple anions to deliver lithographic performance. These new materials are called Multiple Anion Nonvolatile Acetal (MANA) resists. Resists films were exposed with 50kV electrons, post exposure baked (PEB), and developed with 0.26 N TMAH. Resists prepared with the third blocking group, MANA50, gave contrast and imaging performance independent of PEB humidity and were relatively insensitive to PEB temperature and post exposure delay (PED). These resists gave the best resolution (90 nm) and profiles of all the materials tested, as well as showing no outgassing (as measured by film thickness loss).

  13. 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

  14. Challenges of drug-resistant malaria.

    PubMed

    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

  15. Multiple mechanisms contribute to the development of clinically significant azole resistance in Aspergillus fumigatus

    PubMed Central

    Moye-Rowley, W. S.

    2015-01-01

    Infections caused by the filamentous fungus Aspergillus fumigatus are a significant clinical issue and represent the second most-common form of fungal infection. Azole drugs are effective against this pathogen but resistant isolates are being found more frequently. Infections associated with azole resistant A. fumigatus have a significantly increased mortality making understanding drug resistance in this organism a priority. The target of azole drugs is the lanosterol α-14 demethylase enzyme encoded by the cyp51A gene in A. fumigatus. Mutations in cyp51A have been described that give rise to azole resistance and been argued to be the primary, if not sole, contributor to azole resistance. Here, I discuss recent developments that indicate multiple mechanisms, including increased expression of ATP-binding cassette (ABC) transporter proteins, contribute to azole resistance. ABC transporters are well-established determinants of drug resistance in other fungal pathogens and seem likely to play a similar role in A. fumigatus. PMID:25713565

  16. 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

  17. 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

  18. MicroRNAs and drug resistance in prostate cancers.

    PubMed

    Li, Feng; Mahato, Ram I

    2014-08-01

    Prostate cancer is the second leading cause of cancer related death in American men. Androgen deprivation therapy (ADT) is used to treat patients with aggressive prostate cancers. After androgen deprivation therapy, prostate cancers slowly progress to an androgen-independent status. Taxanes (e.g., docetaxel) are used as standard treatments for androgen-independent prostate cancers. However, these chemotherapeutic agents will eventually become ineffective due to the development of drug resistance. A microRNA (miRNA) is a small noncoding RNA molecule, which can regulate gene expression at the post-transcription level. miRNAs elicit their effects by binding to the 3'-untranslated region (3'-UTR) of their target mRNAs, leading to the inhibition of translation or the degradation of the mRNAs. miRNAs have received increasing attention as targets for cancer therapy, as they can target multiple signaling pathways related to tumor progression, metastasis, invasion, and chemoresistance. Emerging evidence suggests that aberrant expression of miRNAs can lead to the development of resistant prostate cancers. Here, we discuss the roles of miRNAs in the development of resistant prostate cancers and their involvement in various drug resistant mechanisms including androgen signaling, apoptosis avoidance, multiple drug resistance (MDR) transporters, epithelialmesenchymal transition (EMT), and cancer stem cells (CSCs). In addition, we also discuss strategies for treating resistant prostate cancers by targeting specific miRNAs. Different delivery strategies are also discussed with focus on those that have been successfully used in human clinical trials. PMID:24742219

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  1. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae.

    PubMed

    Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman

    2011-10-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea. PMID:22089602

  2. An insight into the drug resistance profile & mechanism of drug resistance in Neisseria gonorrhoeae

    PubMed Central

    Patel, Achchhe Lal; Chaudhry, Uma; Sachdev, Divya; Sachdeva, Poonam Nagpal; Bala, Manju; Saluja, Daman

    2011-01-01

    Among the aetiological agents of treatable sexually transmitted diseases (STDs), Neissseria gonorrhoeae is considered to be most important because of emerging antibiotic resistant strains that compromise the effectiveness of treatment of the disease - gonorrhoea. In most of the developing countries, treatment of gonorrhoea relies mainly on syndromic management rather than the aetiological based therapy. Gonococcal infections are usually treated with single-dose therapy with an agent found to cure > 95 per cent of cases. Unfortunately during the last few decades, N. gonorrhoeae has developed resistance not only to less expensive antimicrobials such as sulphonamides, penicillin and tetracyclines but also to fluoroquinolones. The resistance trend of N. gonorrhoeae towards these antimicrobials can be categorised into pre-quinolone, quinolone and post-quinolone era. Among the antimicrobials available so far, only the third-generation cephalosporins could be safely recommended as first-line therapy for gonorrhoea globally. However, resistance to oral third-generation cephalosporins has also started emerging in some countries. Therefore, it has become imperative to initiate sustained national and international efforts to reduce infection and misuse of antibiotics so as to prevent further emergence and spread of antimicrobial resistance. It is necessary not only to monitor drug resistance and optimise treatment regimens, but also to gain insight into how gonococcus develops drug resistance. Knowledge of mechanism of resistance would help us to devise methods to prevent the occurrence of drug resistance against existing and new drugs. Such studies could also help in finding out new drug targets in N. gonorrhoeae and also a possibility of identification of new drugs for treating gonorrhoea. PMID:22089602

  3. Emerging Technologies for Monitoring Drug-Resistant Tuberculosis at the Point-of-Care

    PubMed Central

    Mani, Vigneshwaran; Wang, ShuQi; Inci, Fatih; De Libero, Gennaro; Singhal, Amit; Demirci, Utkan

    2014-01-01

    Infectious diseases are the leading cause of death worldwide. Among them, tuberculosis (TB) remains a major threat to public health, exacerbated by the emergence of multiple drug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis (Mtb). MDR-Mtb strains are resistant to first-line anti-TB drugs such as isoniazid and rifampicin; whereas XDR-Mtb strains are resistant to additional drugs including at least to any fluoroquinolone and at least one of the second-line anti-TB injectable drugs such as kanamycin, capreomycin, or amikacin. Clinically, these strains have significantly impacted the management of TB in high-incidence developing countries, where systemic surveillance of TB drug resistance is lacking. For effective management of TB on-site, early detection of drug resistance is critical to initiate treatment, to reduce mortality, and to thwart drug-resistant TB transmission. In this review, we discuss the diagnostic challenges to detect drug-resistant TB at the point-of-care (POC). Moreover, we present the latest advances in nano/microscale technologies that can potentially detect TB drug resistance to improve on-site patient care. PMID:24882226

  4. Ceftaroline desensitization procedure in a pregnant patient with multiple drug allergies.

    PubMed

    Kuhlen, James L; Blumenthal, Kimberly G; Sokol, Caroline L; Balekian, Diana S; Weil, Ana A; Varughese, Christy A; Shenoy, Erica S; Banerji, Aleena

    2015-01-01

    Validated skin testing is lacking for many drugs, including ceftaroline. The cross-reactivity between ceftaroline and other β-lactam antibiotics is unknown. We report a case of a pregnant patient with cystic fibrosis and multiple drug allergies who required ceftaroline for methicillin-resistant Staphylococcus aureus pneumonia and underwent an uncomplicated empiric desensitization procedure. PMID:26034776

  5. 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

  6. 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

  7. Upregulation of Cyclooxygenase-2/Prostaglandin E2 (COX-2/PGE2) Pathway Member Multiple Drug Resistance-Associated Protein 4 (MRP4) and Downregulation of Prostaglandin Transporter (PGT) and 15-Prostaglandin Dehydrogenase (15-PGDH) in Triple-Negative Breast Cancer

    PubMed Central

    Kochel, Tyler J.; Goloubeva, Olga G.; Fulton, Amy M.

    2016-01-01

    Elevated levels of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) are indicators of a poor prognosis in breast cancer. Using several independent publicly available breast cancer gene expression databases, we investigated other members of the PGE2 pathway. PGE2 is produced by COX-2 and actively exported by multiple drug resistance-associated protein 4 (MRP4) into the extracellular microenvironment, where PGE2 can bind four cognate EP receptors (EP1–EP4) and initiate diverse biological signaling pathways. Alternatively, PGE2 is imported via the prostaglandin transporter (PGT) and metabolized by 15-prostaglandin dehydrogenase (15-PGDH/HPGD). We made the novel observation that MRP4, PGT, and 15-PGDH are differentially expressed among distinct breast cancer molecular subtypes; this finding was confirmed in independent datasets. In triple-negative breast cancer, the observed gene expression pattern (high COX-2, high MRP4, low PGT, and low 15-PGDH) would favor high levels of tumor-promoting PGE2 in the tumor microenvironment that may contribute to the overall poor prognosis of triple-negative breast cancer. PMID:27257388

  8. Drugs in development for relapsing multiple sclerosis.

    PubMed

    Ali, Rehiana; Nicholas, Richard St John; Muraro, Paolo Antonio

    2013-05-01

    Drug development for multiple sclerosis (MS), as with any other neurological disease, faces numerous challenges, with many drugs failing at various stages of development. The disease-modifying therapies (DMTs) first introduced for MS are only moderately effective, but given the lack of competition, they have been widely accepted in clinical practice. Although safety and efficacy continue to be the two main metrics by which drugs will be judged, the newer agents in the market also face challenges of a more comparative nature-are they more efficacious than the currently available drugs on the market? Are they safer or better tolerated? Do they offer any practical advantages over current treatments? Fingolimod represented a milestone following its approval as an oral drug for MS in 2010, offering patients a far more convenient administration route. However, association with cardiovascular complications has led to a more cautious approach in its initial prescribing, now requiring cardiac monitoring for the first 6 h as well as subsequent monitoring of blood pressure and for macular oedema. Natalizumab, amongst licensed drugs, represents the current benchmark for efficacy. The risk of progressive multifocal leukoencephalopathy during natalizumab treatment is now more quantifiable. Other monoclonal antibodies are in various phases of development. Marketing authorisation for alemtuzumab has been filed, and whilst trial data suggest that its efficacy outperforms both licensed drugs and others in development, there is a significant risk of secondary autoimmunity. Its once-yearly administration, however, seems particularly advantageous. Rituximab is unlikely to be developed further as its license will expire, but ocrelizumab, another monoclonal antibody directly targeting B cells, is currently in phase 2 development and looks promising. Daclizumab is also moderately efficacious but may struggle to establish itself given its monthly subcutaneous dosing. There are new oral

  9. 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

  10. Rates and risk factors for drug resistance tuberculosis in Northeastern China

    PubMed Central

    2013-01-01

    Background Drug-resistant tuberculosis (TB) has emerged as a major challenge toward TB control and prevention. In Lianyungang city, the extent and trend of drug resistant TB is not well known. The objective of the survey was to assess drug resistance pattern of MTB and risk factors for drug resistant TB, including multidrug resistance tuberculosis (MDR-TB) in this area. Methods We performed drug susceptibility testing on Mycobacterium tuberculosis (MTB) isolates with first- and second-line anti-tuberculosis drugs of 1012 culture positive TB cases by using the proportion method, who were consecutively enrolled from January 2011 to December 2012 in Lianyungang city, China. The patterns of drug resistance in MTB were investigated and multiple logistic regression analysis was performed to assess the risk factors for drug resistant TB. Results Among the 1012 strains tested, 308 (30.4%) strains were resistant to at least one first-line drug; the prevalence of MDR-TB was 88 (8.7%), 5 (0.5%) strains were found to be extensively drug-resistant tuberculosis (XDR-TB). Female gender was a risk factor for MDR-TB (adjusted odds ratio (aOR) 1.763, 95% CI (1.060-2.934). The aged 28–54 years was significantly associated with the risk of MDR-TB with an aOR: 2.224, 95% CI (1.158-4.273) when compared with those 65 years or older. Patients with previous treatment history had a more than 7-fold increased risk of MDR-TB, compared with those never previously treated. Conclusions The burden of drug resistant TB cases is sizeable, which highlights an urgent need to reinforce control, detection and treatment strategies for drug resistant TB. PMID:24330553

  11. Aberrant splicing and drug resistance in AML.

    PubMed

    de Necochea-Campion, Rosalia; Shouse, Geoffrey P; Zhou, Qi; Mirshahidi, Saied; Chen, Chien-Shing

    2016-01-01

    The advent of next-generation sequencing technologies has unveiled a new window into the heterogeneity of acute myeloid leukemia (AML). In particular, recurrent mutations in spliceosome machinery and genome-wide aberrant splicing events have been recognized as a prominent component of this disease. This review will focus on how these factors influence drug resistance through altered splicing of tumor suppressor and oncogenes and dysregulation of the apoptotic signaling network. A better understanding of these factors in disease progression is necessary to design appropriate therapeutic strategies recognizing specific alternatively spliced or mutated oncogenic targets. PMID:27613060

  12. Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment.

    PubMed

    Bagaglio, Sabrina; Andolina, Andrea; Merli, Marco; Uberti-Foppa, Caterina; Morsica, Giulia

    2016-01-01

    Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs. PMID:27023593

  13. Frequency of Natural Resistance within NS5a Replication Complex Domain in Hepatitis C Genotypes 1a, 1b: Possible Implication of Subtype-Specific Resistance Selection in Multiple Direct Acting Antivirals Drugs Combination Treatment

    PubMed Central

    Bagaglio, Sabrina; Andolina, Andrea; Merli, Marco; Uberti-Foppa, Caterina; Morsica, Giulia

    2016-01-01

    Different HCV subtypes may naturally harbor different resistance selection to anti-NS5a inhibitors. 2761 sequences retrieved from the Los Alamos HCV database were analyzed in the NS5a domain 1, the target of NS5a inhibitors. The NS5a resistance-associated polymorphisms (RAPs) were more frequently detected in HCV G1b compared to G1a. The prevalence of polymorphisms associated with cross-resistance to compounds in clinical use (daclatasvir, DCV, ledipasvir, LDV, ombitasvir, and OMV) or scheduled to come into clinical use in the near future (IDX719, elbasvir, and ELV) was higher in G1b compared to G1a (37/1552 (2.4%) in 1b sequences and 15/1209 (1.2%) in 1a isolates, p = 0.040). Interestingly, on the basis of the genotype-specific resistance pattern, 95 (6.1%) G1b sequences had L31M RAP to DCV/IDX719, while 6 sequences of G1a (0.5%) harbored L31M RAP, conferring resistance to DCV/LDV/IDX719/ELV (p < 0.0001). Finally, 28 (2.3%) G1a and none of G1b isolates harbored M28V RAP to OMV (p < 0.0001). In conclusion, the pattern of subtype-specific resistance selection in the naturally occurring strains may guide the treatment option in association with direct acting antivirals (DAAs) targeting different regions, particularly in patients that are difficult to cure, such as those with advanced liver disease or individuals who have failed previous DAAs. PMID:27023593

  14. Multi-Drug Resistance among Salmonella spp. Isolated from Food Animals

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Introduction: Since the early 1990’s there has been increasing awareness and concern regarding the development of antimicrobial resistance among bacteria of public health significance. Of particular concern starting in 2000, was the emergence of multiple drug resistant (MDR) Salmonella Newport. How...

  15. 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…

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

    ERIC Educational Resources Information Center

    Silva, Roberta K.

    The goal of DARE (Drug Abuse Resistance Education) is not to completely eliminate the drug and alcohol problems of society. It is a proactive prevention program designed to equip youth (focusing on elementary school) with skills for resisting peer pressure to experiment with drugs, and to manage anger without resorting to violence or the use of…

  17. 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…

  18. 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…

  19. Bioinformatics Identification of Drug Resistance-Associated Gene Pairs in Mycobacterium tuberculosis.

    PubMed

    Cui, Ze-Jia; Yang, Qing-Yong; Zhang, Hong-Yu; Zhu, Qiang; Zhang, Qing-Ye

    2016-01-01

    Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb). Due to the extensive use of anti-tuberculosis drugs and the development of mutations, the emergence and spread of multidrug-resistant tuberculosis is recognized as one of the most dangerous threats to global tuberculosis control. Some single mutations have been identified to be significantly linked with drug resistance. However, the prior research did not take gene-gene interactions into account, and the emergence of transmissible drug resistance is connected with multiple genetic mutations. In this study we use the bioinformatics software GBOOST (The Hong Kong University, Clear Water Bay, Kowloon, Hong Kong, China) to calculate the interactions of Single Nucleotide Polymorphism (SNP) pairs and identify gene pairs associated with drug resistance. A large part of the non-synonymous mutations in the drug target genes that were included in the screened gene pairs were confirmed by previous reports, which lent sound solid credits to the effectiveness of our method. Notably, most of the identified gene pairs containing drug targets also comprise Pro-Pro-Glu (PPE) family proteins, suggesting that PPE family proteins play important roles in the drug resistance of Mtb. Therefore, this study provides deeper insights into the mechanisms underlying anti-tuberculosis drug resistance, and the present method is useful for exploring the drug resistance mechanisms for other microorganisms. PMID:27618895

  20. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network.

    PubMed

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K; Rosenthal, Philip J

    2015-09-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. PMID:26259943

  1. Antimalarial Drug Resistance: Literature Review and Activities and Findings of the ICEMR Network

    PubMed Central

    Cui, Liwang; Mharakurwa, Sungano; Ndiaye, Daouda; Rathod, Pradipsinh K.; Rosenthal, Philip J.

    2015-01-01

    Antimalarial drugs are key tools for the control and elimination of malaria. Recent decreases in the global malaria burden are likely due, in part, to the deployment of artemisinin-based combination therapies. Therefore, the emergence and potential spread of artemisinin-resistant parasites in southeast Asia and changes in sensitivities to artemisinin partner drugs have raised concerns. In recognition of this urgent threat, the International Centers of Excellence for Malaria Research (ICEMRs) are closely monitoring antimalarial drug efficacy and studying the mechanisms underlying drug resistance. At multiple sentinel sites of the global ICEMR network, research activities include clinical studies to track the efficacies of antimalarial drugs, ex vivo/in vitro assays to measure drug susceptibilities of parasite isolates, and characterization of resistance-mediating parasite polymorphisms. Taken together, these efforts offer an increasingly comprehensive assessment of the efficacies of antimalarial therapies, and enable us to predict the emergence of drug resistance and to guide local antimalarial drug policies. Here we briefly review worldwide antimalarial drug resistance concerns, summarize research activities of the ICEMRs related to drug resistance, and assess the global impacts of the ICEMR programs. PMID:26259943

  2. Prevalence of multi-drug resistant Salmonella on comercial dairies utilizing a single heifer raising facility

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objectives of the current research were two-fold: 1) Determine the prevalence of multiple drug resistant (MDR) Salmonella in the various classes of dairy cattle; and 2) Determine if co-mingling of calves from multiple farms at a heifer feedlot serves as a transmission vector for Salmonella back ...

  3. Drug resistance of organisms isolated from feces of laboratory mice and rats.

    PubMed

    Maejima, K; Urano, T; Tamura, H; Terakado, N

    1980-01-01

    A total of 248 strains of EScherichia coli, 132 of Staphylococcus epidermidis, 137 of Streptococcus faecalis and 89 of STr. faecium were collected from feces of 40 mice and 36 rats of 8 colonies in 1978, and drug resistance were examined by an agar dieution method using 23 antibiotics. The results indicated a positive relation between use of antibiotics and appearance of multiple drug resistant organisms. PMID:6772455

  4. The Use of Multiple Matrix Sampling for Drug Questionnaires

    ERIC Educational Resources Information Center

    Pascale, Pietro J.

    1976-01-01

    This paper presents a procedure called multiple matrix sampling which simplifies data collection for drug incidence surveys. Advantages for the use of multiple matrix sampling with drug surveys are discussed and a practical example is outlined presenting the guidelines for a sampling plan. (Author)

  5. Polymeric micelles and nanoemulsions as drug carriers: Therapeutic efficacy, toxicity, and drug resistance.

    PubMed

    Gupta, Roohi; Shea, Jill; Scafe, Courtney; Shurlygina, Anna; Rapoport, Natalya

    2015-08-28

    The manuscript reports the side-by-side comparison of therapeutic properties of polymeric micelles and nanoemulsions generated from micelles. The effect of the structure of a hydrophobic block of block copolymer on the therapeutic efficacy, tumor recurrence, and development of drug resistance was studied in pancreatic tumor bearing mice. Mice were treated with paclitaxel (PTX) loaded poly(ethylene oxide)-co-polylactide micelles or corresponding perfluorocarbon nanoemulsions. Two structures of the polylactide block differing in a physical state of micelle cores or corresponding nanodroplet shells were compared. Poly(ethylene oxide)-co-poly(d,l-lactide) (PEG-PDLA) formed micelles with elastic amorphous cores while poly(ethylene oxide)-co-poly(l-lactide) (PEG-PLLA) formed micelles with solid crystalline cores. Micelles and nanoemulsions stabilized with PEG-PDLA copolymer manifested higher therapeutic efficacy than those formed with PEG-PLLA copolymer studied earlier. Better performance of PEG-PDLA micelles and nanodroplets was attributed to the elastic physical state of micelle cores (or droplet shells) allowing adequate rate of drug release via drug diffusion and/or copolymer biodegradation. The biodegradation of PEG-PDLA stabilized nanoemulsions was monitored by the ultrasonography of nanodroplets injected directly into the tumor; the PEG-PDLA stabilized nanodroplets disappeared from the injection site within 48h. In contrast, nanodroplets stabilized with PEG-PLLA copolymer were preserved at the injection site for weeks and months indicating extremely slow biodegradation of solid PLLA blocks. Multiple injections of PTX-loaded PEG-PDLA micelles or nanoemulsions to pancreatic tumor bearing mice resulted in complete tumor resolution. Two of ten tumors treated with either PEG-PDLA micellar or nanoemulsion formulation recurred after the completion of treatment but proved sensitive to the second treatment cycle indicating that drug resistance has not been developed. This

  6. [Factors of multiple resistance to antibiotics in nodule bacteria].

    PubMed

    Pariĭskaia, A N; Gorelova, O P

    1976-01-01

    Multiple resistance to antibiotics (penicillin, levomycetin, neomycin, tetracycline) was found in 15% of collection strains of nodule bacteria and in strains isolated from natural environment. PMID:1050635

  7. Stop the Spread of Superbugs: Help Fight Drug Resistant Bacteria

    MedlinePlus

    ... the Spread of Superbugs Help Fight Drug-Resistant Bacteria For nearly a century, bacteria-fighting drugs known as antibiotics have helped to control and destroy many of the harmful bacteria that can make us sick. But in recent ...

  8. Engineered reversal of drug resistance in cancer cells—metastases suppressor factors as change agents

    PubMed Central

    Yadav, Vinod Kumar; Kumar, Akinchan; Mann, Anita; Aggarwal, Suruchi; Kumar, Maneesh; Roy, Sumitabho Deb; Pore, Subrata Kumar; Banerjee, Rajkumar; Mahesh Kumar, Jerald; Thakur, Ram Krishna; Chowdhury, Shantanu

    2014-01-01

    Building molecular correlates of drug resistance in cancer and exploiting them for therapeutic intervention remains a pressing clinical need. To identify factors that impact drug resistance herein we built a model that couples inherent cell-based response toward drugs with transcriptomes of resistant/sensitive cells. To test this model, we focused on a group of genes called metastasis suppressor genes (MSGs) that influence aggressiveness and metastatic potential of cancers. Interestingly, modeling of 84 000 drug response transcriptome combinations predicted multiple MSGs to be associated with resistance of different cell types and drugs. As a case study, on inducing MSG levels in a drug resistant breast cancer line resistance to anticancer drugs caerulomycin, camptothecin and topotecan decreased by more than 50–60%, in both culture conditions and also in tumors generated in mice, in contrast to control un-induced cells. To our knowledge, this is the first demonstration of engineered reversal of drug resistance in cancer cells based on a model that exploits inherent cellular response profiles. PMID:24157835

  9. In vitro Development of Chemotherapy and Targeted Therapy Drug-Resistant Cancer Cell Lines: A Practical Guide with Case Studies

    PubMed Central

    McDermott, Martina; Eustace, Alex J.; Busschots, Steven; Breen, Laura; Crown, John; Clynes, Martin; O’Donovan, Norma; Stordal, Britta

    2014-01-01

    The development of a drug-resistant cell line can take from 3 to 18 months. However, little is published on the methodology of this development process. This article will discuss key decisions to be made prior to starting resistant cell line development; the choice of parent cell line, dose of selecting agent, treatment interval, and optimizing the dose of drug for the parent cell line. Clinically relevant drug-resistant cell lines are developed by mimicking the conditions cancer patients experience during chemotherapy and cell lines display between two- and eight-fold resistance compared to their parental cell line. Doses of drug administered are low, and a pulsed treatment strategy is often used where the cells recover in drug-free media. High-level laboratory models are developed with the aim of understanding potential mechanisms of resistance to chemotherapy agents. Doses of drug are higher and escalated over time. It is common to have difficulty developing stable clinically relevant drug-resistant cell lines. A comparative selection strategy of multiple cell lines or multiple chemotherapeutic agents mitigates this risk and gives insight into which agents or type of cell line develops resistance easily. Successful selection strategies from our research are presented. Pulsed-selection produced platinum or taxane-resistant large cell lung cancer (H1299 and H460) and temozolomide-resistant melanoma (Malme-3M and HT144) cell lines. Continuous selection produced a lapatinib-resistant breast cancer cell line (HCC1954). Techniques for maintaining drug-resistant cell lines are outlined including; maintaining cells with chemotherapy, pulse treating with chemotherapy, or returning to master drug-resistant stocks. The heterogeneity of drug-resistant models produced from the same parent cell line with the same chemotherapy agent is explored with reference to P-glycoprotein. Heterogeneity in drug-resistant cell lines reflects the heterogeneity that can occur in clinical

  10. Fatal case of extensively drug-resistant Mycobacterium tuberculosis Beijing genotype infection in an injecting drug user, Athens, Greece, 2012.

    PubMed

    Leuow, K; Papaventsis, D; Kourkoundi, S; Ioannidis, P; Karabela, S; Tsikrika, S; Marinou, I; Papavasileiou, A; Stone, M; Drobniewski, F; Paparisos, V; Vogiatzakis, E

    2013-01-01

    We present the first fatal case of extensively drug-resistant tuberculosis (XDR-TB) in an injecting drug user (IDU) in Athens, Greece, co-infected with human immunodeficiency virus and hepatitis C virus and discuss the implications for public health. Despite immediate initiation of treatment, the patient's condition gradually deteriorated and he died 16 days after hospital admission because of multiple organ failure. The contact tracing investigation revealed no further infections among the patient's contacts. PMID:23557942

  11. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015.

    PubMed

    Zhang, Y; Yew, W-W

    2015-11-01

    Drug-resistant tuberculosis (DR-TB), including multi- and extensively drug-resistant TB, is posing a significant challenge to effective treatment and TB control worldwide. New progress has been made in our understanding of the mechanisms of resistance to anti-tuberculosis drugs. This review provides an update on the major advances in drug resistance mechanisms since the previous publication in 2009, as well as added information on mechanisms of resistance to new drugs and repurposed agents. The recent application of whole genome sequencing technologies has provided new insight into the mechanisms and complexity of drug resistance. However, further research is needed to address the significance of newly discovered gene mutations in causing drug resistance. Improved knowledge of drug resistance mechanisms will help understand the mechanisms of action of the drugs, devise better molecular diagnostic tests for more effective DR-TB management (and for personalised treatment), and facilitate the development of new drugs to improve the treatment of this disease. PMID:26467578

  12. Klebsiella pneumoniae Antimicrobial Drug Resistance, United States, 1998–2010

    PubMed Central

    Sanchez, Guillermo V.; Master, Ronald N.; Clark, Richard B.; Fyyaz, Madiha; Duvvuri, Padmaraj; Ekta, Gupta

    2013-01-01

    We studied antimicrobial-resistant Klebsiella pneumoniae for 1998–2010 by using data from The Surveillance Network. Susceptibility results (n = 3,132,354) demonstrated significant increases in resistance to all antimicrobial drugs studied, except tetracycline. Cross-resistance among carbapenem-resistant K. pneumoniae was lower for tetracycline and amikacin. PMID:23260464

  13. Resistance to antimalarial drugs: molecular, pharmacological and clinical considerations

    PubMed Central

    Travassos, Mark A.; Laufer, Miriam K.

    2009-01-01

    One of the greatest obstacles to the control of malaria has been the spread of resistance to drugs used on a large scale. This review provides an update of the current understanding of the molecular basis for antimalarial drug resistance. Parasite intrinsic resistance is just one component that determines the in vivo efficacy of a drug. Human immune responses and pharmacological properties play important roles in determining the clinical outcome of treatment. The emergence and spread of resistance also results from an interplay of these factors. Current efforts to characterize and deter resistance to new combination therapy are also discussed. PMID:19918214

  14. New approaches for understanding mechanisms of drug resistance in schistosomes

    PubMed Central

    GREENBERG, ROBERT M.

    2013-01-01

    SUMMARY Schistosomes are parasitic flatworms that cause schistosomiasis, a neglected tropical disease that affects hundreds of millions worldwide. Treatment and control of schistosomiasis relies almost entirely on the single drug praziquantel (PZQ), making the prospect of emerging drug resistance particularly worrisome. This review will survey reports of PZQ (and other drug) resistance in schistosomes and other platyhelminths, and explore mechanisms by which drug resistance might develop. Newer genomic and post-genomic strategies that offer the promise of better understanding of how drug resistance might arise in these organisms will be discussed. These approaches could also lead to insights into the mode of action of these drugs and potentially provide markers for monitoring the emergence of resistance. PMID:23552512

  15. Public health implications of antiretroviral therapy and HIV drug resistance.

    PubMed

    Wainberg, M A; Friedland, G

    1998-06-24

    Widespread use of antiretroviral agents and increasing occurrence of human immunodeficiency virus (HIV) strains resistant to these drugs have given rise to a number of important issues. Some of these concerns are distinct from the obvious question of the relationship between drug resistance and treatment failure and have potentially widespread public health implications. The relevant issues include but are not limited to the following: (1) frequency with which drug-resistant virus may be transmitted via sexual, intravenous, or mother-to-child routes; (2) ability of drug-resistant variants to be transmitted, a question that relates, in part, to the relative fitness of such strains; (3) effectiveness of antiviral therapy in diminishing viral burden in both blood and genital secretions, and whether this may be compromised in persons harboring resistant virus; and (4) importance of patient adherence to antiviral therapy and its relationship to sustained reduction in viral load to minimize the appearance in and transmission of drug-resistant virus from both blood and genital secretions. Thus, prevention of both development of HIV drug resistance as well as transmission of drug-resistant variants is a central issue of public health importance. Unless this topic is appropriately addressed, the likelihood is that drug-resistant variants of HIV, if able to successfully replicate, will sustain the epidemic and limit the effectiveness of antiviral therapy. PMID:9643862

  16. [Dynamics of drug resistance in Proteus mirabilis cultures 1970-1985].

    PubMed

    Shvidenko, I G

    1988-04-01

    Resistance of 669 clinical strains of Proteus mirabilis to 18 chemotherapeutic drugs was studied in dynamics within 1970-1985. An increase in the number of cultures resistant to ampicillin and carbenicillin was noted while the number of cultures resistant to cephalosporines did not change. Within the period from 1970 to 1975 there was observed a marked increase in the number of Proteus strains resistant to aminoglycoside antibiotics. After that period their number gradually lowered and in 1985 reached the level of 1970. Beginning from 1973 there were observed a decrease in the number of Proteus chloramphenicol resistant strains and simultaneous occurrence of cultures sensitive to this antibiotic. The predominating number of the tested strains preserved during the whole observation period their resistance to tetracycline, doxycycline, rifampicin, novobiocin, furazolidone and furagin. No increase in the number of Proteus strains with multiple drug resistance including those resistant to 5-7 drugs was noted in the observation periods of 1970-1975, 1980 and 1985. The most frequent were Proteus strains resistant to 2-4 drugs. Among them cultures resistant to chloramphenicol and aminoglycoside antibiotics of the first generation predominated. Grouping of the strains by the same resistance spectra provided dividing the rested cultures of Proteus mirabilis into 69 variants. PMID:3291802

  17. Action of anti-HIV drugs and resistance: reverse transcriptase inhibitors and protease inhibitors.

    PubMed

    Imamichi, Tomozumi

    2004-01-01

    Currently, 20 drugs have been approved for Human Immunodeficiency Virus type-1 (HIV-1) clinical therapy. These drugs inhibit HIV-1 reverse transcriptase, protease, or virus entry. Introduction of a combination therapy with reverse transcriptase inhibitors and protease inhibitors has resulted in a drastic decrease in HIV-1 related mortality. Although the combination therapy can suppress viral replication below detection levels in current available assays, low levels of on-going viral replication still persist in some patients. Long-term administration of the combination therapy may increase selective pressure against viruses, and subsequently induce emergence of multiple drug-resistant HIV-1 variants. Attempts have been made to design novel antiretroviral drugs that would be able to suppress replication of the resistant variants. At present, several investigational drugs are being tested in clinical trials. These drugs target not only the resistant variants, but also improvement in oral bioavilability or other viral proteins such as HIV-1 integrase, ribonuclease H, and HIV-1 entry (CD4 attachment inhibitors, chemokine receptors antagonists, and fusion inhibitors). Understanding mechanism(s) of action of the drugs and mechanisms of drug resistance is necessary for successful designs in the next generation of anti-HIV-1 drugs. In this review, the mechanisms of action of reverse transcriptase- and protease-inhibitors, and the mechanism of resistance to these inhibitors, are described. PMID:15579086

  18. 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

  19. 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

  20. Presenting Multiple Drug Alerts in an Ambulatory Electronic Prescribing System

    PubMed Central

    Weinger, M.B.; Gregg, W.M.; Johnson, K.B.

    2014-01-01

    Summary Objective This study explores alternative approaches to the display of drug alerts, and examines whether and how human-factors based interface design can be used to improve the prescriber’s perception about drug alert presentation, signal detection from noisy alert data, and their comprehension of clinical decision support during electronic prescribing. Methods We reviewed issues with presenting multiple drug alerts in electronic prescribing systems. User-centered design, consisting of iterative usability and prototype testing was applied. After an iterative design phase, we proposed several novel drug alert presentation interfaces; expert evaluation and formal usability testing were applied to access physician prescribers’ perceptions of the tools. We mapped drug alert attributes to different interface constructs. We examined four different interfaces for presenting multiple drug alerts. Results A TreeDashboard View was better perceived than a text-based ScrollText View with respect to the ability to detect critical information, the ability to accomplish tasks, and the perceptional efficacy of finding information. Conclusion A robust model for studying multiple drug-alert presentations was developed. Several drug alert presentation interfaces were proposed. The TreeDashboard View was better perceived than the text-based ScrollText View in delivering multiple drug alerts during a simulation of electronic prescribing. PMID:25024753

  1. Multiple Myeloma Gets Three New Drugs.

    PubMed

    Poh, Alissa

    2016-01-01

    In the last few weeks, the FDA approved three new therapies for multiple myeloma: ixazomib, the first oral proteasome inhibitor; and daratumumab and elotuzumab, two monoclonal antibodies that target CD38 and SLAMF7, respectively. PMID:26658418

  2. 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

  3. Improving Viral Protease Inhibitors to Counter Drug Resistance.

    PubMed

    Kurt Yilmaz, Nese; Swanstrom, Ronald; Schiffer, Celia A

    2016-07-01

    Drug resistance is a major problem in health care, undermining therapy outcomes and necessitating novel approaches to drug design. Extensive studies on resistance to viral protease inhibitors, particularly those of HIV-1 and hepatitis C virus (HCV) protease, revealed a plethora of information on the structural and molecular mechanisms underlying resistance. These insights led to several strategies to improve viral protease inhibitors to counter resistance, such as exploiting the essential biological function and leveraging evolutionary constraints. Incorporation of these strategies into structure-based drug design can minimize vulnerability to resistance, not only for viral proteases but for other quickly evolving drug targets as well, toward designing inhibitors one step ahead of evolution to counter resistance with more intelligent and rational design. PMID:27090931

  4. 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

  5. Drug Abuse - Multiple Languages: MedlinePlus

    MedlinePlus

    ... drogas Tagalog (Tagalog) Substance Abuse or Dependence Pag-abuso sa Paggamit ng Mga Bagay o Dependensya - Tagalog (Tagalog) Bilingual PDF Health Information Translations Vietnamese (Tiếng Việt) Drugs, Alcohol and HIV/AIDS: A Consumer Guide English Rượu & ...

  6. 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

  7. Drug-Resistant Malaria: The Era of ACT

    PubMed Central

    Lin, Jessica T.; Juliano, Jonathan J.

    2010-01-01

    As drug-resistant falciparum malaria has continued to evolve and spread worldwide, artemisinin-based combination therapies (ACT) have become the centerpiece of global malaria control over the past decade. This review discusses how advances in antimalarial drug resistance monitoring and rational use of the array of ACTs now available can maximize the impact of this highly efficacious therapy, even as resistance to artemisinins is emerging in Southeast Asia. PMID:21308525

  8. 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

  9. 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

  10. 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

  11. 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

  12. Drug Abuse - Multiple Languages: MedlinePlus

    MedlinePlus

    ... 繁體中文) French (français) Hindi (हिन्दी) Japanese (日本語) Korean (한국어) Portuguese (português) Russian (Русский) Somali (af Soomaali) ... 薬物の乱用または依存症 - 日本語 (Japanese) Bilingual PDF Health Information Translations Korean (한국어) Drugs, Alcohol and HIV/AIDS: A Consumer ...

  13. Unusual regioversatility of acetyltransferase Eis, a cause of drug resistance in XDR-TB

    SciTech Connect

    Chen, Wenjing; Biswas, Tapan; Porter, Vanessa R.; Tsodikov, Oleg V.; Garneau-Tsodikova, Sylvie

    2011-09-06

    The emergence of multidrug-resistant and extensively drug-resistant (XDR) tuberculosis (TB) is a serious global threat. Aminoglycoside antibiotics are used as a last resort to treat XDR-TB. Resistance to the aminoglycoside kanamycin is a hallmark of XDR-TB. Here, we reveal the function and structure of the mycobacterial protein Eis responsible for resistance to kanamycin in a significant fraction of kanamycin-resistant Mycobacterium tuberculosis clinical isolates. We demonstrate that Eis has an unprecedented ability to acetylate multiple amines of many aminoglycosides. Structural and mutagenesis studies of Eis indicate that its acetylation mechanism is enabled by a complex tripartite fold that includes two general control non-derepressible 5 (GCN5)-related N-acetyltransferase regions. An intricate negatively charged substrate-binding pocket of Eis is a potential target of new antitubercular drugs expected to overcome aminoglycoside resistance.

  14. Prevalence of pyrazinamide resistance across the spectrum of drug resistant phenotypes of Mycobacterium tuberculosis.

    PubMed

    Whitfield, Michael G; Streicher, Elizabeth M; Dolby, Tania; Simpson, John A; Sampson, Samantha L; Van Helden, Paul D; Van Rie, Annelies; Warren, Robin M

    2016-07-01

    Pyrazinamide resistance is largely unknown in the spectrum of drug resistant phenotypes. We summarize data on PZA resistance in clinical isolates from South Africa. PZA DST should be performed when considering its inclusion in treatment of patients with rifampicin-resistant TB or MDR-TB. PMID:27450014

  15. 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

  16. Bayesian analysis of complex interacting mutations in HIV drug resistance and cross-resistance.

    PubMed

    Kozyryev, Ivan; Zhang, Jing

    2015-01-01

    A successful treatment of AIDS world-wide is severely hindered by the HIV virus' drug resistance capability resulting from complicated mutation patterns of viral proteins. Such a system of mutations enables the virus to survive and reproduce despite the presence of various antiretroviral drugs by disrupting their binding capability. Although these interacting mutation patterns are extremely difficult to efficiently uncover and interpret, they contribute valuable information to personalized therapeutic regimen design. The use of Bayesian statistical modeling provides an unprecedented opportunity in the field of anti-HIV therapy to understand detailed interaction structures of drug resistant mutations. Multiple Bayesian models equipped with Markov Chain Monte Carlo (MCMC) methods have been recently proposed in this field (Zhang et al. in PNAS 107:1321, 2010 [1]; Zhang et al. in J Proteome Sci Comput Biol 1:2, 2012 [2]; Svicher et al. in Antiviral Res 93(1):86-93, 2012 [3]; Svicher et al. in Antiviral Therapy 16(7):1035-1045, 2011 [4]; Svicher et al. in Antiviral Ther 16(4):A14-A14, 2011 [5]; Svicher et al. in Antiviral Ther 16(4):A85-A85, 2011 [6]; Alteri et al. in Signature mutations in V3 and bridging sheet domain of HIV-1 gp120 HIV-1 are specifically associated with dual tropism and modulate the interaction with CCR5 N-Terminus, 2011 [7]). Probabilistically modeling mutations in the HIV-1 protease or reverse transcriptase (RT) isolated from drug-treated patients provides a powerful statistical procedure that first detects mutation combinations associated with single or multiple-drug resistance, and then infers detailed dependence structures among the interacting mutations in viral proteins (Zhang et al. in PNAS 107:1321, 2010 [1]; Zhang et al. in J Proteome Sci Comput Biol 1:2, 2012 [2]). Combined with molecular dynamics simulations and free energy calculations, Bayesian analysis predictions help to uncover genetic and structural mechanisms in the HIV treatment

  17. Drug Resistance among Pulmonary Tuberculosis Patients in Calabar, Nigeria

    PubMed Central

    Otu, Akaninyene; Umoh, Victor; Habib, Abdulrazak; Ameh, Soter; Lawson, Lovett

    2013-01-01

    Background. This study aimed to determine the pattern of drug susceptibility to first-line drugs among pulmonary TB patients in two hospitals in Calabar, Nigeria. Methods. This was a descriptive cross-sectional study carried out between February 2011 and April 2012. Sputum samples from consecutive TB patients in Calabar were subjected to culture on Lowenstein-Jensen (LJ) slopes followed by drug susceptibility testing (DST). The DST was performed on LJ medium by the proportion method. Results. Forty-two of the 100 Mycobacterium tuberculosis strains were found to be resistant to at least one drug. Resistance to only one drug (monoresistance) was found in 17 patients. No strains with monoresistance to rifampicin were found. Resistance to two drugs was found in 22 patients, while one patient was resistant to both three and four drugs. MDR TB was seen in 4% (4/100). The independent variables of HIV serology and sex were not significantly associated with resistance (P > 0.05). Conclusion. There was a high prevalence of anti-TB drug resistance in Calabar. PMID:24078872

  18. Drug interactions and the evolution of antibiotic resistance

    PubMed Central

    Yeh, Pamela J.; Hegreness, Matthew J.; Aiden, Aviva Presser; Kishony, Roy

    2010-01-01

    Large-scale, systems biology approaches now allow us to systematically map synergistic and antagonistic interactions between drugs. Consequently, drug antagonism is emerging as a powerful tool to study biological function and relatedness between cellular components as well as to uncover mechanisms of drug action. Furthermore, theoretical models and new experiments suggest that antagonistic interactions between antibiotics can counteract the evolution of drug resistance. PMID:19444248

  19. Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance

    PubMed Central

    Shafer, Robert W.

    2002-01-01

    There are 16 approved human immunodeficiency virus type 1 (HIV-1) drugs belonging to three mechanistic classes: protease inhibitors, nucleoside and nucleotide reverse transcriptase (RT) inhibitors, and nonnucleoside RT inhibitors. HIV-1 resistance to these drugs is caused by mutations in the protease and RT enzymes, the molecular targets of these drugs. Drug resistance mutations arise most often in treated individuals, resulting from selective drug pressure in the presence of incompletely suppressed virus replication. HIV-1 isolates with drug resistance mutations, however, may also be transmitted to newly infected individuals. Three expert panels have recommended that HIV-1 protease and RT susceptibility testing should be used to help select HIV drug therapy. Although genotypic testing is more complex than typical antimicrobial susceptibility tests, there is a rich literature supporting the prognostic value of HIV-1 protease and RT mutations. This review describes the genetic mechanisms of HIV-1 drug resistance and summarizes published data linking individual RT and protease mutations to in vitro and in vivo resistance to the currently available HIV drugs. PMID:11932232

  20. 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

  1. 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

  2. The Impact of Microenvironmental Heterogeneity on the Evolution of Drug Resistance in Cancer Cells

    PubMed Central

    Mumenthaler, Shannon M; Foo, Jasmine; Choi, Nathan C; Heise, Nicholas; Leder, Kevin; Agus, David B; Pao, William; Michor, Franziska; Mallick, Parag

    2015-01-01

    Therapeutic resistance arises as a result of evolutionary processes driven by dynamic feedback between a heterogeneous cell population and environmental selective pressures. Previous studies have suggested that mutations conferring resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in non-small-cell lung cancer (NSCLC) cells lower the fitness of resistant cells relative to drug-sensitive cells in a drug-free environment. Here, we hypothesize that the local tumor microenvironment could influence the magnitude and directionality of the selective effect, both in the presence and absence of a drug. Using a combined experimental and computational approach, we developed a mathematical model of preexisting drug resistance describing multiple cellular compartments, each representing a specific tumor environmental niche. This model was parameterized using a novel experimental dataset derived from the HCC827 erlotinib-sensitive and -resistant NSCLC cell lines. We found that, in contrast to in the drug-free environment, resistant cells may hold a fitness advantage compared to parental cells in microenvironments deficient in oxygen and nutrients. We then utilized the model to predict the impact of drug and nutrient gradients on tumor composition and recurrence times, demonstrating that these endpoints are strongly dependent on the microenvironment. Our interdisciplinary approach provides a model system to quantitatively investigate the impact of microenvironmental effects on the evolutionary dynamics of tumor cells. PMID:26244007

  3. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants

    PubMed Central

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F. M.; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance. PMID:25988960

  4. Fluorometric assay for phenotypic differentiation of drug-resistant HIV mutants.

    PubMed

    Zhu, Qinchang; Yu, Zhiqiang; Kabashima, Tsutomu; Yin, Sheng; Dragusha, Shpend; El-Mahdy, Ahmed F M; Ejupi, Valon; Shibata, Takayuki; Kai, Masaaki

    2015-01-01

    Convenient drug-resistance testing of viral mutants is indispensable to effective treatment of viral infection. We developed a novel fluorometric assay for phenotypic differentiation of drug-resistant mutants of human immunodeficiency virus-I protease (HIV-PR) which uses enzymatic and peptide-specific fluorescence (FL) reactions and high-performance liquid chromatography (HPLC) of three HIV-PR substrates. This assay protocol enables use of non-purified enzyme sources and multiple substrates for the enzymatic reaction. In this study, susceptibility of HIV mutations to drugs was evaluated by selective formation of three FL products after the enzymatic HIV-PR reaction. This proof-of-concept study indicates that the present HPLC-FL method could be an alternative to current phenotypic assays for the evaluation of HIV drug resistance. PMID:25988960

  5. Bedaquiline for the treatment of drug-resistant tuberculosis.

    PubMed

    Bélard, Sabine; Heuvelings, Charlotte C; Janssen, Saskia; Grobusch, Martin P

    2015-05-01

    Bedaquiline is a much-needed novel drug which is highly effective against drug-resistant tuberculosis. While its clinical development has been laudably fast-tracked and the drug is now available for inclusion into treatment regimens when no suitable alternatives exist, clinical experience with bedaquiline is still limited. Phase III trial data and Phase IV studies are needed particularly to study different patient populations and to optimize treatment regimens. Drug resistance to bedaquiline needs to be monitored carefully, and full access to bedaquiline treatment where it is appropriate and needed must be promoted. PMID:25797824

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

    PubMed Central

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

    2014-01-01

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

  7. Longitudinal Detection and Persistence of Minority Drug-Resistant Populations and Their Effect on Salvage Therapy

    PubMed Central

    Nishizawa, Masako; Matsuda, Masakazu; Hattori, Junko; Shiino, Teiichiro; Matano, Tetsuro; Heneine, Walid; Johnson, Jeffrey A.; Sugiura, Wataru

    2015-01-01

    Background Drug-resistant HIV are more prevalent and persist longer than previously demonstrated by bulk sequencing due to the ability to detect low-frequency variants. To clarify a clinical benefit to monitoring minority-level drug resistance populations as a guide to select active drugs for salvage therapy, we retrospectively analyzed the dynamics of low-frequency drug-resistant population in antiretroviral (ARV)-exposed drug resistant individuals. Materials and Methods Six HIV-infected individuals treated with ARV for more than five years were analyzed. These individuals had difficulty in controlling viremia, and treatment regimens were switched multiple times guided by standard drug resistance testing using bulk sequencing. To detect minority variant populations with drug resistance, we used a highly sensitive allele-specific PCR (AS-PCR) with detection thresholds of 0.3–2%. According to ARV used in these individuals, we focused on the following seven reverse transcriptase inhibitor-resistant mutations: M41L, K65R, K70R, K103N, Y181C, M184V, and T215F/Y. Results of AS-PCR were compared with bulk sequencing data for concordance and presence of additional mutations. To clarify the genetic relationship between low-frequency and high-frequency populations, AS-PCR amplicon sequences were compared with bulk sequences in phylogenetic analysis. Results The use of AS-PCR enabled detection of the drug-resistant mutations, M41L, K103N, Y181C, M184V and T215Y, present as low-frequency populations in five of the six individuals. These drug resistant variants persisted for several years without ARV pressure. Phylogenetic analysis indicated that pre-existing K103N and T215I variants had close genetic relationships with high-frequency K103N and T215I observed during treatment. Discussion and Conclusion Our results demonstrate the long-term persistence of drug-resistant viruses in the absence of drug pressure. The rapid virologic failures with pre-existing mutant viruses

  8. 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

  9. [Resistance to antiplatelet drugs in patients with cerebrovascular disorders].

    PubMed

    Suslina, Z A; Tanashian, M M; Domashenko, M A

    2011-01-01

    This review concerns clinical and laboratory resistance to antiplatelet drugs (aspirin and clopidogrel) in patients with cerebrovascular disorders. Results of certain clinical trials showed that laboratory resistance to antiaggregants is associated with recurrent thromboembolic vascular events. The commonest causes of aspirin resistance are production of arachidonic acid metabolites via the lipoxygenase pathway, poor compliance with the treatment, polymorphism of the genes encoding for cyclooxygenase and glycoprotein (GP) IIb/IIIa, endothelial dysfunction. The causes of clopidogrel resistance include inadequate doses of the drug, its low absorption, poor compliance with the treatment, polymorphism of ADP receptors, GP IIb/IIIa and cytochrome P450 genes, acute coronary syndrome and stroke, metabolic syndrome. Therapeutic efficacy of antiaggregants can be improved by increasing their doses, using membranotropic agents, correcting endothelial dysfunction, etc. Because the apparent variability of antiplatelet drug resistance is currently due to the use of different test-systems by different authors, the evaluation of individual sensitivity to a given drug showing laboratory resistance and the choice of alternative therapy are thus far possible only in the framework of clinical studies. Large-scale prospective multicenter trials of antiplatelet drug resistance are needed along with research for better understanding mechanisms of individual platelet sensitivity and resistance to antiaggregants and developing efficacious methods for their correction. PMID:21901881

  10. Systematic identification of signaling pathways with potential to confer anticancer drug resistance.

    PubMed

    Martz, Colin A; Ottina, Kathleen A; Singleton, Katherine R; Jasper, Jeff S; Wardell, Suzanne E; Peraza-Penton, Ashley; Anderson, Grace R; Winter, Peter S; Wang, Tim; Alley, Holly M; Kwong, Lawrence N; Cooper, Zachary A; Tetzlaff, Michael; Chen, Pei-Ling; Rathmell, Jeffrey C; Flaherty, Keith T; Wargo, Jennifer A; McDonnell, Donald P; Sabatini, David M; Wood, Kris C

    2014-12-23

    Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant complementary DNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS-MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)-mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAF(V600E) melanoma cells in culture, and the abundance of Notch1 pathway markers was increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts. PMID:25538079

  11. Systematic identification of signaling pathways with potential to confer anticancer drug resistance

    PubMed Central

    Martz, Colin A.; Ottina, Kathleen A.; Singleton, Katherine R.; Jasper, Jeff S.; Wardell, Suzanne E.; Peraza-Penton, Ashley; Anderson, Grace R.; Winter, Peter S.; Wang, Tim; Alley, Holly M.; Kwong, Lawrence N.; Cooper, Zachary A.; Tetzlaff, Michael; Chen, Pei-Ling; Rathmell, Jeffrey C.; Flaherty, Keith T.; Wargo, Jennifer A.; McDonnell, Donald P.; Sabatini, David M.; Wood, Kris C.

    2015-01-01

    Cancer cells can activate diverse signaling pathways to evade the cytotoxic action of drugs. We created and screened a library of barcoded pathway-activating mutant cDNAs to identify those that enhanced the survival of cancer cells in the presence of 13 clinically relevant, targeted therapies. We found that activation of the RAS– MAPK (mitogen-activated protein kinase), Notch1, PI3K (phosphoinositide 3-kinase)–mTOR (mechanistic target of rapamycin), and ER (estrogen receptor) signaling pathways often conferred resistance to this selection of drugs. Activation of the Notch1 pathway promoted acquired resistance to tamoxifen (an ER-targeted therapy) in serially-passaged breast cancer xenografts in mice, and treating mice with a γ-secretase inhibitor to inhibit Notch signaling restored tamoxifen sensitivity. Markers of Notch1 activity in tumor tissue correlated with resistance to tamoxifen in breast cancer patients. Similarly, activation of Notch1 signaling promoted acquired resistance to MAPK inhibitors in BRAFV600E melanoma cells in culture, and the abundance of Notch1 pathway markers were increased in tumors from a subset of melanoma patients. Thus, Notch1 signaling may be a therapeutic target in some drug-resistant breast cancers and melanomas. Additionally, multiple resistance pathways were activated in melanoma cell lines with intrinsic resistance to MAPK inhibitors, and simultaneous inhibition of these pathways synergistically induced drug sensitivity. These data illustrate the potential for systematic identification of the signaling pathways controlling drug resistance that could inform clinical strategies and drug development for multiple types of cancer. This approach may also be used to advance clinical options in other disease contexts. PMID:25538079

  12. Classical and Targeted Anticancer Drugs: An Appraisal of Mechanisms of Multidrug Resistance.

    PubMed

    Baguley, Bruce C

    2016-01-01

    The mechanisms by which tumor cells resist the action of multiple anticancer drugs, often with widely different chemical structures, have been pursued for more than 30 years. The identification of P-glycoprotein (P-gp), a drug efflux transporter protein with affinity for multiple therapeutic drugs, provided an important potential mechanism and further work, which identified other members of ATP-binding cassette (ABC) family that act as drug transporters. Several observations, including results of clinical trials with pharmacological inhibitors of P-gp, have suggested that mechanisms other than efflux transporters should be considered as contributors to resistance, and in this review mechanisms of anticancer drug resistance are considered more broadly. Cells in human tumors exist is a state of continuous turnover, allowing ongoing selection and "survival of the fittest." Tumor cells die not only as a consequence of drug therapy but also by apoptosis induced by their microenvironment. Cell death can be mediated by host immune mechanisms and by nonimmune cells acting on so-called death receptors. The tumor cell proliferation rate is also important because it controls tumor regeneration. Resistance to therapy might therefore be considered to arise from a reduction of several distinct cell death mechanisms, as well as from an increased ability to regenerate. This review provides a perspective on these mechanisms, together with brief descriptions of some of the methods that can be used to investigate them in a clinical situation. PMID:26910066

  13. Multiple insect resistance in 53 commmercial corn hybrids - 2015

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Commercial corn hybrids were screened for ear- and kernel-feeding insect resistance under field conditions at Tifton, GA. Fifteen hybrids were rated Very Good (VG), the highest rating for multiple insect resistance in 2015 (Table 1). Sixteen were Good (G), 9 were Fair (F), and 13 were Poor (P). Two...

  14. Multiple insect resistance in 53 commercial corn hybrids - 2015

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Commercial corn hybrids were screened for ear- and kernel-feeding insect resistance under field conditions at Tifton, GA. Fifteen hybrids were rated Very Good (VG), the highest rating for multiple insect resistance in 2015 (Table 1). Sixteen were Good (G), 9 were Fair (F), and 13 were Poor (P). Two...

  15. Multiple insect resistance in 70 commercial corn hybrids - 2013

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Commercial corn hybrids were screened for ear- and kernel-feeding insect resistance under the field conditions at Tifton, GA. Nineteen hybrids were rated as very good (VG), the highest rating for multiple insect resistance in 2013. Five hybrids were developed utilizing YHR or BHR traits (also known ...

  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. Bioerodible system for sequential release of multiple drugs.

    PubMed

    Sundararaj, Sharath C; Thomas, Mark V; Dziubla, Thomas D; Puleo, David A

    2014-01-01

    Because many complex physiological processes are controlled by multiple biomolecules, comprehensive treatment of certain disease conditions may be more effectively achieved by administration of more than one type of drug. Thus, the objective of the present research was to develop a multilayered, polymer-based system for sequential delivery of multiple drugs. The polymers used were cellulose acetate phthalate (CAP) complexed with Pluronic F-127 (P). After evaluating morphology of the resulting CAPP system, in vitro release of small molecule drugs and a model protein was studied from both single and multilayered devices. Drug release from single-layered CAPP films followed zero-order kinetics related to surface erosion of the association polymer. Release studies from multilayered CAPP devices showed the possibility of achieving intermittent release of one type of drug as well as sequential release of more than one type of drug. Mathematical modeling accurately predicted the release profiles for both single layer and multilayered devices. The present CAPP association polymer-based multilayer devices can be used for localized, sequential delivery of multiple drugs for the possible treatment of complex disease conditions, and perhaps for tissue engineering applications, that require delivery of more than one type of biomolecule. PMID:24096151

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

    PubMed Central

    Friedman, Ran

    2016-01-01

    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

  19. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia

    PubMed Central

    Park, Eugene; Gang, Eun Ji; Hsieh, Yao-Te; Schaefer, Paul; Chae, Sanna; Klemm, Lars; Huantes, Sandra; Loh, Mignon; Conway, Edward M.; Kang, Eun-Suk; Hoe Koo, Hong; Hofmann, Wolf-Karsten; Heisterkamp, Nora; Pelus, Louis; Keerthivasan, Ganesan; Crispino, John; Kahn, Michael; Müschen, Markus

    2011-01-01

    Relapse of drug-resistant acute lymphoblastic leukemia (ALL) has been associated with increased expression of survivin/BIRC5, an inhibitor of apoptosis protein, suggesting a survival advantage for ALL cells. In the present study, we report that inhibition of survivin in patient-derived ALL can eradicate leukemia. Targeting survivin with shRNA in combination with chemotherapy resulted in no detectable minimal residual disease in a xenograft model of primary ALL. Similarly, pharmacologic knock-down of survivin using EZN-3042, a novel locked nucleic acid antisense oligonucleotide, in combination with chemotherapy eliminated drug-resistant ALL cells. These findings show the importance of survivin expression in drug resistance and demonstrate that survivin inhibition may represent a powerful approach to overcoming drug resistance and preventing relapse in patients with ALL. PMID:21715311

  20. Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story

    PubMed Central

    Baker, Nicola; de Koning, Harry P.; Mäser, Pascal; Horn, David

    2013-01-01

    Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over sixty years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well-known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss-of-function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites. PMID:23375541

  1. 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

  2. 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

  3. Highly active ozonides selected against drug resistant malaria.

    PubMed

    Lobo, Lis; Sousa, Bruno de; Cabral, Lília; Cristiano, Maria Ls; Nogueira, Fátima

    2016-06-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  4. Highly active ozonides selected against drug resistant malaria

    PubMed Central

    Lobo, Lis; de Sousa, Bruno; Cabral, Lília; Cristiano, Maria LS; Nogueira, Fátima

    2016-01-01

    Ever increasing multi-drug resistance by Plasmodium falciparum is creating new challenges in malaria chemotherapy. In the absence of licensed vaccines, treatment and prevention of malaria is heavily dependent on drugs. Potency, range of activity, safety, low cost and ease of administration are crucial issues in the design and formulation of antimalarials. We have tested three synthetic ozonides NAC89, LC50 and LCD67 in vitro and in vivo against multidrug resistant Plasmodium. In vitro, LC50 was at least 10 times more efficient inhibiting P. falciparum multidrug resistant Dd2 strain than chloroquine and mefloquine and as efficient as artemisinin (ART), artesunate and dihydroartemisinin. All three ozonides showed high efficacy in clearing parasitaemia in mice, caused by multi-drug resistant Plasmodium chabaudi strains, by subcutaneous administration, demonstrating high efficacy in vivo against ART and artesunate resistant parasites. PMID:27276364

  5. Targeting imperfect vaccines against drug-resistance determinants: a strategy for countering the rise of drug resistance.

    PubMed

    Joice, Regina; Lipsitch, Marc

    2013-01-01

    The growing prevalence of antimicrobial resistance in major pathogens is outpacing discovery of new antimicrobial classes. Vaccines mitigate the effect of antimicrobial resistance by reducing the need for treatment, but vaccines for many drug-resistant pathogens remain undiscovered or have limited efficacy, in part because some vaccines selectively favor pathogen strains that escape vaccine-induced immunity. A strain with even a modest advantage in vaccinated hosts can have high fitness in a population with high vaccine coverage, which can offset a strong selection pressure such as antimicrobial use that occurs in a small fraction of hosts. We propose a strategy to target vaccines against drug-resistant pathogens, by using resistance-conferring proteins as antigens in multicomponent vaccines. Resistance determinants may be weakly immunogenic, offering only modest specific protection against resistant strains. Therefore, we assess here how varying the specific efficacy of the vaccine against resistant strains would affect the proportion of drug-resistant vs. -sensitive strains population-wide for three pathogens--Streptococcus pneumoniae, Staphylococcus aureus, and influenza virus--in which drug resistance is a problem. Notably, if such vaccines confer even slightly higher protection (additional efficacy between 1% and 8%) against resistant variants than sensitive ones, they may be an effective tool in controlling the rise of resistant strains, given current levels of use for many antimicrobial agents. We show that the population-wide impact of such vaccines depends on the additional effect on resistant strains and on the overall effect (against all strains). Resistance-conferring accessory gene products or resistant alleles of essential genes could be valuable as components of vaccines even if their specific protective effect is weak. PMID:23935910

  6. 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

  7. Sparse Representation for Prediction of HIV-1 Protease Drug Resistance.

    PubMed

    Yu, Xiaxia; Weber, Irene T; Harrison, Robert W

    2013-01-01

    HIV rapidly evolves drug resistance in response to antiviral drugs used in AIDS therapy. Estimating the specific resistance of a given strain of HIV to individual drugs from sequence data has important benefits for both the therapy of individual patients and the development of novel drugs. We have developed an accurate classification method based on the sparse representation theory, and demonstrate that this method is highly effective with HIV-1 protease. The protease structure is represented using our newly proposed encoding method based on Delaunay triangulation, and combined with the mutated amino acid sequences of known drug-resistant strains to train a machine-learning algorithm both for classification and regression of drug-resistant mutations. An overall cross-validated classification accuracy of 97% is obtained when trained on a publically available data base of approximately 1.5×10(4) known sequences (Stanford HIV database http://hivdb.stanford.edu/cgi-bin/GenoPhenoDS.cgi). Resistance to four FDA approved drugs is computed and comparisons with other algorithms demonstrate that our method shows significant improvements in classification accuracy. PMID:24910813

  8. Sparse Representation for Prediction of HIV-1 Protease Drug Resistance

    PubMed Central

    Yu, Xiaxia; Weber, Irene T.; Harrison, Robert W.

    2013-01-01

    HIV rapidly evolves drug resistance in response to antiviral drugs used in AIDS therapy. Estimating the specific resistance of a given strain of HIV to individual drugs from sequence data has important benefits for both the therapy of individual patients and the development of novel drugs. We have developed an accurate classification method based on the sparse representation theory, and demonstrate that this method is highly effective with HIV-1 protease. The protease structure is represented using our newly proposed encoding method based on Delaunay triangulation, and combined with the mutated amino acid sequences of known drug-resistant strains to train a machine-learning algorithm both for classification and regression of drug-resistant mutations. An overall cross-validated classification accuracy of 97% is obtained when trained on a publically available data base of approximately 1.5×104 known sequences (Stanford HIV database http://hivdb.stanford.edu/cgi-bin/GenoPhenoDS.cgi). Resistance to four FDA approved drugs is computed and comparisons with other algorithms demonstrate that our method shows significant improvements in classification accuracy. PMID:24910813

  9. 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

  10. Old Drugs, New Purpose: Retooling Existing Drugs for Optimized Treatment of Resistant Tuberculosis

    PubMed Central

    Dooley, Kelly E.; Mitnick, Carole D.; Ann DeGroote, Mary; Obuku, Ekwaro; Belitsky, Vera; Hamilton, Carol D.; Makhene, Mamodikoe; Shah, Sarita; Brust, James C. M.; Durakovic, Nadza; Nuermberger, Eric

    2012-01-01

    Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health Organization–defined group 1, 2, and 4 drugs used in drug-resistant tuberculosis regimens to inform clinical trials and identify critical research questions. Results suggest that optimizing the dosing of pyrazinamide, the injectables, and isoniazid for drug-resistant tuberculosis is a high priority. Additional pharmacokinetic, pharmacodynamic, and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for Mycobacterium tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against drug-resistant tuberculosis is paramount. PMID:22615332

  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. An autopsy case of multiple psychotropic drug poisoning.

    PubMed

    Tanaka, Naoko; Kinoshita, Hiroshi; Nishiguchi, Minori; Jamal, Mostofa; Kumihashi, Mitsuru; Takahashi, Motonori; Nishio, Hajime; Ameno, Kiyoshi

    2011-07-01

    A fatal poisoning case involving etizolam, phenobarbital, promethazine and chlorpromazine is presented. Quantitative toxicological analysis showed that the concentrations of etizolam, phenobarbital, promethazine and chlorpromazine in the femoral blood were 86 ng/ml, 5082 microg/ml, 0.107 microg/ml and 0.144 microg/ml, respectively, and large amounts of drugs were also detected in the stomach contents. We conclude that the cause of death was due to the interaction of multiple psychotropic drugs. PMID:21887897

  13. Multiple antimicrobial resistance in Enterobacteriaceae isolates from pristine freshwater.

    PubMed

    Lima-Bittencourt, C I; Cursino, L; Gonçalves-Dornelas, H; Pontes, D S; Nardi, R M D; Callisto, M; Chartone-Souza, E; Nascimento, A M A

    2007-01-01

    A freshwater enterobacterial population (N = 111) was studied for antimicrobial and mercury resistance patterns, and for its possible association with biotic and abiotic factors in that environment. Conventional biochemical tests identified Klebsiella sp, Morganella sp, Serratia sp, Escherichia sp, Enterobacter sp, Edwarsiella sp, Proteus sp, Citrobacter sp, Providencia sp, and Kluyvera sp. There was no correlation between antimicrobial resistance patterns of isolates and bacterial genera, but resistance patterns varied among water samples and between seasons. Resistance to multiple antimicrobials was common (61%). The percentage of bacteria resistant to at least one antimicrobial differed between the rainy (100%) and dry seasons (89%). Resistance to beta-lactams and chloramphenicol was the most frequent and resistance to amikacin, gentamicin and kanamycin was less frequent. The main water variables examined (abiotic factors pH and temperature; biotic factor chlorophyll a concentration) did not influence antimicrobial resistance. Significant impact on freshwater enterobacteria, as evidenced by antimicrobial-multiple resistance and by the presence of bla(TEM) gene, may point to the fact that it has an important role in horizontal spread of resistance. PMID:17985304

  14. Bortezomib induces AMPK-dependent autophagosome formation uncoupled from apoptosis in drug resistant cells

    PubMed Central

    Jaganathan, Sajjeev; Malek, Ehsan; Vallabhapurapu, Subrahmanya; Vallabhapurapu, Sivakumar; Driscoll, James J.

    2014-01-01

    The proteasome inhibitor bortezomib is an effective anti-cancer agent for the plasma cell malignancy multiple myeloma but clinical response is hindered by the emergence of drug resistance through unknown mechanisms. Drug sensitive myeloma cells were exposed to bortezomib to generate drug resistant cells that displayed a significant increase in subunits of the energy sensor AMP-activated protein kinase (AMPK). AMPK activity in resistant cells was increased and bortezomib resistant cells contained a ~4-fold greater level of autophagosomes than drug sensitive cells. Real-time measurements indicated that bortezomib reduced the oxygen consumption rate in drug sensitive cells more readily than in resistant cells. Genetic ablation of AMPK activity reduced the bortezomib effect on autophagy. The autophagy-related gene (Atg)5 is required for autophagosome formation and enhances cellular susceptibility to apoptotic stimuli. Atg5 knockout eliminated bortezomib-induced autophagosome formation and reduced susceptibility to bortezomib. Bortezomib treatment of myeloma cells lead to ATG5 cleavage through a calpain-dependent manner while calpain inhibition or a calpain-insensitive Atg5 mutant promoted bortezomib-resistance. In contrast, AICAR, an AMPK activator, enhanced bortezomib-induced cleavage of ATG5 and increased bortezomib-induced killing. Taken together, the results demonstrate that ATG5 cleavage provokes apoptosis and represents a molecular link between autophagy and apoptosis with therapeutic implications. PMID:25481044

  15. 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

  16. 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…

  17. Bacteremia and Antimicrobial Drug Resistance over Time, Ghana

    PubMed Central

    Amuzu, Sylvarius K.; de Ciman, Ring; Kassimova, Iparkhan; Groß, Lisa; Rabsch, Wolfgang; Rosenberg, Ulrike; Schulze, Marco; Stich, August; Zimmermann, Ortrud

    2011-01-01

    Bacterial distribution and antimicrobial drug resistance were monitored in patients with bacterial bloodstream infections in rural hospitals in Ghana. In 2001–2002 and in 2009, Salmonella enterica serovar Typhi was the most prevalent pathogen. Although most S. enterica serovar Typhi isolates were chloramphenicol resistant, all isolates tested were susceptible to ciprofloxacin. PMID:22000360

  18. 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

  19. A new multiple-drug applicator with minimal drug cross-talk, leakage, and consumption.

    PubMed

    Fujita, Yosuke; Shimomura, Takeshi; Hosoguchi, Masafumi; Kano, Masanobu; Fukurotani, Kenkichi; Tabata, Toshihide

    2010-04-01

    The relative effects of multiple drugs give an important clue to dissect a neuronal mechanism and to seek for a candidate neurotherapeutical agent. Here we have devised a "flute" applicator which can deliver several drugs to a neural cell preparation. The applicator stands by, cleaning itself with bath perfusate and delivers drugs only during test applications. This minimizes drug cross-talk in and leakage from the applicator and drug consumption. Using the applicator, we successfully compared the relative effects of widely different doses of an agonist in single neurons. The flute applicator would be a useful tool for pharmacological analyses. PMID:20060427

  20. Acquisition of Drug Resistance and Dependence by Prions

    PubMed Central

    Oelschlegel, Anja M.; Weissmann, Charles

    2013-01-01

    We have reported that properties of prion strains may change when propagated in different environments. For example, when swainsonine-sensitive 22L prions were propagated in PK1 cells in the presence of swainsonine, drug-resistant variants emerged. We proposed that prions constitute quasi- populations comprising a range of variants with different properties, from which the fittest are selected in a particular environment. Prion populations developed heterogeneity even after biological cloning, indicating that during propagation mutation-like processes occur at the conformational level. Because brain-derived 22L prions are naturally swainsonine resistant, it was not too surprising that prions which had become swa sensitive after propagation in cells could revert to drug resistance. Because RML prions, both after propagation in brain or in PK1 cells, are swainsonine sensitive, we investigated whether it was nonetheless possible to select swainsonine-resistant variants by propagation in the presence of the drug. Interestingly, this was not possible with the standard line of PK1 cells, but in certain PK1 sublines not only swainsonine-resistant, but even swainsonine-dependent populations (i.e. that propagated more rapidly in the presence of the drug) could be isolated. Once established, they could be passaged indefinitely in PK1 cells, even in the absence of the drug, without losing swainsonine dependence. The misfolded prion protein (PrPSc) associated with a swainsonine-dependent variant was less rapidly cleared in PK1 cells than that associated with its drug-sensitive counterpart, indicating that likely structural differences of the misfolded PrP underlie the properties of the prions. In summary, propagation of prions in the presence of an inhibitory drug may not only cause the selection of drug-resistant prions but even of stable variants that propagate more efficiently in the presence of the drug. These adaptations are most likely due to conformational changes of

  1. 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

  2. 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

  3. 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

  4. Resistance mechanisms and drug susceptibility testing of nontuberculous mycobacteria.

    PubMed

    van Ingen, Jakko; Boeree, Martin J; van Soolingen, Dick; Mouton, Johan W

    2012-06-01

    Nontuberculous mycobacteria (NTM) are increasingly recognized as causative agents of opportunistic infections in humans. For most NTM infections the therapy of choice is drug treatment, but treatment regimens differ by species, in particular between slow (e.g. Mycobacterium avium complex, Mycobacterium kansasii) and rapid growers (e.g. Mycobacterium abscessus, Mycobacterium fortuitum). In general, drug treatment is long, costly, and often associated with drug-related toxicities; outcome of drug treatment is poor and is likely related to the high levels of natural antibiotic resistance in NTM. The role of drug susceptibility testing (DST) in the choice of agents for antimicrobial treatment of NTM disease, mainly that by slow growers, remains subject of debate. There are important discrepancies between drug susceptibility measured in vitro and the activity of the drug observed in vivo. In part, these discrepancies derive from laboratory technical issues. There is still no consensus on a standardized method. With the increasing clinical importance of NTM disease, DST of NTM is again in the spotlight. This review provides a comprehensive overview of the mechanisms of drug resistance in NTM, phenotypic methods for testing susceptibility in past and current use for DST of NTM, as well as molecular approaches to assess drug resistance. PMID:22525524

  5. Update on antifungal drug resistance mechanisms of Aspergillus fumigatus.

    PubMed

    Chamilos, G; Kontoyiannis, D P

    2005-12-01

    Although the arsenal of agents with anti-Aspergillus activity has expanded over the last decade, mortality due to invasive aspergillosis (IA) remains unacceptably high. Aspergillus fumigatus still accounts for the majority of cases of IA; however less susceptible to antifungals non-fumigatus aspergilli began to emerge. Antifungal drug resistance of Aspergillus might partially account for treatment failures. Recent advances in our understanding of mechanisms of antifungal drug action in Aspergillus, along with the standardization of in vitro susceptibility testing methods, has brought resistance testing to the forefront of clinical mycology. In addition, molecular biology has started to shed light on the mechanisms of resistance of A. fumigatus to azoles and the echinocandins, while genome-based assays show promise for high-throughput screening for genotypic antifungal resistance. Several problems remain, however, in the study of this complex area. Large multicenter clinical studies--point prevalence or longitudinal--to capture the incidence and prevalence of antifungal resistance in A. fumigatus isolates are lacking. Correlation of in vitro susceptibility with clinical outcome and susceptibility breakpoints has not been established. In addition, the issue of cross-resistance between the newer triazoles is of concern. Furthermore, in vitro resistance testing for polyenes and echinocandins is difficult, and their mechanisms of resistance are largely unknown. This review examines challenges in the diagnosis, epidemiology, and mechanisms of antifungal drug resistance in A. fumigatus. PMID:16488654

  6. Modeling and predicting drug resistance rate and strength.

    PubMed

    Fullybright, R; Dwivedi, A; Mallawaarachchi, I; Sinsin, B

    2016-08-01

    Drug resistance has been worsening in human infectious diseases medicine over the past several decades. Our ability to successfully control resistance depends to a large extent on our understanding of the features characterizing the process. Part of that understanding includes the rate at which new resistance has been emerging in pathogens. Along that line, resistance data covering 90 infectious diseases, 118 pathogens, and 337 molecules, from 1921 through 2007, are modeled using various statistical tools to generate regression models for the rate of new resistance emergence and for cumulative resistance build-up in pathogens. Thereafter, the strength of the association between the number of molecules put on the market and the number of resulting cases of resistance is statistically tested. Predictive models are presented for the rate at which new resistance has been emerging in infectious diseases medicine, along with predictive models for the rate of cumulative resistance build-up in the aggregate of 118 pathogens as well as in ten individual pathogens. The models are expressed as a function of time and/or as a function of the number of molecules put on the market by the pharmaceutical industry. It is found that molecules significantly induce resistance in pathogens and that new or cumulative drug resistance across infectious diseases medicine has been arising at exponential rates. PMID:27209288

  7. Supramolecular Antibiotic Switches: A Potential Strategy for Combating Drug Resistance.

    PubMed

    Bai, Haotian; Lv, Fengting; Liu, Libing; Wang, Shu

    2016-08-01

    Bacterial infectious disease is a serious public health concern throughout the world. Pathogen drug resistance, arising from both rational use and abuse/misuse of germicides, complicates the situation. Aside from developing novel antibiotics and antimicrobial agents, molecular approaches have become another significant method to overcome the problem of pathogen drug resistance. Established supramolecular systems, the antibiotic properties of which can be switched "on" and "off" through host-guest interactions, show great potential in combating issues regarding antibiotic resistance in the long term, as indicated by several recent studies. In this Concept, recently developed strategies for antibacterial regulation are summarized and further directions for research into antibiotic switches are proposed. PMID:27312106

  8. Nanoparticles: Alternatives Against Drug-Resistant Pathogenic Microbes.

    PubMed

    Rudramurthy, Gudepalya Renukaiah; Swamy, Mallappa Kumara; Sinniah, Uma Rani; Ghasemzadeh, Ali

    2016-01-01

    Antimicrobial substances may be synthetic, semisynthetic, or of natural origin (i.e., from plants and animals). Antimicrobials are considered "miracle drugs" and can determine if an infected patient/animal recovers or dies. However, the misuse of antimicrobials has led to the development of multi-drug-resistant bacteria, which is one of the greatest challenges for healthcare practitioners and is a significant global threat. The major concern with the development of antimicrobial resistance is the spread of resistant organisms. The replacement of conventional antimicrobials by new technology to counteract antimicrobial resistance is ongoing. Nanotechnology-driven innovations provide hope for patients and practitioners in overcoming the problem of drug resistance. Nanomaterials have tremendous potential in both the medical and veterinary fields. Several nanostructures comprising metallic particles have been developed to counteract microbial pathogens. The effectiveness of nanoparticles (NPs) depends on the interaction between the microorganism and the NPs. The development of effective nanomaterials requires in-depth knowledge of the physicochemical properties of NPs and the biological aspects of microorganisms. However, the risks associated with using NPs in healthcare need to be addressed. The present review highlights the antimicrobial effects of various nanomaterials and their potential advantages, drawbacks, or side effects. In addition, this comprehensive information may be useful in the discovery of broad-spectrum antimicrobial drugs for use against multi-drug-resistant microbial pathogens in the near future. PMID:27355939

  9. Molecular characterization of HIV type 1 strains from newly diagnosed patients in Cyprus (2007-2009) recovers multiple clades including unique recombinant strains and lack of transmitted drug resistance.

    PubMed

    Kousiappa, Ioanna; Achilleos, Charis; Hezka, Johana; Lazarou, Yiota; Othonos, Katerina; Demetriades, Ioannis; Kostrikis, Leondios G

    2011-11-01

    HIV-1 evolution generates substantial genetic diversity among isolates, the majority of which are represented in areas where multiple strains cocirculate. A heterogeneous genetic HIV-1 pool has been found in Cyprus, directing us to determine the dynamics of the local HIV-1 infection by characterizing strains isolated from 74 subjects during 2007-2009, representing 88% of the known-living HIV-1-infected population, of whom 53 are newly diagnosed therapy-naive patients and 21 are chronic patients, according to the European HIV Resistance guidelines. Near full-length genome sequences were amplified by RT-nested PCR using diluted RNA from all HIV-1 seropositives and sequenced using a newly designed assay. Resistant mutations were not found among the population of the newly diagnosed therapy-naive patients either to protease, reverse transcriptase, or integrase inhibitors. Phylogenetic analyses indicated subtype B as the main subtype (48.6%), followed by subtype A (18.9%), subtype C (10.8%), CRF02_AG (8.1%), CRF11_cpx (2.7%), and (sub)subtype F1 and CRF37_cpx (1.4% each). Six HIV-1 isolates (8.1%) were not classified in any pure (sub)subtype or circulating recombinant form (CRF). Complete phylogenetic and bootscanning analyses revealed that each isolate had a new, unique recombinant pattern and is distinct from all other CRFs or unique recombinant forms (URFs) reported so far. Two of the six isolates have the same mosaic pattern. Analogous to results of the earlier epidemiological studies, this study expands on the HIV-1 sequence database and reveals the high degree of diversity of HIV-1 infection in Cyprus. PMID:21453134

  10. 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

  11. 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

  12. Combination Approaches to Combat Multi-Drug Resistant Bacteria

    PubMed Central

    Worthington, Roberta J.; Melander, Christian

    2013-01-01

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

  13. Long non-coding RNAs in cancer drug resistance development.

    PubMed

    Majidinia, Maryam; Yousefi, Bahman

    2016-09-01

    The presence or emergence of chemoresistance in tumor cells is a major burden in cancer therapy. While drug resistance is a multifactorial phenomenon arising from altered membrane transport of drugs, altered drug metabolism, altered DNA repair, reduced apoptosis rate and alterations of drug metabolism, it can also be linked to genetic and epigenetic factors. Long non-coding RNAs (lncRNAs) have important regulatory roles in many aspects of genome function including gene transcription, splicing, and epigenetics as well as biological processes involved in cell cycle, cell differentiation, development, and pluripotency. As such, it may not be surprising that some lncRNAs have been recently linked to carcinogenesis and drug resistance/sensitivity. Research is accelerating to decipher the exact molecular mechanism of lncRNA-regulated drug resistance and its therapeutic implications. In this article, we will review the structure, biogenesis, and mode of action of lncRNAs. Then, the involvement of lncRNAs in drug resistance will be discussed in detail. PMID:27427176

  14. Genome Analysis of the First Extensively Drug-Resistant (XDR) Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance.

    PubMed

    Kuan, Chee Sian; Chan, Chai Ling; Yew, Su Mei; Toh, Yue Fen; Khoo, Jia-Shiun; Chong, Jennifer; Lee, Kok Wei; Tan, Yung-Chie; Yee, Wai-Yan; Ngeow, Yun Fong; Ng, Kee Peng

    2015-01-01

    The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia. PMID:26110649

  15. Genome Analysis of the First Extensively Drug-Resistant (XDR) Mycobacterium tuberculosis in Malaysia Provides Insights into the Genetic Basis of Its Biology and Drug Resistance

    PubMed Central

    Kuan, Chee Sian; Chan, Chai Ling; Yew, Su Mei; Toh, Yue Fen; Khoo, Jia-Shiun; Chong, Jennifer; Lee, Kok Wei; Tan, Yung-Chie; Yee, Wai-Yan; Ngeow, Yun Fong; Ng, Kee Peng

    2015-01-01

    The outbreak of extensively drug-resistant tuberculosis (XDR-TB) has become an increasing problem in many TB-burdened countries. The underlying drug resistance mechanisms, including the genetic variation favored by selective pressure in the resistant population, are partially understood. Recently, the first case of XDR-TB was reported in Malaysia. However, the detailed genotype family and mechanisms of the formation of multiple drugs resistance are unknown. We sequenced the whole genome of the UM 1072388579 strain with a 2-kb insert-size library and combined with that from previously sequenced 500-bp-insert paired-end reads to produce an improved sequence with maximal sequencing coverage across the genome. In silico spoligotyping and phylogenetic analyses demonstrated that UM 1072388579 strain belongs to an ancestral-like, non-Beijing clade of East Asia lineage. This is supported by the presence of a number of lineage-specific markers, including fadD28, embA, nuoD and pks7. Polymorphism analysis showed that the drug-susceptibility profile is correlated with the pattern of resistance mutations. Mutations in drug-efflux pumps and the cell wall biogenesis pathway such as mmpL, pks and fadD genes may play an important role in survival and adaptation of this strain to its surrounding environment. In this work, fifty-seven putative promoter SNPs were identified. Among them, we identified a novel SNP located at -4 T allele of TetR/acrR promoter as an informative marker to recognize strains of East Asian lineage. Our work indicates that the UM 1072388579 harbors both classical and uncommon SNPs that allow it to escape from inhibition by many antibiotics. This study provides a strong foundation to dissect the biology and underlying resistance mechanisms of the first reported XDR M. tuberculosis in Malaysia. PMID:26110649

  16. 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

  17. Problems of Glioblastoma Multiforme Drug Resistance.

    PubMed

    Stavrovskaya, A A; Shushanov, S S; Rybalkina, E Yu

    2016-02-01

    Glioblastoma multiforme (GBL) is the most common and aggressive brain neoplasm. A standard therapeutic approach for GBL involves combination therapy consisting of surgery, radiotherapy, and chemotherapy. The latter is based on temozolomide (TMZ). However, even by applying such a radical treatment strategy, the mean patient survival time is only 14.6 months. Here we review the molecular mechanisms underlying the resistance of GBL cells to TMZ including genetic and epigenetic mechanisms. Present data regarding a role for genes and proteins MGMT, IDH1/2, YB-1, MELK, MVP/LRP, MDR1 (ABCB1), and genes encoding other ABC transporters as well as Akt3 kinase in developing resistance of GBL to TMZ are discussed. Some epigenetic regulators of resistance to TMZ such as microRNA and EZH2 are reviewed. PMID:27260389

  18. 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

  19. Resistance and cross-resistance studies with narasin, a new polyether antibiotic anticoccidial drug.

    PubMed

    Jeffers, T K

    1981-01-01

    The Wisconsin (Wis) strain and a field strain (FS-196) of Eimeria tenella were propagated in the presence of 80 ppm narasin in an attempt to select for narasin resistance. Comparisons of the narasin sensitivity of the selected strains (Wis-NR and FS-196-NR) and of the parent strains (Wis and FS-196) from which they were derived revealed no resistance development. These findings agree with the results of similar studies with the polyether antibiotic anticoccidial drugs monensin and lasalocid and support the conclusion that chicken coccidia do not readily develop resistance to this class of anticoccidial drugs. In a separate series of experiments, the efficacy of narasin was evaluated against five E. tenella field strains, one each resistant to amprolium, clopidol, decoquinate, nicarbazin, and robenidine. Narasin effectively controlled infections that were inadequately controlled by the anticoccidial drugs to which the strains were resistant. There was no evidence of cross-resistance to narasin. PMID:7259679

  20. Drug Resistance Pattern of MTB Isolates from PTB Patients

    PubMed Central

    Ranganath, Rajani; Kumar, Vijay G. S.; Ranganath, Ravi; Goud, Gangadhar; Javali, Veerabhadra

    2013-01-01

    Background. TB is a global pandemic disease. All TB control programs were not successful due to the emergence of multidrug resistance in M. tuberculosis strains. Objective of the present study was to detect the rate of MDR-MTB in this part of India. Methods. One hundred and thirty clinical MTB strains isolated from patients on treatment and confirmed as MTB by MPT64 antigen detection were tested for drug susceptibility against Streptomycin, INH, Rifampicin, and Ethambutol by MBBact automated system. Result. Thirty-two were MDRs (25.61%). 31.2%, 28%, 17.6%, and 21.6% were resistant to INH, RIF, Ethambutol, and Streptomycin, respectively. Resistance to either INH or Rifampicin was 20.8% and 13.88%, respectively. Combined INH and Rifampicin resistance was seen in 18.05% isolates. Conclusion. Drug resistance rate is high in patients treated previously and who have been irregular on treatment. PMID:24282636

  1. 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

  2. IS6110 fingerprinting of drug-resistant Mycobacterium tuberculosis strains isolated in Germany during 1995.

    PubMed Central

    Niemann, S; Rüsch-Gerdes, S; Richter, E

    1997-01-01

    The epidemiological relatedness of drug-resistant Mycobacterium tuberculosis strains isolated in Germany in 1995 was evaluated by the standardized IS6110 fingerprinting method. Altogether, 196 M. tuberculosis isolates from 167 patients were analyzed. A large degree of IS6110 polymorphism was found, ranging from 1 to 20 copies. Multiple isolates from one patient generally remained stable over a period of up to 1 year. However, one strain showed an additional fragment 7 months after the first isolate was obtained. Isolates from 55 patients (33%) showed identical fingerprint patterns or fingerprint patterns that differed only in one band, and thus they were clustered in 22 fingerprint groups. Specific transmission links could be established between members of four groups, e.g., transmission by family contacts. In one case, transmission of a multidrug-resistant strain to a patient initially infected with a drug-susceptible strain could be shown. Besides these fingerprint groups, 30 of the 167 isolates (approximately 18%) could be grouped in two fingerprint clusters with a similarity of at least 78%. Approximately 60% of the patients of these two clusters were known to be immigrants from the former Soviet Union, and one patient is still living in Belarus. In conclusion, our results indicate that (i) transmission of drug-resistant strains contributes substantially to the emergence of drug-resistant tuberculosis in Germany and (ii) drug-resistant M. tuberculosis strains were presumably carried over from the former Soviet Union to Germany by immigrants. PMID:9399486

  3. A phylogenetic and Markov model approach for the reconstruction of mutational pathways of drug resistance

    PubMed Central

    Buendia, Patricia; Cadwallader, Brice; DeGruttola, Victor

    2009-01-01

    Motivation: Modern HIV-1, hepatitis B virus and hepatitis C virus antiviral therapies have been successful at keeping viruses suppressed for prolonged periods of time, but therapy failures attributable to the emergence of drug resistant mutations continue to be a distressing reminder that no therapy can fully eradicate these viruses from their host organisms. To better understand the emergence of drug resistance, we combined phylogenetic and statistical models of viral evolution in a 2-phase computational approach that reconstructs mutational pathways of drug resistance. Results: The first phase of the algorithm involved the modeling of the evolution of the virus within the human host environment. The inclusion of longitudinal clonal sequence data was a key aspect of the model due to the progressive fashion in which multiple mutations become linked in the same genome creating drug resistant genotypes. The second phase involved the development of a Markov model to calculate the transition probabilities between the different genotypes. The proposed method was applied to data from an HIV-1 Efavirenz clinical trial study. The obtained model revealed the direction of evolution over time with greater detail than previous models. Our results show that the mutational pathways facilitate the identification of fast versus slow evolutionary pathways to drug resistance. Availability: Source code for the algorithm is publicly available at http://biorg.cis.fiu.edu/vPhyloMM/ Contact: pbuendia@miami.edu PMID:19654117

  4. 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

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

    SciTech Connect

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

    1990-03-05

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

  6. Nanoparticle-mediated combination chemotherapy and photodynamic therapy overcomes tumor drug resistance

    PubMed Central

    Khdair, Ayman; Chen, Di; Patil, Yogesh; Ma, Linan; Dou, Q. Ping; Shekhar, Malathy P.V.; Panyam, Jayanth

    2013-01-01

    Tumor drug resistance significantly limits the success of chemotherapy in the clinic. Tumor cells utilize multiple mechanisms to prevent the accumulation of anticancer drugs at their intracellular site of action. In this study, we investigated the anticancer efficacy of doxorubicin in combination with photodynamic therapy using methylene blue in a drug-resistant mouse tumor model. Surfactant-polymer hybrid nanoparticles formulated using an anionic surfactant, Aerosol-OT™ (AOT), and a naturally occurring polysaccharide polymer, sodium alginate, were used for synchronized delivery of the two drugs. Balb/c mice bearing syngeneic JC tumors (mammary adenocarcinoma) were used as a drug-resistant tumor model. Nanoparticle-mediated combination therapy significantly inhibited tumor growth and improved animal survival. Nanoparticle-mediated combination treatment resulted in enhanced tumor accumulation of both doxorubicin and methylene blue, significant inhibition of tumor cell proliferation, and increased induction of apoptosis. These data suggest that nanoparticle-mediated combination chemotherapy and photodynamic therapy using doxorubicin and methylene blue has significant therapeutic potential against drug-resistant tumors. PMID:19751777

  7. 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

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

    PubMed

    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

  9. 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

  10. Novel Agents for Multiple Myeloma to Overcome Resistance in Phase III Clinical Trials

    PubMed Central

    Orlowski, Robert Z.

    2013-01-01

    The incorporation of novel agents such as bortezomib and lenalidomide into initial therapy for multiple myeloma has improved the response rate of induction regimens. Also, these drugs are being increasingly used in the peri-transplant setting for transplant-eligible patients, and as part of consolidation and/or maintenance after front-line treatment, including in transplant-ineligible patients. Together, these and other strategies have contributed to a prolongation of progression-free and overall survival in myeloma patients, and an increasing proportion are able to sustain a remission for many years. Despite these improvements, however, the vast majority of patients continue to suffer relapses, which suggests a prominent role for either primary, innate drug resistance, or secondary, acquired drug resistance. As a result, there remains a strong need to develop new proteasome inhibitors and immunomodulatory agents, as well as new drug classes, which would be effective in the relapsed and/or refractory setting, and overcome drug resistance. This review will focus on novel drugs that have reached phase III trials, including carfilzomib and pomalidomide, which have recently garnered regulatory approvals. In addition, agents that are in phase II or III, potentially registration-enabling trials will be described as well, to provide an overview of the possible landscape in the relapsed and/or refractory arena over the next five years. PMID:24135408

  11. 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

  12. 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

  13. 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

  14. Salvage Therapy of Multiple Myeloma: The New Generation Drugs

    PubMed Central

    Romano, Alessandra; Conticello, Concetta; Di Raimondo, Cosimo; Schinocca, Elena; La Fauci, Alessia; Parrinello, Nunziatina Laura; Chiarenza, Annalisa

    2014-01-01

    During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways. PMID:24967371

  15. More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1

    PubMed Central

    Feder, Alison F; Rhee, Soo-Yon; Holmes, Susan P; Shafer, Robert W; Petrov, Dmitri A; Pennings, Pleuni S

    2016-01-01

    In the early days of HIV treatment, drug resistance occurred rapidly and predictably in all patients, but under modern treatments, resistance arises slowly, if at all. The probability of resistance should be controlled by the rate of generation of resistance mutations. If many adaptive mutations arise simultaneously, then adaptation proceeds by soft selective sweeps in which multiple adaptive mutations spread concomitantly, but if adaptive mutations occur rarely in the population, then a single adaptive mutation should spread alone in a hard selective sweep. Here, we use 6717 HIV-1 consensus sequences from patients treated with first-line therapies between 1989 and 2013 to confirm that the transition from fast to slow evolution of drug resistance was indeed accompanied with the expected transition from soft to hard selective sweeps. This suggests more generally that evolution proceeds via hard sweeps if resistance is unlikely and via soft sweeps if it is likely. DOI: http://dx.doi.org/10.7554/eLife.10670.001 PMID:26882502

  16. Antiretroviral drug resistance mutations in naïve and experienced patients in Shiraz, Iran, 2014.

    PubMed

    Naziri, Hamed; Baesi, Kazem; Moradi, Abdolvahab; Aghasadeghi, Mohammad R; Tabarraei, Alijan; McFarland, Willi; Davarpanah, Mohamad Ali

    2016-09-01

    Resistance to antiretroviral agents is a significant concern in the clinical management of HIV-infected individuals, particularly in areas of the world where treatment options are limited. In this study, we aimed to identify HIV drug-resistance-associated mutations in 40 drug-naïve patients and 62 patients under antiretroviral therapy (ART) referred to the Shiraz HIV/AIDS Research Center - the first such data available for the south of Iran. HIV reverse transcriptase and protease genes were amplified and sequenced to determine subtypes and antiretroviral- resistance-associated mutations (RAMs). Subtype CRF35-AD recombinant was the most prevalent in all patients (98 of 102, 96 %), followed by subtype A1, and subtype B (one each, 2 %). Among the 40 ART-naïve patients, two mutations associated with nucleoside reverse transcriptase inhibitor (NRTI) resistance (two with Y115F and T215I) and three associated with non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance (two with G190S and Y181C, four with V179T) were found. Among ART-experienced patients, four mutations associated with resistance to NRTI, four with NNRTI, and five with protease inhibitors (PI) were found. Twenty patients with high levels of resistance were already on second-line therapy. We document for the first time in this region of Iran high levels of ART resistance to multiple drugs. Our findings call for more vigilant systematic ART resistance surveillance, increased resistance testing, careful management of patients with existing regimens, and strong advocacy for expansion of available drugs in Iran. PMID:27368990

  17. Multiple Origins and Regional Dispersal of Resistant dhps in African Plasmodium falciparum Malaria

    PubMed Central

    Pearce, Richard J.; Pota, Hirva; Evehe, Marie-Solange B.; Bâ, El-Hadj; Mombo-Ngoma, Ghyslain; Malisa, Allen L.; Ord, Rosalynn; Inojosa, Walter; Matondo, Alexandre; Diallo, Diadier A.; Mbacham, Wilfred; van den Broek, Ingrid V.; Swarthout, Todd D.; Getachew, Asefaw; Dejene, Seyoum; Grobusch, Martin P.; Njie, Fanta; Kweku, Margaret; Owusu-Agyei, Seth; Chandramohan, Daniel; Bonnet, Maryline; Guthmann, Jean-Paul; Clarke, Sian; Barnes, Karen I.; Streat, Elizabeth; Katokele, Stark T.; Uusiku, Petrina; Agboghoroma, Chris O.; Elegba, Olufunmilayo Y.; Cissé, Badara; A-Elbasit, Ishraga E.; Giha, Hayder A.; Kachur, S. Patrick; Lynch, Caroline; Rwakimari, John B.; Chanda, Pascalina; Hawela, Moonga; Naidoo, Inbarani; Roper, Cally

    2009-01-01

    Background Although the molecular basis of resistance to a number of common antimalarial drugs is well known, a geographic description of the emergence and dispersal of resistance mutations across Africa has not been attempted. To that end we have characterised the evolutionary origins of antifolate resistance mutations in the dihydropteroate synthase (dhps) gene and mapped their contemporary distribution. Methods and Findings We used microsatellite polymorphism flanking the dhps gene to determine which resistance alleles shared common ancestry and found five major lineages each of which had a unique geographical distribution. The extent to which allelic lineages were shared among 20 African Plasmodium falciparum populations revealed five major geographical groupings. Resistance lineages were common to all sites within these regions. The most marked differentiation was between east and west African P. falciparum, in which resistance alleles were not only of different ancestry but also carried different resistance mutations. Conclusions Resistant dhps has emerged independently in multiple sites in Africa during the past 10–20 years. Our data show the molecular basis of resistance differs between east and west Africa, which is likely to translate into differing antifolate sensitivity. We have also demonstrated that the dispersal patterns of resistance lineages give unique insights into recent parasite migration patterns. PMID:19365539

  18. Within-host competition and drug resistance in the human malaria parasite Plasmodium falciparum.

    PubMed

    Bushman, Mary; Morton, Lindsay; Duah, Nancy; Quashie, Neils; Abuaku, Benjamin; Koram, Kwadwo A; Dimbu, Pedro Rafael; Plucinski, Mateusz; Gutman, Julie; Lyaruu, Peter; Kachur, S Patrick; de Roode, Jacobus C; Udhayakumar, Venkatachalam

    2016-03-16

    Infections with the malaria parasite Plasmodium falciparum typically comprise multiple strains, especially in high-transmission areas where infectious mosquito bites occur frequently. However, little is known about the dynamics of mixed-strain infections, particularly whether strains sharing a host compete or grow independently. Competition between drug-sensitive and drug-resistant strains, if it occurs, could be a crucial determinant of the spread of resistance. We analysed 1341 P. falciparum infections in children from Angola, Ghana and Tanzania and found compelling evidence for competition in mixed-strain infections: overall parasite density did not increase with additional strains, and densities of individual chloroquine-sensitive (CQS) and chloroquine-resistant (CQR) strains were reduced in the presence of competitors. We also found that CQR strains exhibited low densities compared with CQS strains (in the absence of chloroquine), which may underlie observed declines of chloroquine resistance in many countries following retirement of chloroquine as a first-line therapy. Our observations support a key role for within-host competition in the evolution of drug-resistant malaria. Malaria control and resistance-management efforts in high-transmission regions may be significantly aided or hindered by the effects of competition in mixed-strain infections. Consideration of within-host dynamics may spur development of novel strategies to minimize resistance while maximizing the benefits of control measures. PMID:26984625

  19. 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

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

    PubMed

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

    2016-03-01

    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

  1. 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

  2. An Intravaginal Ring for the Simultaneous Delivery of Multiple Drugs

    PubMed Central

    Baum, Marc M.; Butkyavichene, Irina; Gilman, Joshua; Kennedy, Sean; Kopin, Etana; Malone, Amanda M.; Nguyen, Cali; Smith, Thomas J.; Friend, David R.; Clark, Meredith R.; Moss, John A.

    2013-01-01

    Intravaginal delivery of microbicide combinations is a promising approach for the prevention of sexually transmitted infections, but requires a method of providing simultaneous, independent release of multiple agents into the vaginal compartment. A novel intravaginal ring (IVR) platform has been developed for simultaneous delivery of the reverse-transcriptase inhibitor tenofovir (TFV) and the guanosine analogue antiviral acyclovir (ACV) with independent control of release rate for each drug. The IVR is based on a pod design, with up to 10 individual polymer-coated drug cores embedded in the ring releasing through preformed delivery channels. The release rate from each pod is controlled independently of the others by the drug properties, polymer coating, and size and number of delivery channels. Pseudo-zero-order in vitro release of TFV (144 ± 10 µg day) and ACV (120 ± 19 µg day−1) from an IVR containing both drugs was sustained for 28 days. The mechanical properties of the pod IVR were evaluated and compared with the commercially available Estring® (Pfizer, NY, NY). The pod-IVR design enables the vaginal delivery of multiple microbicides with differing physicochemical properties, and is an attractive approach for the sustained intravaginal delivery of relatively hydrophilic drugs that are difficult to deliver using conventional matrix IVR technology. PMID:22619076

  3. Clinical Prediction Rule of Drug Resistant Epilepsy in Children

    PubMed Central

    Boonluksiri, Pairoj; Visuthibhan, Anannit; Katanyuwong, Kamornwan

    2015-01-01

    Background and Purpose: Clinical prediction rules (CPR) are clinical decision-making tools containing variables such as history, physical examination, diagnostic tests by developing scoring model from potential risk factors. This study is to establish clinical prediction scoring of drug-resistant epilepsy (DRE) in children using clinical manifestationa and only basic electroencephalography (EEG). Methods: Retrospective cohort study was conducted. A total of 308 children with diagnosed epilepsy were recruited. Primary outcome was the incidence of DRE. Independent determinants were patient characteristics, clinical manifestations and electroencephalography. CPR was performed based on multiple logistic regression. Results: The incidence of DRE was 42%. Risk factors were age onset, prior neurological deficits, and abnormal EEG. CPR can be established and stratified the prediction using scores into 3 levels such as low risk (score<6), moderate risk (score 6–12) and high risk (score>12) with positive likelihood ratio of 0.5, 1.8 and 12.5 respectively. Conclusions: CPR with scoring risks were stratified into 3 levels. The strongest risk is prior global neurological deficits. PMID:26819940

  4. 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

  5. Drug rechallenge and treatment beyond progression—implications for drug resistance

    PubMed Central

    Kuczynski, Elizabeth A.; Sargent, Daniel J.; Grothey, Axel; Kerbel, Robert S.

    2015-01-01

    The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. PMID:23999218

  6. "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…

  7. Reversing drug resistance of cisplatin by hsp90 inhibitors in human ovarian cancer cells

    PubMed Central

    Zhang, Zhengmao; Xie, Zhen; Sun, Guangyu; Yang, Pingfang; Li, Jia; Yang, Hongfang; Xiao, Shuang; Liu, Yang; Qiu, Hongbing; Qin, Lijun; Zhang, Chao; Zhang, Fenghua; Shan, Baoen

    2015-01-01

    Objective: To investigate the mechanisms for reversing drug resistance of cisplatin (DDP) by Hsp90 inhibitors (geldanamycin (GA), 17-AAG, 17-DMAG) in human ovarian cancer. Methods: Cell proliferation rate in DDP resistant human ovarian cancer cell line SKOV3/DDP and its parent cell line SKOV3 after treatment with Hsp90 inhibitors and/or DDP were tested by MTT assay, and the reversing fold (RF) of DDP by Hsp90 inhibitors was calculated. Cell cycle and cell apoptosis status after treatment were analyzed by flow cytometry. The expression of multiple drug resistance related genes was analyzed by RT-PCR and Western-blot. Results: All three tested Hsp90 inhibitors synergistically inhibited the cell proliferation of SKOV3 with DDP and enhanced the sensitivity of SKOV3/DDP cells to DDP. The RF of DDP by Hsp90 inhibitors were all more than two fold. GA caused cell cycle arrest in G2/M phasein SKOV3 cells. 17-AAG increased cell apoptosis but did not change cell cycle in SKOV3/DDP cells. The mRNA and protein expression levels of various drug resistant related genes including LRP, GST-π, p53, bcl-2, survivin, ERCC1, XRCC1, BRCA1 and BRCA2 were more dramatically altered by Hsp90 inhibitors and DDP in combination compared to Hsp90 inhibitors or DDP treatment alone. Conclusions: Exposure of SKOV3/DDP cells to Hsp90 inhibitors and DDP in combination results in synergistic cytotoxic and pro-apoptotic effects. Hsp90 inhibitors reverse the drug resistance of SKOV3/DDP cells to DDP by modifying the expression of multiple drug resistance related genes. PMID:26221207

  8. 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

  9. Molecular and virulence characteristics of multi-drug resistant Salmonella Enteritidis strains isolated from poultry.

    PubMed

    Hur, Jin; Kim, Ji Hee; Park, Jong Ho; Lee, Young-Ju; Lee, John Hwa

    2011-09-01

    Forty-six Salmonella enterica subspecies enterica serovar Enteritidis (S. Enteritidis) strains were isolated from chicken meat, faeces, and eggshells collected from hatcheries throughout Korea. The strains were examined for the presence of antimicrobial resistance and virulence genes. All 46 isolates were resistant to at least one of 21 antibiotics used in this study, 30 (65.2%) were resistant to three or more antimicrobials, and a single remarkable isolate was resistant to 15 antimicrobials. The isolates were primarily resistant to penicillins, sulfisoxazole, streptomycin, tetracycline and quinolones. The high rate of resistance in S. Enteritidis strains, sometimes to multiple drugs, may complicate future options for treating human infections. Nineteen of the 21 penicillin resistant isolates carried the bla(TEM) gene, while one strain, resistant both to penicillins and ceftriaxone, carried the bla(CTX-M) gene. Thirty-seven of the 45 sulfisoxazole resistant isolates carried sul2, and 23/24 streptomycin resistant isolates carried both strA and strB. All 10 tetracycline resistant isolates carried the tet(A) gene. Most isolates harboured both SPI-1 and SPI-2-associated genes, and the spv operon, which are known to be associated with human infections. The presence of these genes suggests that these strains could give rise to public health problems if dispersed in the general human population. PMID:20822940

  10. Antibiotic residues and drug resistance in human intestinal flora.

    PubMed Central

    Corpet, D E

    1987-01-01

    The effect of residual levels of ampicillin on the drug resistance of fecal flora was studied in human volunteers given 1.5 mg of ampicillin orally per day for 21 days. This treatment failed to have any significant reproducible effect on the number of resistant Escherichia coli in their feces. The effect of continuous administration of small doses of ampicillin, chlortetracycline, or streptomycin in the drinking water was studied in gnotobiotic mice inoculated with a human fecal flora. In this animal model, which is free of many interfering factors, an increase in the fecal concentration of resistant E. coli was observed when the mice were given 0.5 microgram of ampicillin or chlortetracycline per ml of water. This model is therefore a sensitive system for testing the effect of antimicrobial drugs on the resistance characteristics of the intestinal flora. PMID:3300533

  11. The new concepts on overcoming drug resistance in lung cancer

    PubMed Central

    Zhang, Weisan; Lei, Ping; Dong, Xifeng; Xu, Cuiping

    2014-01-01

    Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies. PMID:24944510

  12. (Post-) Genomic approaches to tackle drug resistance in Leishmania.

    PubMed

    Berg, Maya; Mannaert, An; Vanaerschot, Manu; Van Der Auwera, Gert; Dujardin, Jean-Claude

    2013-10-01

    Leishmaniasis, like other neglected diseases is characterized by a small arsenal of drugs for its control. To safeguard the efficacy of current drugs and guide the development of new ones it is thus of utmost importance to acquire a deep understanding of the phenomenon of drug resistance and its link with treatment outcome. We discuss here how (post-)genomic approaches may contribute to this purpose. We highlight the need for a clear definition of the phenotypes under consideration: innate and acquired resistance versus treatment failure. We provide a recent update of our knowledge on the Leishmania genome structure and dynamics, and compare the contribution of targeted and untargeted methods for the understanding of drug resistance and show their limits. We also present the main assays allowing the experimental validation of the genes putatively involved in drug resistance. The importance of analysing information downstream of the genome is stressed and further illustrated by recent metabolomics findings. Finally, the attention is called onto the challenges for implementing the acquired knowledge to the benefit of the patients and the population at risk. PMID:23480865

  13. Drug resistance as influenced by inactivated sensitivity discs.

    PubMed

    Griffith, L J; Mullins, C G

    1968-04-01

    Reports of staphylococci resistant to the semisynthetic penicillins stimulated a study of the factors influencing the stability of the drugs in discs. The behavior of penicillin G, methicillin, oxacillin, cloxacillin, and cephalothin discs under different humidity and temperature conditions is described. Humidity was found to be the most significant factor in drug inactivation. Storage of discs in a vacuum desiccator at -20 C provides maximal antibiotic stability. PMID:4869619

  14. Multiple Drug Transport Pathways through human P-Glycoprotein(†)

    PubMed Central

    McCormick, James W.; Vogel, Pia D.; Wise, John G.

    2015-01-01

    P-glycoprotein (P-gp) is a plasma membrane efflux pump that is commonly associated with therapy resistances in cancers and infectious diseases. P-gp can lower the intracellular concentrations of many drugs to subtherapeutic levels by translocating them out of the cell. Because of the broad range of substrates transported by P-gp, overexpression of P-gp causes multidrug resistance. We reported previously on dynamic transitions of P-gp as it moved through conformations based on crystal structures of homologous ABCB1 proteins using in silico targeted molecular dynamics techniques. We expanded these studies here by docking transport substrates to drug binding sites of P-gp in conformations open to the cytoplasm, followed by cycling the pump through conformations that opened to the extracellular space. We observed reproducible transport of two substrates, daunorubicin and verapamil, by an average of 11 to 12 Å through the plane of the membrane as P-gp progressed through a catalytic cycle. Methyl-pyrophosphate, a ligand that should not be transported by P-gp, did not show this movement through P-gp. Drug binding to either of two subsites on P-gp appeared to determine the initial pathway used for drug movement through the membrane. The specific side-chain interactions with drugs within each pathway seemed to be, at least in part, stochastic. The docking and transport properties of a P-gp inhibitor, tariquidar, were also studied. A mechanism of inhibition by tariquidar is presented that involves stabilization of an outward open conformation with tariquidar bound in intracellular loops or at the drug binding domain of P-gp. PMID:26125482

  15. Multiple cutaneous sensitization to nonsteroidal anti-inflammatory drugs.

    PubMed

    Gonzalo, M A; Revenga, F

    1996-01-01

    The use of topical nonsteroidal anti-inflammatory drugs is widespread (particularly in countries bordering the Mediterranean). Compared to their wide use, the incidence of published adverse cutaneous effects appears minimal, although they are increasing. Most of them are a form of allergic contact dermatitis (ACD). Multiple sensitization and/or cross-reactions are rarely reported. Interestingly, our patient presented ACD with diclofenac and etofenamate (both from different chemical groups) and, furthermore, patch tests were positive with bencydamine and indomethacin (both indolacetic acid derivatives), piroxicam and fepradinol. We think that our results could not be explained due to cross-reactivity, and that multiple sensitization was more likely. PMID:8864624

  16. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance

    PubMed Central

    Wei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Liang, Xing-Jie; Rocchi, Palma; Peng, Ling

    2015-01-01

    Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy. PMID:25713374

  17. Anticancer drug nanomicelles formed by self-assembling amphiphilic dendrimer to combat cancer drug resistance.

    PubMed

    Wei, Tuo; Chen, Chao; Liu, Juan; Liu, Cheng; Posocco, Paola; Liu, Xiaoxuan; Cheng, Qiang; Huo, Shuaidong; Liang, Zicai; Fermeglia, Maurizio; Pricl, Sabrina; Liang, Xing-Jie; Rocchi, Palma; Peng, Ling

    2015-03-10

    Drug resistance and toxicity constitute challenging hurdles for cancer therapy. The application of nanotechnology for anticancer drug delivery is expected to address these issues and bring new hope for cancer treatment. In this context, we established an original nanomicellar drug delivery system based on an amphiphilic dendrimer (AmDM), which could generate supramolecular micelles to effectively encapsulate the anticancer drug doxorubicin (DOX) with high drug-loading capacity (>40%), thanks to the unique dendritic structure creating large void space for drug accommodation. The resulting AmDM/DOX nanomicelles were able to enhance drug potency and combat doxorubicin resistance in breast cancer models by significantly enhancing cellular uptake while considerably decreasing efflux of the drug. In addition, the AmDM/DOX nanoparticles abolished significantly the toxicity related to the free drug. Collectively, our studies demonstrate that the drug delivery system based on nanomicelles formed with the self-assembling amphiphilic dendrimer constitutes a promising and effective drug carrier in cancer therapy. PMID:25713374

  18. Detection of multi-drug resistant Escherichia coli in the urban waterways of Milwaukee, WI

    PubMed Central

    Kappell, Anthony D.; DeNies, Maxwell S.; Ahuja, Neha H.; Ledeboer, Nathan A.; Newton, Ryan J.; Hristova, Krassimira R.

    2015-01-01

    Urban waterways represent a natural reservoir of antibiotic resistance which may provide a source of transferable genetic elements to human commensal bacteria and pathogens. The objective of this study was to evaluate antibiotic resistance of Escherichia coli isolated from the urban waterways of Milwaukee, WI compared to those from Milwaukee sewage and a clinical setting in Milwaukee. Antibiotics covering 10 different families were utilized to determine the phenotypic antibiotic resistance for all 259 E. coli isolates. All obtained isolates were determined to be multi-drug resistant. The E. coli isolates were also screened for the presence of the genetic determinants of resistance including ermB (macrolide resistance), tet(M) (tetracycline resistance), and β-lactamases (blaOXA, blaSHV, and blaPSE). E. coli from urban waterways showed a greater incidence of antibiotic resistance to 8 of 17 antibiotics tested compared to human derived sources. These E. coli isolates also demonstrated a greater incidence of resistance to higher numbers of antibiotics compared to the human derived isolates. The urban waterways demonstrated a greater abundance of isolates with co-occurrence of antibiotic resistance than human derived sources. When screened for five different antibiotic resistance genes conferring macrolide, tetracycline, and β-lactam resistance, clinical E. coli isolates were more likely to harbor ermB and blaOXA than isolates from urban waterway. These results indicate that Milwaukee’s urban waterways may select or allow for a greater incidence of multiple antibiotic resistance organisms and likely harbor a different antibiotic resistance gene pool than clinical sources. The implications of this study are significant to understanding the presence of resistance in urban freshwater environments by supporting the idea that sediment from urban waterways serves as a reservoir of antibiotic resistance. PMID:25972844

  19. Effect and Safety of Shihogyejitang for Drug Resistant Childhood Epilepsy.

    PubMed

    Lee, Jinsoo; Son, Kwanghyun; Hwang, Gwiseo; Kim, Moonju

    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

  20. 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

  1. Two cases of possible transmitted drug-resistant HIV: likely HIV superinfection and unmasking of pre-existing resistance

    PubMed Central

    Lee, John; Thomson, Emma; Tarrant, Nick; Hale, Antony; Lacey, Charles J

    2016-01-01

    In the UK, patients undergo HIV viral load and genotype testing before they are prescribed antiretroviral therapy. The genotype test guides clinicians in prescribing antiretroviral therapy with maximum efficacy against the patient’s specific viral strain. HIV viral load escape under antiretroviral drug therapy, to which the virus was thought to be genotypically susceptible, is commonly observed in patients with poor adherence. We observed early viral escapes in two-newly diagnosed patients, during antiretroviral treatment, with different sequences compared to their original viral resistance test and who reported excellent adherence to and tolerance of their therapy. HIV superinfection with a new viral strain was identified in a patient with multiple risk factors and co-infections with sexually transmitted infections. The second patient was a case of the emergence of primary resistant virus under drug pressure. Both suppressed their virus promptly after treatment switch. PMID:25663247

  2. Two cases of possible transmitted drug-resistant HIV: likely HIV superinfection and unmasking of pre-existing resistance.

    PubMed

    Martin, Fabiola; Lee, John; Thomson, Emma; Tarrant, Nick; Hale, Antony; Lacey, Charles J

    2016-01-01

    In the UK, patients undergo HIV viral load and genotype testing before they are prescribed antiretroviral therapy. The genotype test guides clinicians in prescribing antiretroviral therapy with maximum efficacy against the patient's specific viral strain. HIV viral load escape under antiretroviral drug therapy, to which the virus was thought to be genotypically susceptible, is commonly observed in patients with poor adherence. We observed early viral escapes in two-newly diagnosed patients, during antiretroviral treatment, with different sequences compared to their original viral resistance test and who reported excellent adherence to and tolerance of their therapy. HIV superinfection with a new viral strain was identified in a patient with multiple risk factors and co-infections with sexually transmitted infections. The second patient was a case of the emergence of primary resistant virus under drug pressure. Both suppressed their virus promptly after treatment switch. PMID:25663247

  3. Skin conditions: emerging drug-resistant skin infections and infestations.

    PubMed

    Zuniga, Ramiro; Nguyen, Tam

    2013-04-01

    Methicillin-resistant Staphylococcus aureus (MRSA) skin infections are increasingly common. Automated microbiology systems are now available to detect MRSA and to determine antibiotic resistance patterns. Abscesses should be drained and antibiotics administered, with systemic antibiotics used to manage more severe infections. Until sensitivities are known and depending on local resistance rates, clindamycin is an option for empiric management of stable patients without bacteremia. For patients who are more ill, linezolid and vancomycin are alternatives, the latter being first-line treatment for children hospitalized with MRSA skin infections. Drug resistance also occurs in head lice management. Although topical permethrin is still the first-line drug management, its effectiveness has decreased due to permethrin-resistant strains. Patients who do not benefit from 2 applications of permethrin can be treated with topical malathion or topical ivermectin. Though not approved by the Food and Drug Administration (FDA) for treating head lice, oral ivermectin is sometimes used for difficult-to-treat cases. Permethrin is also the first-line management for scabies, though there is a concern that permethrin-resistant scabies may soon occur. For patients with scabies who do not benefit from topical treatment, oral ivermectin is recommended by the Centers for Disease Control and Prevention, although it is not approved by the FDA for this purpose. PMID:23600335

  4. Determinants of Genetic Diversity of Spontaneous Drug Resistance in Bacteria.

    PubMed

    Couce, Alejandro; Rodríguez-Rojas, Alexandro; Blázquez, Jesús

    2016-07-01

    Any pathogen population sufficiently large is expected to harbor spontaneous drug-resistant mutants, often responsible for disease relapse after antibiotic therapy. It is seldom appreciated, however, that while larger populations harbor more mutants, the abundance distribution of these mutants is expected to be markedly uneven. This is because a larger population size allows early mutants to expand for longer, exacerbating their predominance in the final mutant subpopulation. Here, we investigate the extent to which this reduction in evenness can constrain the genetic diversity of spontaneous drug resistance in bacteria. Combining theory and experiments, we show that even small variations in growth rate between resistant mutants and the wild type result in orders-of-magnitude differences in genetic diversity. Indeed, only a slight fitness advantage for the mutant is enough to keep diversity low and independent of population size. These results have important clinical implications. Genetic diversity at antibiotic resistance loci can determine a population's capacity to cope with future challenges (i.e., second-line therapy). We thus revealed an unanticipated way in which the fitness effects of antibiotic resistance can affect the evolvability of pathogens surviving a drug-induced bottleneck. This insight will assist in the fight against multidrug-resistant microbes, as well as contribute to theories aimed at predicting cancer evolution. PMID:27182949

  5. Evidence for epistatic interactions in antiepileptic drug resistance.

    PubMed

    Kim, Myeong-Kyu; Moore, Jason H; Kim, Jong-Ki; Cho, Ki-Hyun; Cho, Yong-Won; Kim, Yo-Sik; Lee, Min-Cheol; Kim, Young-Ok; Shin, Min-Ho

    2011-01-01

    To investigate the epistatic interactions involved in antiepileptic drug (AED) resistance, 26 coding single-nucleotide polymorphisms (SNPs) were selected from 16 candidate genes. A total of 200 patients with drug-resistant localization-related epilepsy and 200 patients with drug-responsive localization-related epilepsy were genotyped individually for the SNPs. Rather than using the traditional parametric statistical method, a new statistical method, multifactor dimensionality reduction (MDR), was used to determine whether gene-gene interactions increase the risk of AED resistance. The MDR method indicated that a combination of four SNPs (rs12658835 and rs35166395 from GABRA1, rs2228622 from EAAT3 and rs2304725 from GAT3) was the best model for predicting susceptibility to AED resistance with a statistically significant testing accuracy of 0.625 (P < 0.001) and cross-validation consistency of 10/10. This best model had an odds ratio of 3.68 with a significant 95% confidence interval of 2.32-5.85 (P < 0.0001). Our results may provide meaningful information on the mechanism underlying AED resistance and, to the best of our knowledge, this is the first report of evidence for gene-gene interactions underlying AED resistance. PMID:21124337

  6. Gender Differences in Drug Resistance Skills of Youth in Guanajuato, Mexico

    PubMed Central

    Marsiglia, Flavio F.; Ayers, Stephanie L.; Calderón-Tena, Carlos O.; Nuño-Gutiérrez, Bertha L.

    2011-01-01

    Research is limited or absent on Mexican adolescents’ exposure to substance offers, ways of dealing with these offers, and possible gender differences in responses to offers. Extending U.S.-based research, this study examines how youth living in the Mexican state of Guanajuato employ the four drug resistance strategies—refuse, explain, avoid, and leave—that are part of the Keepin’ It REAL evidence-based drug prevention intervention. The analysis uses cross-sectional survey data from 702 students enrolled in eight alternative secondary education sites in 2007. Participants reported the drug resistance behaviors they used to deal with offers of alcohol, cigarettes, and marijuana. Using multivariate regression, findings indicate most youth had developed repertoires of drug resistance strategies that involved multiple REAL strategies and some other strategy as well. For those receiving offers, the most common strategy was to refuse the offer with a simple ‘‘no.’’ However, males used all the strategies significantly more often than females for situations involving cigarettes and marijuana as well as when using refuse and non-REAL strategies for alcohol. Possible reasons for the gender difference in use of strategies are discussed. The findings can help inform effective prevention programs based on teaching culturally appropriate drug resistance and communication skills. PMID:21424398

  7. Drug-resistant tuberculosis in Mumbai, India: An agenda for operations research

    PubMed Central

    Mistry, Nerges; Tolani, Monica; Osrin, David

    2012-01-01

    Operations research (OR) is well established in India and is also a prominent feature of the global and local agendas for tuberculosis (TB) control. India accounts for a quarter of the global burden of TB and of new cases. Multidrug-resistant TB is a significant problem in Mumbai, India’s most populous city, and there have been recent reports of totally resistant TB. Much thought has been given to the role of OR in addressing programmatic challenges, by both international partnerships and India’s Revised National TB Control Programme. We attempt to summarize the major challenges to TB control in Mumbai, with an emphasis on drug resistance. Specific challenges include diagnosis of TB and defining cure, detecting drug resistant TB, multiple sources of health care in the private, public and informal sectors, co-infection with human immunodeficiency virus (HIV) and a concurrent epidemic of non-communicable diseases, suboptimal prescribing practices, and infection control. We propose a local agenda for OR: modeling the effects of newer technologies, active case detection, and changes in timing of activities, and mapping hotspots and contact networks; modeling the effects of drug control, changing the balance of ambulatory and inpatient care, and adverse drug reactions; modeling the effects of integration of TB and HIV diagnosis and management, and preventive drug therapy; and modeling the effects of initiatives to improve infection control. PMID:24501697

  8. Genome Analysis of 17 Extensively Drug-Resistant Strains Reveals New Potential Mutations for Resistance

    PubMed Central

    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

  9. Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance

    PubMed Central

    Wu, Hao; Xie, Jiansheng; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

    2013-01-01

    Purpose Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. Experimental Design Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. Results After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of βII-tubulin, which physically interacted with shikonin. Conclusion Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance. PMID:23300986

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

    PubMed

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

    2016-09-01

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

  11. The impact of drug resistance on Mycobacterium tuberculosis physiology: what can we learn from rifampicin?

    PubMed Central

    Koch, Anastasia; Mizrahi, Valerie; Warner, Digby F

    2014-01-01

    The emergence of drug-resistant pathogens poses a major threat to public health. Although influenced by multiple factors, high-level resistance is often associated with mutations in target-encoding or related genes. The fitness cost of these mutations is, in turn, a key determinant of the spread of drug-resistant strains. Rifampicin (RIF) is a frontline anti-tuberculosis agent that targets the rpoB-encoded β subunit of the DNA-dependent RNA polymerase (RNAP). In Mycobacterium tuberculosis (Mtb), RIF resistance (RIFR) maps to mutations in rpoB that are likely to impact RNAP function and, therefore, the ability of the organism to cause disease. However, while numerous studies have assessed the impact of RIFR on key Mtb fitness indicators in vitro, the consequences of rpoB mutations for pathogenesis remain poorly understood. Here, we examine evidence from diverse bacterial systems indicating very specific effects of rpoB polymorphisms on cellular physiology, and consider these observations in the context of Mtb. In addition, we discuss the implications of these findings for the propagation of clinically relevant RIFR mutations. While our focus is on RIF, we also highlight results which suggest that drug-independent effects might apply to a broad range of resistance-associated mutations, especially in an obligate pathogen increasingly linked with multidrug resistance. PMID:26038512

  12. Paradoxical Hypersusceptibility of Drug-resistant Mycobacteriumtuberculosis to β-lactam Antibiotics.

    PubMed

    Cohen, Keira A; El-Hay, Tal; Wyres, Kelly L; Weissbrod, Omer; Munsamy, Vanisha; Yanover, Chen; Aharonov, Ranit; Shaham, Oded; Conway, Thomas C; Goldschmidt, Yaara; Bishai, William R; Pym, Alexander S

    2016-07-01

    Mycobacterium tuberculosis (M. tuberculosis) is considered innately resistant to β-lactam antibiotics. However, there is evidence that susceptibility to β-lactam antibiotics in combination with β-lactamase inhibitors is variable among clinical isolates, and these may present therapeutic options for drug-resistant cases. Here we report our investigation of susceptibility to β-lactam/β-lactamase inhibitor combinations among clinical isolates of M. tuberculosis, and the use of comparative genomics to understand the observed heterogeneity in susceptibility. Eighty-nine South African clinical isolates of varying first and second-line drug susceptibility patterns and two reference strains of M. tuberculosis underwent minimum inhibitory concentration (MIC) determination to two β-lactams: amoxicillin and meropenem, both alone and in combination with clavulanate, a β-lactamase inhibitor. 41/91 (45%) of tested isolates were found to be hypersusceptible to amoxicillin/clavulanate relative to reference strains, including 14/24 (58%) of multiple drug-resistant (MDR) and 22/38 (58%) of extensively drug-resistant (XDR) isolates. Genome-wide polymorphisms identified using whole-genome sequencing were used in a phylogenetically-aware linear mixed model to identify polymorphisms associated with amoxicillin/clavulanate susceptibility. Susceptibility to amoxicillin/clavulanate was over-represented among isolates within a specific clade (LAM4), in particular among XDR strains. Twelve sets of polymorphisms were identified as putative markers of amoxicillin/clavulanate susceptibility, five of which were confined solely to LAM4. Within the LAM4 clade, 'paradoxical hypersusceptibility' to amoxicillin/clavulanate has evolved in parallel to first and second-line drug resistance. Given the high prevalence of LAM4 among XDR TB in South Africa, our data support an expanded role for β-lactam/β-lactamase inhibitor combinations for treatment of drug-resistant M. tuberculosis. PMID

  13. 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

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

    PubMed

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

    2015-06-01

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

  15. Drug metabolism and clearance system in tumor cells of patients with multiple myeloma

    PubMed Central

    Hassen, Wafa; Kassambara, Alboukadel; Reme, Thierry; Sahota, Surinder; Seckinger, Anja; Vincent, Laure; Cartron, Guillaume; Moreaux, Jérôme; Hose, Dirk; Klein, Bernard

    2015-01-01

    Resistance to chemotherapy is a major limitation of cancer treatments with several molecular mechanisms involved, in particular altered local drug metabolism and detoxification process. The role of drug metabolism and clearance system has not been satisfactorily investigated in Multiple Myeloma (MM), a malignant plasma cell cancer for which a majority of patients escapes treatment. The expression of 350 genes encoding for uptake carriers, xenobiotic receptors, phase I and II Drug Metabolizing Enzymes (DMEs) and efflux transporters was interrogated in MM cells (MMCs) of newly-diagnosed patients in relation to their event free survival. MMCs of patients with a favourable outcome have an increased expression of genes coding for xenobiotic receptors (RXRα, LXR, CAR and FXR) and accordingly of their gene targets, influx transporters and phase I/II DMEs. On the contrary, MMCs of patients with unfavourable outcome displayed a global down regulation of genes coding for xenobiotic receptors and the downstream detoxification genes but had a high expression of genes coding for ARNT and Nrf2 pathways and ABC transporters. Altogether, these data suggests ARNT and Nrf2 pathways could be involved in MM primary resistance and that targeting RXRα, PXR, LXR and FXR through agonists could open new perspectives to alleviate or reverse MM drug resistance. PMID:25669983

  16. Biophysical principles predict fitness landscapes of drug resistance.

    PubMed

    Rodrigues, João V; Bershtein, Shimon; Li, Anna; Lozovsky, Elena R; Hartl, Daniel L; Shakhnovich, Eugene I

    2016-03-15

    Fitness landscapes of drug resistance constitute powerful tools to elucidate mutational pathways of antibiotic escape. Here, we developed a predictive biophysics-based fitness landscape of trimethoprim (TMP) resistance for Escherichia coli dihydrofolate reductase (DHFR). We investigated the activity, binding, folding stability, and intracellular abundance for a complete set of combinatorial DHFR mutants made out of three key resistance mutations and extended this analysis to DHFR originated from Chlamydia muridarum and Listeria grayi We found that the acquisition of TMP resistance via decreased drug affinity is limited by a trade-off in catalytic efficiency. Protein stability is concurrently affected by the resistant mutants, which precludes a precise description of fitness from a single molecular trait. Application of the kinetic flux theory provided an accurate model to predict resistance phenotypes (IC50) quantitatively from a unique combination of the in vitro protein molecular properties. Further, we found that a controlled modulation of the GroEL/ES chaperonins and Lon protease levels affects the intracellular steady-state concentration of DHFR in a mutation-specific manner, whereas IC50 is changed proportionally, as indeed predicted by the model. This unveils a molecular rationale for the pleiotropic role of the protein quality control machinery on the evolution of antibiotic resistance, which, as we illustrate here, may drastically confound the evolutionary outcome. These results provide a comprehensive quantitative genotype-phenotype map for the essential enzyme that serves as an important target of antibiotic and anticancer therapies. PMID:26929328

  17. 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

  18. 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

  19. Bayesian Estimation of Mixture Models with Prespecified Elements to Compare Drug Resistance in Treatment-Naïve and Experienced Tuberculosis Cases

    PubMed Central

    Izu, Alane; Cohen, Ted; DeGruttola, Victor

    2013-01-01

    We propose a Bayesian approach for estimating branching tree mixture models to compare drug-resistance pathways (i.e. patterns of sequential acquisition of resistance to individual antibiotics) that are observed among Mycobacterium tuberculosis isolates collected from treatment-naïve and treatment-experienced patients. Resistant pathogens collected from treatment-naïve patients are strains for which fitness costs of resistance were not sufficient to prevent transmission, whereas those collected from treatment-experienced patients reflect both transmitted and acquired resistance, the latter of which may or may not be associated with lower transmissibility. The comparison of the resistance pathways constructed from these two groups of drug-resistant strains provides insight into which pathways preferentially lead to the development of multiple drug resistant strains that are transmissible. We apply the proposed statistical methods to data from worldwide surveillance of drug-resistant tuberculosis collected by the World Health Organization over 13 years. PMID:23555210

  20. Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents

    ERIC Educational Resources Information Center

    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…

  1. P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases

    PubMed Central

    Picchianti-Diamanti, Andrea; Rosado, Maria Manuela; Scarsella, Marco; Laganà, Bruno; D’Amelio, Raffaele

    2014-01-01

    Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are chronic inflammatory disorders of unknown etiology characterized by a wide range of abnormalities of the immune system that may compromise the function of several organs, such as kidney, heart, joints, brain and skin. Corticosteroids (CCS), synthetic and biologic immunosuppressive agents have demonstrated the capacity to improve the course of autoimmune diseases. However, a significant number of patients do not respond or develop resistance to these therapies over time. P-glycoprotein (P-gp) is a transmembrane protein that pumps several drugs out of the cell, including CCS and immunosuppressants; thus, its over-expression or hyper-function has been proposed as a possible mechanism of drug resistance in patients with autoimmune disorders. Recently, different authors have demonstrated that P-gp inhibitors, such as cyclosporine A (CsA) and its analogue Tacrolimus, are able to reduce P-gp expression and or function in SLE, RA and PsA patients. These observations suggest that P-gp antagonists could be adopted to revert drug resistance and improve disease outcome. The complex inter-relationship among drug resistance, P-gp expression and autoimmunity still remains elusive. PMID:24658440

  2. "Applied" Aspects of the Drug Resistance Strategies Project

    ERIC Educational Resources Information Center

    Hecht, Michael L.; Miller-Day, Michelle A.

    2010-01-01

    This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1," in order to consider theory-grounded, theory testing and theory developing applied research. We…

  3. Are transporter genes other than the chloroquine resistance locus (pfcrt) and multidrug resistance gene (pfmdr) associated with antimalarial drug resistance?

    PubMed

    Anderson, Timothy J C; Nair, Shalini; Qin, Huang; Singlam, Sittaporn; Brockman, Alan; Paiphun, Lucy; Nosten, François

    2005-06-01

    Mu et al. (Mu, J., M. T. Ferdig, X. Feng, D. A. Joy, J. Duan, T. Furuya, G. Subramanian, L. Aravind, R. A. Cooper, J. C. Wootton, M. Xiong, and X. Z. Su, Mol. Microbiol. 49:977-989, 2003) recently reported exciting associations between nine new candidate transporter genes and in vitro resistance to chloroquine (CQ) and quinine (QN), with six of these loci showing association with CQ or QN in a southeast Asian population sample. We replicated and extended this work by examining polymorphisms in these genes and in vitro resistance to eight drugs in parasites collected from the Thailand-Burma border. To minimize problems of multiple testing, we used a two-phase study design, while to minimize problems caused by population structure, we analyzed parasite isolates collected from a single clinic. We first examined associations between genotype and drug response in 108 unique single-clone parasite isolates. We found strong associations between single nucleotide polymorphisms in pfmdr and mefloquine (MFQ), artesunate (AS), and lumefantrine (LUM) response. We also observed associations between an ABC transporter (G7) and response to QN and AS and between another ABC transporter (G49) and response to dihydro-artemisinin (DHA). We reexamined significant associations in an independent sample of 199 unique single-clone infections from the same location. The significant associations with pfmdr-1042 detected in the first survey remained. However, with the exception of the G7-artesunate association, all other associations observed with the nine new candidate transporters disappeared. We also examined linkage disequilibrium (LD) between markers and phenotypic correlations between drug responses. We found minimal LD between genes. Furthermore, we found no correlation between chloroquine and quinine responses, although we did find expected strong correlations between MFQ, QN, AS, DHA, and LUM. To conclude, we found no evidence for an association between 8/9 candidate genes and

  4. Targeting AMPK Signaling Pathway to Overcome Drug Resistance for Cancer Therapy.

    PubMed

    Wang, Zhiyu; Liu, Pengxi; Chen, Qianjun; Deng, Shigui; Liu, Xiaoyan; Situ, Honglin; Zhong, Shaowen; Hann, Swei; Lin, Yi

    2016-01-01

    Mulitdrug resistance (MDR) is one of critical factorslimiting the efficacy of cancer chemoor radiotherapy. Emerging evidence has indicated that MDR is a complex process regulated by multiple factors, among which stress response molecules are considered as central players. AMP-activated protein kinase (AMPK) is a major regulator balancing energy supply and ultimately protects cells from harmful stresses via coordinating multiple metabolic pathways Notably, AMPK activation was recently shown to mediate the metabolism reprogramming in drug resistant cancer cells including promoting Warburg effects and mitochondrial biogenesis. Furthermore, AMPK activity has also been shown to regulate the self-renewal ability of cancer stem cells that are often refractory to chemotherapy. In addition, AMPK phosphorylation was critical in mediating autophagy induction, a process demonstrated to be effective in chemosensitivity modulation via degrading cellular components to satisfy nutrients requirement under stressful condition. Meanwhile, drug discovery targeting AMPK has been developed to validate the pathological significance of AMPK in cancer prevention and treatment. Although conflicting evidence focusing on the AMPK modulation for cancer treatment is still remained, this might be attributed to differences in AMPK isotypes in specific tissues, off-targets effects, the degree and duration of drug administration and experimental setting of stress conditions. This review will focus on AMPK mediated resistance to cancer therapy and discuss its potential therapeutic implication and targeting drug development. PMID:25777274

  5. Design of a Multiple Drug Delivery System Directed at Periodontitis

    PubMed Central

    Sundararaj, Sharath C.; Thomas, Mark V.; Peyyala, Rebecca; Dziubla, Thomas D.; Puleo, David A.

    2013-01-01

    Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions. PMID:23948165

  6. Design of a multiple drug delivery system directed at periodontitis.

    PubMed

    Sundararaj, Sharath C; Thomas, Mark V; Peyyala, Rebecca; Dziubla, Thomas D; Puleo, David A

    2013-11-01

    Periodontal disease is highly prevalent, with 90% of the world population affected by either periodontitis or its preceding condition, gingivitis. These conditions are caused by bacterial biofilms on teeth, which stimulate a chronic inflammatory response that leads to loss of alveolar bone and, ultimately, the tooth. Current treatment methods for periodontitis address specific parts of the disease, with no individual treatment serving as a complete therapy. The present research sought to demonstrate development of a multiple drug delivery system for stepwise treatment of different stages of periodontal disease. More specifically, multilayered films were fabricated from an association polymer comprising cellulose acetate phthalate and Pluronic F-127 to achieve sequential release of drugs. The four types of drugs used were metronidazole, ketoprofen, doxycycline, and simvastatin to eliminate infection, inhibit inflammation, prevent tissue destruction, and aid bone regeneration, respectively. Different erosion times and adjustable sequential release profiles were achieved by modifying the number of layers or by inclusion of a slower-eroding polymer layer. Analysis of antibiotic and anti-inflammatory bioactivity showed that drugs released from the devices retained 100% bioactivity. The multilayered CAPP delivery system offers a versatile approach for releasing different drugs based on the pathogenesis of periodontitis and other conditions. PMID:23948165

  7. 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.

  8. Drug Resistance Characteristics and Macrolide-Resistant Mechanisms of Streptococcus pneumoniae in Wenzhou City, China.

    PubMed

    Hu, Dakang; Sun, Zheng; Luo, Xinhua; Liu, Shuangchun; Yu, Lianhua; Qu, Ying; Yang, Jinhong; Yu, Jian; Li, Xiangyang; Zhang, Jin

    2016-01-01

    BACKGROUND Streptococcus pneumoniae (SP) is a Gram-positive, alpha-hemolytic, facultative anaerobic member of the genus Streptococcus. The erythromycin-resistant methylase (erm) gene and macrolide efflux (mef) gene are the 2 main genes that can mediate SP. Transposon (Tn) also plays an important role in the collection and metastasis of the gene. In the present study we investigated the drug resistance characteristics and the macrolide-resistant mechanisms of SP in Wenzhou City, China. MATERIAL AND METHODS Sixty-eight strains of SP were isolated from sputum samples of hospitalized children in the Second Affiliated Hospital of Wenzhou Medical University. These strains were analyzed using antimicrobial susceptibility tests to determine their drug resistance to 10 kinds of antibacterials. Macrolide-resistant phenotypes were identified using K-B method. PCR method was used to analyze the erm B gene, mef A gene, and int Tn gene. RESULTS Drug resistance rates of 68 strains of SP were 98.5%, 100.0%, 63.2%, 52.9%, 94.1%, 89.7%, 0.0%, 0.0%, 16.2%, and 14.7% for clindamycin, erythromycin, penicillin G, cefotaxime, tetracycline, sulfamethoxazole/trimethoprim, levofloxacin, vancomycin, chloramphenicol, and amoxicillin, respectively. Total detection rates of the erm B gene, mef A gene, and int Tn gene were 98.5%, 91.2%, and 100.0%, respectively. CONCLUSIONS SP shows significant multi-drug resistance in Wenzhou City, whereas there is no clinical value of macrolides antibiotics for SP. cMLSB mediated by erm B gene is the most predominant phenotype among macrolide-resistant SP. The int Tn gene may play an important role in horizontal transfer and clonal dissemination of SP drug resistance genes in Wenzhou City. PMID:27483416

  9. Drug Resistance Characteristics and Macrolide-Resistant Mechanisms of Streptococcus pneumoniae in Wenzhou City, China

    PubMed Central

    Hu, Dakang; Sun, Zheng; Luo, Xinhua; Liu, Shuangchun; Yu, Lianhua; Qu, Ying; Yang, Jinhong; Yu, Jian; Li, Xiangyang; Zhang, Jin

    2016-01-01

    Background Streptococcus pneumoniae (SP) is a Gram-positive, alpha-hemolytic, facultative anaerobic member of the genus Streptococcus. The erythromycin-resistant methylase (erm) gene and macrolide efflux (mef) gene are the 2 main genes that can mediate SP. Transposon (Tn) also plays an important role in the collection and metastasis of the gene. In the present study we investigated the drug resistance characteristics and the macrolide-resistant mechanisms of SP in Wenzhou City, China. Material/Methods Sixty-eight strains of SP were isolated from sputum samples of hospitalized children in the Second Affiliated Hospital of Wenzhou Medical University. These strains were analyzed using antimicrobial susceptibility tests to determine their drug resistance to 10 kinds of antibacterials. Macrolide-resistant phenotypes were identified using K-B method. PCR method was used to analyze the erm B gene, mef A gene, and int Tn gene. Results Drug resistance rates of 68 strains of SP were 98.5%, 100.0%, 63.2%, 52.9%, 94.1%, 89.7%, 0.0%, 0.0%, 16.2%, and 14.7% for clindamycin, erythromycin, penicillin G, cefotaxime, tetracycline, sulfamethoxazole/trimethoprim, levofloxacin, vancomycin, chloramphenicol, and amoxicillin, respectively. Total detection rates of the erm B gene, mef A gene, and int Tn gene were 98.5%, 91.2%, and 100.0%, respectively. Conclusions SP shows significant multi-drug resistance in Wenzhou City, whereas there is no clinical value of macrolides antibiotics for SP. cMLSB mediated by erm B gene is the most predominant phenotype among macrolide-resistant SP. The int Tn gene may play an important role in horizontal transfer and clonal dissemination of SP drug resistance genes in Wenzhou City. PMID:27483416

  10. Pharmacological telomerase inhibition can sensitize drug-resistant and drug-sensitive cells to chemotherapeutic treatment.

    PubMed

    Ward, Ryan J; Autexier, Chantal

    2005-09-01

    Effective strategies to reverse or prevent chemotherapeutic resistance are required before cancer therapies can be curative. Telomerase is the ribonucleoprotein responsible for de novo synthesis and maintenance of telomeres, and its activity is predominantly observed in cancer cells. The telomerase enzyme has been successfully inhibited or inactivated to sensitize cells to cellular stresses; however, no studies have determined yet the effect of combining a pharmacological inhibitor of telomerase catalysis and traditional chemotherapeutics for the treatment of drug-sensitive or drug-resistant cancers. Here, we describe the effect of 2-[(E)-3-naphtalen-2-yl-but-2-enoylamino]-benzoic acid (BIBR1532), a small-molecule inhibitor of telomerase catalytic activity, on drug-resistant leukemia and breast cancer cells and their parental counterparts when treated in combination with chemotherapeutics. We observed that BIBR1532-treated cells show progressive telomere shortening, decreased proliferative capacity, and sensitization to chemotherapeutic treatment. These effects are telomere length-dependent, because cells insensitive to BIBR1532 or cells released from telomerase inhibition did not demonstrate changes in growth ability or drug sensitivity. Our novel observations suggest that pharmacological telomerase inhibition in combination therapy may be a valid strategy for the treatment of both drug-sensitive and drug-resistant cancers. PMID:15939802

  11. Copper–zinc superoxide dismutase-mediated redox regulation of bortezomib resistance in multiple myeloma

    PubMed Central

    Salem, Kelley; McCormick, Michael L.; Wendlandt, Erik; Zhan, Fenghuang; Goel, Apollina

    2014-01-01

    Multiple myeloma (MM) is an incurable B-cell malignancy. The proteasome inhibitor bortezomib (BTZ) is a frontline MM drug; however, intrinsic or acquired resistance to BTZ remains a clinical hurdle. As BTZ induces oxidative stress in MM cells, we queried if altered redox homeostasis promotes BTZ resistance. In primary human MM samples, increased gene expression of copper–zinc superoxide dismutase (CuZnSOD or SOD1) correlated with cancer progression, high-risk disease, and adverse overall and event-free survival outcomes. As an in vitro model, human MM cell lines (MM.1S, 8226, U266) and the BTZ-resistant (BR) lines (MM.1SBR, 8226BR) were utilized to determine the role of antioxidants in intrinsic or acquired BTZ-resistance. An up-regulation of CuZnSOD, glutathione peroxidase-1 (GPx-1), and glutathione (GSH) were associated with BTZ resistance and attenuated prooxidant production by BTZ. Enforced overexpression of SOD1 induced BTZ resistance and pharmacological inhibition of CuZnSOD with disulfiram (DSF) augmented BTZ cytotoxicity in both BTZ-sensitive and BTZ-resistant cell lines. Our data validates CuZnSOD as a novel therapeutic target in MM. We propose DSF as an adjuvant to BTZ in MM that is expected to overcome intrinsic and acquired BTZ resistance as well as augment BTZ cytotoxicity. PMID:25485927

  12. Persistent Infection of Drug-resistant Influenza A Virus during Chemotherapy for Malignant Lymphoma.

    PubMed

    Kawakami, Toru; Hirabayashi, Yukio; Kawakami, Fumihiro; Isobe, Rei; Kaneko, Naoto; Mimura, Yuto; Ito, Toshiro; Furuta, Kiyoshi; Shimazaki, Mami; Nakazawa, Hideyuki; Kitano, Kiyoshi

    2016-01-01

    We herein report the case of an 80-year-old man with malignant lymphoma who became persistently infected with influenza A virus. Although he was repeatedly treated with NA inhibitors, such as oseltamivir or peramivir, nasal cavity swab tests for influenza A antigen continued to be positive for more than 2 months. Virological analyses revealed that he was infected with the NA inhibitor-resistant A (H3N2) virus possessing an R292K substitution in the NA protein. These findings suggest that a drug-resistant influenza virus strain might selectively survive antiviral therapy in elderly patients with refractory malignant lymphoma undergoing multiple chemotherapies. PMID:27374689

  13. Multiple Antimicrobial Resistance of Escherichia coli Isolated from Chickens in Iran.

    PubMed

    Talebiyan, Reza; Kheradmand, Mehdi; Khamesipour, Faham; Rabiee-Faradonbeh, Mohammad

    2014-01-01

    Antimicrobial agents are used extremely in order to reduce the great losses caused by Escherichia coli infections in poultry industry. In this study, 318 pathogenic Escherichia coli (APEC) strains isolated from commercial broiler flocks with coli-septicemia were examined for antimicrobials of both veterinary and human significance by disc diffusion method. Multiple resistances to antimicrobial agents were observed in all the isolates. Resistance to the antibiotics was as follows: Tylosin (88.68%), Erythromycin (71.70%), Oxytetracycline (43.40%), Sulfadimethoxine-Trimethoprim (39.62%), Enrofloxacin (37.74%), Florfenicol (35.85%), Chlortetracycline (33.96%), Doxycycline (16.98%), Difloxacin (32.08%), Danofloxacin (28.30%), Chloramphenicol (20.75%), Ciprofloxacin (7.55%), and Gentamicin (5.66%). This study showed resistance against the antimicrobial agents that are commonly applied in poultry, although resistance against the antibiotics that are only applied in humans or less frequently used in poultry was significantly low. This study emphasizes on the occurrence of multiple drug resistant E. coli among diseased broiler chickens in Iran. The data revealed the relative risks of using antimicrobials in poultry industry. It also concluded that use of antibiotics must be limited in poultry farms in order to reduce the antibiotic resistances. PMID:25548716

  14. Multiple Antimicrobial Resistance of Escherichia coli Isolated from Chickens in Iran

    PubMed Central

    Talebiyan, Reza; Kheradmand, Mehdi; Khamesipour, Faham; Rabiee-Faradonbeh, Mohammad

    2014-01-01

    Antimicrobial agents are used extremely in order to reduce the great losses caused by Escherichia coli infections in poultry industry. In this study, 318 pathogenic Escherichia coli (APEC) strains isolated from commercial broiler flocks with coli-septicemia were examined for antimicrobials of both veterinary and human significance by disc diffusion method. Multiple resistances to antimicrobial agents were observed in all the isolates. Resistance to the antibiotics was as follows: Tylosin (88.68%), Erythromycin (71.70%), Oxytetracycline (43.40%), Sulfadimethoxine-Trimethoprim (39.62%), Enrofloxacin (37.74%), Florfenicol (35.85%), Chlortetracycline (33.96%), Doxycycline (16.98%), Difloxacin (32.08%), Danofloxacin (28.30%), Chloramphenicol (20.75%), Ciprofloxacin (7.55%), and Gentamicin (5.66%). This study showed resistance against the antimicrobial agents that are commonly applied in poultry, although resistance against the antibiotics that are only applied in humans or less frequently used in poultry was significantly low. This study emphasizes on the occurrence of multiple drug resistant E. coli among diseased broiler chickens in Iran. The data revealed the relative risks of using antimicrobials in poultry industry. It also concluded that use of antibiotics must be limited in poultry farms in order to reduce the antibiotic resistances. PMID:25548716

  15. Bacterial recombination promotes the evolution of multi-drug-resistance in functionally diverse populations

    PubMed Central

    Perron, Gabriel G.; Lee, Alexander E. G.; Wang, Yun; Huang, Wei E.; Barraclough, Timothy G.

    2012-01-01

    Bacterial recombination is believed to be a major factor explaining the prevalence of multi-drug-resistance (MDR) among pathogenic bacteria. Despite extensive evidence for exchange of resistance genes from retrospective sequence analyses, experimental evidence for the evolutionary benefits of bacterial recombination is scarce. We compared the evolution of MDR between populations of Acinetobacter baylyi in which we manipulated both the recombination rate and the initial diversity of strains with resistance to single drugs. In populations lacking recombination, the initial presence of multiple strains resistant to different antibiotics inhibits the evolution of MDR. However, in populations with recombination, the inhibitory effect of standing diversity is alleviated and MDR evolves rapidly. Moreover, only the presence of DNA harbouring resistance genes promotes the evolution of resistance, ruling out other proposed benefits for recombination. Together, these results provide direct evidence for the fitness benefits of bacterial recombination and show that this occurs by mitigation of functional interference between genotypes resistant to single antibiotics. Although analogous to previously described mechanisms of clonal interference among alternative beneficial mutations, our results actually highlight a different mechanism by which interactions among co-occurring strains determine the benefits of recombination for bacterial evolution. PMID:22048956

  16. Multiple routes of drug administration and HIV risk among injecting drug users

    PubMed Central

    Vorobjov, Sigrid; Uusküla, Anneli; Des Jarlais, Don C.; Abel-Ollo, Katri; Talu, Ave; Rüütel, Kristi

    2011-01-01

    This study assesses relationships between drug administration routes and HIV serostatus, drug-use and sexual behaviors among current injecting drug users (IDUs) in Tallinn, Estonia. We recruited 350 IDUs for a cross-sectional risk behavior survey. Adjusted odds ratios (AORs) were calculated to explore injection risk behavior, sexual behavior and HIV serostatus associated with multiple route use. Focus groups explored reasons why injectors might use non-injecting routes of administration. Those reporting multiple drug administration routes were less likely to be HIV seropositive (AOR 0.49; 95%CI 0.25-0.97), had almost twice the odds of having more than one sexual partner (AOR 1.90; 95%CI 1.01-3.60) and of reporting having sexually transmitted diseases (AOR 2.38; 95%CI 1.02-5.59). IDUs who engage in non-injecting drug use may be reducing their risk of acquiring HIV though sharing injection equipment, but if infected may be a critical group for sexual transmission of HIV to people who do not inject drugs. PMID:22116012

  17. 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

  18. 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

  19. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  20. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  1. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  2. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  3. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay....

  4. The population genetics of drug resistance evolution in natural populations of viral, bacterial and eukaryotic pathogens.

    PubMed

    Wilson, Benjamin A; Garud, Nandita R; Feder, Alison F; Assaf, Zoe J; Pennings, Pleuni S

    2016-01-01

    Drug resistance is a costly consequence of pathogen evolution and a major concern in public health. In this review, we show how population genetics can be used to study the evolution of drug resistance and also how drug resistance evolution is informative as an evolutionary model system. We highlight five examples from diverse organisms with particular focus on: (i) identifying drug resistance loci in the malaria parasite Plasmodium falciparum using the genomic signatures of selective sweeps, (ii) determining the role of epistasis in drug resistance evolution in influenza, (iii) quantifying the role of standing genetic variation in the evolution of drug resistance in HIV, (iv) using drug resistance mutations to study clonal interference dynamics in tuberculosis and (v) analysing the population structure of the core and accessory genome of Staphylococcus aureus to understand the spread of methicillin resistance. Throughout this review, we discuss the uses of sequence data and population genetic theory in studying the evolution of drug resistance. PMID:26578204

  5. 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

  6. A Reprofiled Drug, Auranofin, Is Effective against Metronidazole-Resistant Giardia lamblia

    PubMed Central

    Tejman-Yarden, Noa; Miyamoto, Yukiko; Leitsch, David; Santini, Jennifer; Debnath, Anjan; Gut, Jiri; McKerrow, James H.; Reed, Sharon L.

    2013-01-01

    Giardiasis is one of the most common causes of diarrheal disease worldwide. Treatment is primarily with 5-nitro antimicrobials, particularly metronidazole. Resistance to metronidazole has been described, and treatment failures can occur in up to 20% of cases, making development of alternative antigiardials an important goal. To this end, we have screened a chemical library of 746 approved human drugs and 164 additional bioactive compounds for activity against Giardia lamblia. We identified 56 compounds that caused significant inhibition of G. lamblia growth and attachment. Of these, 15 were previously reported to have antigiardial activity, 20 were bioactive but not approved for human use, and 21 were drugs approved for human use for other indications. One notable compound of the last group was the antirheumatic drug auranofin. Further testing revealed that auranofin was active in the low (4 to 6)-micromolar range against a range of divergent G. lamblia isolates representing both human-pathogenic assemblages A and B. Most importantly, auranofin was active against multiple metronidazole-resistant strains. Mechanistically, auranofin blocked the activity of giardial thioredoxin oxidoreductase, a critical enzyme involved in maintaining normal protein function and combating oxidative damage, suggesting that this inhibition contributes to the antigiardial activity. Furthermore, auranofin was efficacious in vivo, as it eradicated infection with different G. lamblia isolates in different rodent models. These results indicate that the approved human drug auranofin could be developed as a novel agent in the armamentarium of antigiardial drugs, particularly against metronidazole-resistant strains. PMID:23403423

  7. Structure-Based Tetravalent Zanamivir with Potent Inhibitory Activity against Drug-Resistant Influenza Viruses.

    PubMed

    Fu, Lifeng; Bi, Yuhai; Wu, Yan; Zhang, Shanshan; Qi, Jianxun; Li, Yan; Lu, Xuancheng; Zhang, Zhenning; Lv, Xun; Yan, Jinghua; Gao, George F; Li, Xuebing

    2016-07-14

    Zanamivir and oseltamivir are principal influenza antiviral drugs that target viral neuraminidase (NA), but resistant viruses containing mutant NAs with diminished drug affinity are increasingly emerging. Using the structural knowledge of both drug-binding sites and their spatial arrangement on the homotetrameric NA, we have developed a tetravalent zanamivir (TZ) molecule that exhibited marked increases in NA binding affinity, inhibition of NA enzyme activity, and in vitro plus in vivo antiviral efficacy over zanamivir. TZ functioned against both human seasonal H3N2 and avian H7N9 viruses, including drug-resistant mutants. Crystal structure of a resistant N9 NA in complex with TZ explained the function, which showed that four zanamivir residues simultaneously bound to all four monomers of NA. The design method of TZ described in this study may be useful to develop drugs or ligands that target proteins with multiple binding sites. The potent anti-influenza activity of TZ makes it attractive for further development. PMID:27341624

  8. The evolution of drug resistance in clinical isolates of Candida albicans

    PubMed Central

    Guiducci, Candace; Martinez, Diego A; Delorey, Toni; Li, Bi yu; White, Theodore C; Cuomo, Christina; Rao, Reeta P; Berman, Judith; Thompson, Dawn A; Regev, Aviv

    2015-01-01

    Candida albicans is both a member of the healthy human microbiome and a major pathogen in immunocompromised individuals. Infections are typically treated with azole inhibitors of ergosterol biosynthesis often leading to drug resistance. Studies in clinical isolates have implicated multiple mechanisms in resistance, but have focused on large-scale aberrations or candidate genes, and do not comprehensively chart the genetic basis of adaptation. Here, we leveraged next-generation sequencing to analyze 43 isolates from 11 oral candidiasis patients. We detected newly selected mutations, including single-nucleotide polymorphisms (SNPs), copy-number variations and loss-of-heterozygosity (LOH) events. LOH events were commonly associated with acquired resistance, and SNPs in 240 genes may be related to host adaptation. Conversely, most aneuploidies were transient and did not correlate with drug resistance. Our analysis also shows that isolates also varied in adherence, filamentation, and virulence. Our work reveals new molecular mechanisms underlying the evolution of drug resistance and host adaptation. DOI: http://dx.doi.org/10.7554/eLife.00662.001 PMID:25646566

  9. 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

  10. 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

  11. 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

  12. IGF-1 receptor targeted nanoparticles for image-guided therapy of stroma-rich and drug resistant human cancer

    PubMed Central

    Zhou, Hongyu; Qian, Weiping; Uckun, Fatih M.; Zhou, Zhiyang; Wang, Liya; Wang, Andrew; Mao, Hui

    2016-01-01

    Low drug delivery efficiency and drug resistance from highly heterogeneous cancer cells and tumor microenvironment represent major challenges in clinical oncology. Growth factor receptor, IGF-1R, is overexpressed in both human tumor cells and tumor associated stromal cells. The level of IGF-1R expression is further up-regulated in drug resistant tumor cells. We have developed IGF-1R targeted magnetic iron oxide nanoparticles (IONPs) carrying multiple anticancer drugs into human tumors. This IGF-1R targeted theranostic nanoparticle delivery system has an iron core for non-invasive MR imaging, amphiphilic polymer coating to ensure the biocompatibility as well as for drug loading and conjugation of recombinant human IGF-1 as targeting molecules. Chemotherapy drugs, Doxorubicin (Dox), was encapsulated into the polymer coating and/or conjugated to the IONP surface by coupling with the carboxyl groups. The ability of IGF1R targeted theranostic nanoparticles to penetrate tumor stromal barrier and enhance tumor cell killing has been demonstrated in human pancreatic cancer patient tissue derived xenograft (PDX) models. Repeated systemic administrations of those IGF-1R targeted theranostic IONP carrying Dox led to breaking the tumor stromal barrier and improved therapeutic effect. Near infrared (NIR) optical and MR imaging enabled noninvasive monitoring of nanoparticle-drug delivery and therapeutic responses. Our results demonstrated that IGF-1R targeted nanoparticles carrying multiple drugs are promising combination therapy approaches for image-guided therapy of stroma-rich and drug resistant human cancer, such as pancreatic cancer. PMID:27313332

  13. 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.

  14. Resistance to antiplatelet drugs: molecular mechanisms and laboratory detection.

    PubMed

    Cattaneo, M

    2007-07-01

    The definition 'resistance to antiplatelet drugs' should be limited to situations in which failure of the drug to hit its pharmacological target has been documented by specific laboratory tests. Aspirin resistance, as determined by specific tests (e.g. serum thromboxane B(2)), appears to be rare (1-2%) and, in most instances, is caused by poor compliance. In contrast to aspirin, studies that used specific tests to measure the pharmacological effect of thienopyridines [e.g. vasodilator-stimulated phosphoprotein (VASP)] showed a wide variability of responses to these drugs, with significant proportions of subjects (15-30%) who are very poor responders. Inter-individual differences in the extent of metabolism of thienopyridines to their active metabolites is the most plausible mechanism for the observed inter-individual variability in platelet inhibition. The demonstration that some patients may be 'resistant' or 'poor responders' to the pharmacological effect of antiplatelet drugs, has prompted the need of laboratory monitoring of antiplatelet therapy. However, many published studies have been performed using unspecific tests of platelet function, which identify patients on antiplatelet treatment with high residual platelet reactivity, which is not necessarily because of resistance to antiplatelet drugs. Despite this drawback, identification of patients with high residual platelet reactivity may be useful to predict their risk of atherothrombotic events. However, many studies still need to be carried out to identify the ideal laboratory test and to answer basic questions on its clinical utility and cost-effectiveness, before monitoring antiplatelet therapy can be recommended in the clinical practise. Until then, monitoring of antiplatelet therapy should be considered for investigational purposes only. PMID:17635731

  15. 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.

  16. Genome-wide screening of loci associated with drug resistance to 5-fluorouracil-based drugs.

    PubMed

    Ooyama, Akio; Okayama, Yoshihiro; Takechi, Teiji; Sugimoto, Yoshikazu; Oka, Toshinori; Fukushima, Masakazu

    2007-04-01

    Resistance to chemotherapeutic agents represents the chief cause of mortality in cancer patients with advanced disease. Chromosomal aberration and altered gene expression are the main genetic mechanisms of tumor chemoresistance. In this study, we have established an algorithm to calculate DNA copy number using the Affymetrix 10K array, and performed a genome-wide correlation analysis between DNA copy number and antitumor activity against 5-fluorouracil (5-FU)-based drugs (S-1, tegafur + uracil [UFT], 5'-DFUR and capecitabine) to screen for loci influencing drug resistance using 27 human cancer xenografts. A correlation analysis confirmed that the single nucleotide polymorphism (SNP) showing significant associations with drug sensitivity were concentrated in some cytogenetic regions (18p, 17p13.2, 17p12, 11q14.1, 11q11 and 11p11.12), and we identified some genes that have been indicated their relations to drug sensitivity. Among these regions, 18p11.32 at the location of the thymidylate synthase gene (TYMS) was strongly associated with resistance to 5-FU-based drugs. A change in copy number of the TYMS gene was reflected in the TYMS expression level, and showed a significant negative correlation with sensitivity against 5-FU-based drugs. These results suggest that amplification of the TYMS gene is associated with innate resistance, supporting the possibility that TYMS copy number might be a predictive marker of drug sensitivity to fluoropyrimidines. Further study is necessary to clarify the functional roles of other genes coded in significant cytogenetic regions. These promising data suggest that a comprehensive DNA copy number analysis might aid in the quest for optimal markers of drug response. PMID:17425594

  17. 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

  18. How Fitness Reduced, Antimicrobial Resistant Bacteria Survive and Spread: A Multiple Pig - Multiple Bacterial Strain Model

    PubMed Central

    Græsbøll, Kaare; Nielsen, Søren Saxmose; Toft, Nils; Christiansen, Lasse Engbo

    2014-01-01

    More than 30% of E. coli strains sampled from pig farms in Denmark over the last five years were resistant to the commonly used antimicrobial tetracycline. This raises a number of questions: How is this high level sustained if resistant bacteria have reduced growth rates? Given that there are multiple susceptible and resistant bacterial strains in the pig intestines, how can we describe their coexistence? To what extent does the composition of these multiple strains in individual pigs influence the total bacterial population of the pig pen? What happens to a complex population when antimicrobials are used? To investigate these questions, we created a model where multiple strains of bacteria coexist in the intestines of pigs sharing a pen, and explored the parameter limits of a stable system; both with and without an antimicrobial treatment. The approach taken is a deterministic bacterial population model with stochastic elements of bacterial distributions and transmission. The rates that govern the model are process-oriented to represent growth, excretion, and uptake from environment, independent of herd and meta-population structures. Furthermore, an entry barrier and elimination process for the individual strains in each pig were implemented. We demonstrate how competitive growth between multiple bacterial strains in individual pigs, and the transmission between pigs in a pen allow for strains of antimicrobial resistant bacteria to persist in a pig population to different extents, and how quickly they can become dominant if antimicrobial treatment is initiated. The level of spread depends in a non-linear way of the parameters that govern excretion and uptake. Furthermore, the sampling of initial distributions of strains and stochastic transmission events give rise to large variation in how homogenous and how resistant the bacterial population becomes. Most important: resistant bacteria are demonstrated to survive with a disadvantage in growth rate of well over 10

  19. ATP7B expression confers multidrug resistance through drug sequestration

    PubMed Central

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

    2016-01-01

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

  20. Elaboration of a global strategy for containing microbial drug resistance.

    PubMed

    Zabicki, W

    2001-01-01

    The World Health Organization is engaged in developing the Global Strategy for Containment of Antimicrobial Resistance. The preliminary document WHO/CDC/CSR/DRS/2000.I Draft has already been distributed, and remarks have been solicited.
    The World Health Assembly Resolution of 1998 urged Member States to encourage the appropriate and cost-effective use of antimicrobials. Member States were requested to implement effective systems of microbial resistance surveillance and to monitor volumes and patterns of antimicrobial drug use.
    The phenomenon of antimicrobial resistance is rising rapidly and causing growing international concern. Many countries have undertaken their own national plans to address the problem.
    The overall aim of the strategy being developed is to find the most effective forms and to prevent the spread of antimicrobial resistance and resistant microbes. The strategy covers the following topics: patients and general community, prescribers, hospitals, veterinarians, manufacturers and drug dispensers, and international aspects.
    The strategy is being developed on the basis of expert opinions, published reports, reviews of specific topics specially commissioned by various international and national bodies, and a large body of literature with a list of publications containing over 100 items. PMID:17986973

  1. [MOLECULAR MECHANISMS OF DRUG RESISTANCE NEISSERIA GONORRHOEAE HISTORY AND PROSPECTS].

    PubMed

    Bodoev, I N; Il'ina, E N

    2015-01-01

    Neisseria gonorrhoeae (gonococcus) is a strict human pathogen, which causes gonorrhea--an infectious disease, whose origin dates back to more than two thousand years. Due to the unique plasticity of the genetic material, these bacteria have acquired the capacity to adapt to the host immune system, cause repeated infections, as well as withstand antimicrobials. Since the introduction of antibiotics in 1930s, gonococcus has displayed its propensity to develop resistance to all clinically useful antibiotics. It is important to note that the known resistance determinants of N. gonorrhoeae were acquired through horizontal gene transfer, recombination and spontaneous mutagenesis, and may be located both in the chromosome and on the plasmid. After introduction of a new antimicrobial drug, gonococcus becomes resistant within two decades and replaces sensitive bacterial population. Currently Ceftriaxone is the last remaining antibiotic for first-line treatment of gonorrhea. However, the first gonococcus displaying high-level resistance to Ceftriaxone was isolated in Japan a few years ago. Therefore, in the near future, gonorrhea may become untreatable. In the present review, we discuss the chronology of the anti-gonorrhea drugs (antibiotics) replacement, the evolution of resistance mechanisms emergence and future perspectives of N. gonorrhoeae treatment. PMID:26665738

  2. Coherent feedforward transcriptional regulatory motifs enhance drug resistance

    NASA Astrophysics Data System (ADS)

    Charlebois, Daniel A.; Balázsi, Gábor; Kærn, Mads

    2014-05-01

    Fluctuations in gene expression give identical cells access to a spectrum of phenotypes that can serve as a transient, nongenetic basis for natural selection by temporarily increasing drug resistance. In this study, we demonstrate using mathematical modeling and simulation that certain gene regulatory network motifs, specifically coherent feedforward loop motifs, can facilitate the development of nongenetic resistance by increasing cell-to-cell variability and the time scale at which beneficial phenotypic states can be maintained. Our results highlight how regulatory network motifs enabling transient, nongenetic inheritance play an important role in defining reproductive fitness in adverse environments and provide a selective advantage subject to evolutionary pressure.

  3. 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

  4. Drug therapy for the patient with resistant hypertension.

    PubMed

    Donazzan, Luca; Ewen, Sebastian; Papademetriou, Vasilios; Linicus, Yvonne; Linz, Dominik; Böhm, Michael; Mahfoud, Felix

    2015-03-01

    Resistant hypertension is associated with high morbidity and mortality. Resistant hypertension is defined as blood pressure above targets despite treatment with at least three antihypertensive drugs in adequate dose and combination. Nonadherence is a frequent cause of uncontrolled hypertension and can be improved by providing fixed dose (of two or three agents) single pill combination. Triple combination of the most widely used antihypertensive agents (renin-angiotensin-aldosterone system antagonists, calcium channel blockers and diuretics) is a safe and effective therapy. Fourth line therapy is the use of an aldosterone antagonist. Renal denervation and baroreceptor stimulation can be considered in patients who remained uncontrolled despite optimal medical therapy. PMID:25760878

  5. Personalized Cancer Medicine: Molecular Diagnostics, Predictive biomarkers, and Drug Resistance

    PubMed Central

    Gonzalez de Castro, D; Clarke, P A; Al-Lazikani, B; Workman, P

    2013-01-01

    The progressive elucidation of the molecular pathogenesis of cancer has fueled the rational development of targeted drugs for patient populations stratified by genetic characteristics. Here we discuss general challenges relating to molecular diagnostics and describe predictive biomarkers for personalized cancer medicine. We also highlight resistance mechanisms for epidermal growth factor receptor (EGFR) kinase inhibitors in lung cancer. We envisage a future requiring the use of longitudinal genome sequencing and other omics technologies alongside combinatorial treatment to overcome cellular and molecular heterogeneity and prevent resistance caused by clonal evolution. PMID:23361103

  6. Microarray-based detection and expression analysis of ABC and SLC transporters in drug-resistant ovarian cancer cell lines.

    PubMed

    Januchowski, Radosław; Zawierucha, Piotr; Andrzejewska, Małgorzata; Ruciński, Marcin; Zabel, Maciej

    2013-04-01

    Multiple drug resistance of cancer cells is multifactorial. A microarray technique may provide information about new candidate genes playing a role in drug resistance. Drug membrane transporters from ABC and SLC families play a main role in this phenomenon. This study demonstrates alterations in ABC and SLC gene expression levels in methotrexate, cisplatin, doxorubicin, vincristine, topotecan and paclitaxel-resistant variant of W1 ovarian cancer cell line. Resistant W1 cell lines were derived by stepwise selection of cells in increasing concentration of drugs. Affymetrix GeneChip(®) Human Genome U219 Array Strip was used for hybridizations. Statistical significance was determined by independent sample t-test. The genes having altered expression levels in drug-resistant sublines were selected and filtered by scater plot. Genes up/downregulated more than threefolds were selected and listed. Among ABC genes, seven were upregulated and three were downregulated. Three genes: ABCB1, ABCB4 and ABCG2 were upregulated very significantly (over tenfold). One ABCA8 was significantly downregulated. Among 38 SLC genes, 18 were upregulated, 16 were downregulated and four were up- or downregulated dependent on the cell line. Expression of 10 SLC genes was changed very significantly (over tenfold). Four genes were significantly increased: SLC6A1, SLC9A2, SLC12A1, SLC16A6 and six genes were significantly decreased: SLC2A14, SLC7A3, SLC7A8, SLC7A11, SLC16A14, SLC38A9. Based on the expression profiles, our results provide a preliminary insight into the relationship between drug resistance and expression of membrane transporters involved in drug resistance. Correlation of specific drug transporter with drug resistance requires further analysis. PMID:23462296

  7. Smart doxorubicin nanoparticles with high drug payload for enhanced chemotherapy against drug resistance and cancer diagnosis.

    PubMed

    Yu, Caitong; Zhou, Mengjiao; Zhang, Xiujuan; Wei, Weijia; Chen, Xianfeng; Zhang, Xiaohong

    2015-03-19

    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. PMID:25740312

  8. 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

  9. Risk factors for anti-MRSA drug resistance.

    PubMed

    Abe, Yasuhisa; Shigemura, Katsumi; Yoshida, Hiroyuki; Fujisawa, Masato; Arakawa, Soichi

    2012-11-01

    Meticillin-resistant Staphylococcus aureus (MRSA)-related infections have recently been spreading and are difficult to control, partly because affected patients are frequently in a poor condition. This study retrospectively investigated recent MRSA-related infections focusing on the relationship between clinical risk factors and anti-MRSA drug resistance. The patients with MRSA-related infections in Kobe University Hospital (Kobe, Japan) in 2009 were enrolled in the study. The relationships between various clinical risk factors as well as MRSA bacterial DNA concentration with minimum inhibitory concentrations (MICs) of anti-MRSA drugs were examined. In total, 44 patients were enrolled in the study and MRSA was isolated from blood (23 patients), urine (12 patients) and nasal secretions (9 patients). There was only one resistant strain to linezolid (LZD) among the anti-MRSA drugs tested, and this strain was considered staphylococcal cassette chromosome mec (SCCmec) type IIa from phage open-reading frame typing analyses. Statistical analyses showed that MRSA bacterial DNA concentration, cancer and use of a respirator, respectively, had a significant relationship with the MICs of LZD (P=0.0058) and arbekacin (ABK) (P=0.0003), of quinupristin/dalfopristin (Q/D) (P=0.0500) and ABK (P=0.0133), and of Q/D (P=0.0198) and vancomycin (P=0.0036). In conclusion, bacterial DNA concentration, cancer and use of a respirator were found to be significant risk factors for lower susceptibilities to anti-MRSA drugs; one strain was resistant to LZD. We suggest that further investigation and surveillance for MRSA-related infection are necessary for preventing the spread of MRSA-related infections. PMID:22999766

  10. Overcoming Resistance of Cancer Cells to PARP-1 Inhibitors with Three Different Drug Combinations

    PubMed Central

    Castel, David; Moshe, Itai; Mazal, Inbal; Cohen, Osher; Avivi, Camila; Rosenblatt, Kineret; Aviel-Ronen, Sarit; Schiby, Ginette; Yahalom, Joachim; Amariglio, Ninette; Pfeffer, Raphael; Lawrence, Yaacov; Toren, Amos; Rechavi, Gideon; Paglin, Shoshana

    2016-01-01

    Inhibitors of poly[ADP-ribose] polymerase 1 (PARPis) show promise for treatment of cancers which lack capacity for homologous recombination repair (HRR). However, new therapeutic strategies are required in order to overcome innate and acquired resistance to these drugs and thus expand the array of cancers that could benefit from them. We show that human cancer cell lines which respond poorly to ABT-888 (a PARPi), become sensitive to it when co-treated with vorinostat (a histone deacetylase inhibitor (HDACi)). Vorinostat also sensitized PARPis insensitive cancer cell lines to 6-thioguanine (6-TG)–a drug that targets PARPis sensitive cells. The sensitizing effect of vorinostat was associated with increased phosphorylation of eukaryotic initiation factor (eIF) 2α which in and of itself increases the sensitivity of cancer cells to ABT-888. Importantly, these drug combinations did not affect survival of normal fibroblasts and breast cells, and significantly increased the inhibition of xenograft tumor growth relative to each drug alone, without affecting the mice weight or their liver and kidney function. Our results show that combination of vorinostat and ABT-888 could potentially prove useful for treatment of cancer with innate resistance to PARPis due to active HRR machinery, while the combination of vorinostat and 6-TG could potentially overcome innate or acquired resistance to PARPis due to secondary or reversal BRCA mutations, to decreased PARP-1 level or to increased expression of multiple drug resistant proteins. Importantly, drugs which increase phosphorylation of eIF2α may mimic the sensitizing effect of vorinostat on cellular response to PARPis or to 6-TG, without activating all of its downstream effectors. PMID:27196668

  11. Overcoming MITF-conferred drug resistance through dual AURKA/MAPK targeting in human melanoma cells

    PubMed Central

    Pathria, G; Garg, B; Borgdorff, V; Garg, K; Wagner, C; Superti-Furga, G; Wagner, S N

    2016-01-01

    MITF (microphthalmia-associated transcription factor) is a frequently amplified lineage-specific oncogene in human melanoma, whose role in intrinsic drug resistance has not been systematically investigated. Utilizing chemical inhibitors for major signaling pathways/cellular processes, we witness MITF as an elicitor of intrinsic drug resistance. To search kinase(s) targets able to bypass MITF-conferred drug resistance, we employed a multi-kinase inhibitor-directed chemical proteomics-based differential affinity screen in human melanocytes carrying ectopic MITF overexpression. A subsequent methodical interrogation informed mitotic Ser/Thr kinase Aurora Kinase A (AURKA) as a crucial regulator of melanoma cell proliferation and migration, independent of the underlying molecular alterations, including TP53 functional status and MITF levels. Crucially, assessing the efficacy of investigational AURKA inhibitor MLN8237, we pre-emptively witness the procurement of a molecular program consistent with acquired drug resistance. This involved induction of multiple MAPK (mitogen-activated protein kinase) signaling pathway components and their downstream proliferation effectors (Cyclin D1 and c-JUN) and apoptotic regulators (MITF and Bcl-2). A concomitant AURKA/BRAF and AURKA/MEK targeting overcame MAPK signaling activation-associated resistance signature in BRAF- and NRAS-mutated melanomas, respectively, and elicited heightened anti-proliferative activity and apoptotic cell death. These findings reveal a previously unreported MAPK signaling-mediated mechanism of immediate resistance to AURKA inhibitors. These findings could bear significant implications for the application and the success of anti-AURKA approaches that have already entered phase-II clinical trials for human melanoma. PMID:26962685

  12. Overcoming MITF-conferred drug resistance through dual AURKA/MAPK targeting in human melanoma cells.

    PubMed

    Pathria, G; Garg, B; Borgdorff, V; Garg, K; Wagner, C; Superti-Furga, G; Wagner, S N

    2016-01-01

    MITF (microphthalmia-associated transcription factor) is a frequently amplified lineage-specific oncogene in human melanoma, whose role in intrinsic drug resistance has not been systematically investigated. Utilizing chemical inhibitors for major signaling pathways/cellular processes, we witness MITF as an elicitor of intrinsic drug resistance. To search kinase(s) targets able to bypass MITF-conferred drug resistance, we employed a multi-kinase inhibitor-directed chemical proteomics-based differential affinity screen in human melanocytes carrying ectopic MITF overexpression. A subsequent methodical interrogation informed mitotic Ser/Thr kinase Aurora Kinase A (AURKA) as a crucial regulator of melanoma cell proliferation and migration, independent of the underlying molecular alterations, including TP53 functional status and MITF levels. Crucially, assessing the efficacy of investigational AURKA inhibitor MLN8237, we pre-emptively witness the procurement of a molecular program consistent with acquired drug resistance. This involved induction of multiple MAPK (mitogen-activated protein kinase) signaling pathway components and their downstream proliferation effectors (Cyclin D1 and c-JUN) and apoptotic regulators (MITF and Bcl-2). A concomitant AURKA/BRAF and AURKA/MEK targeting overcame MAPK signaling activation-associated resistance signature in BRAF- and NRAS-mutated melanomas, respectively, and elicited heightened anti-proliferative activity and apoptotic cell death. These findings reveal a previously unreported MAPK signaling-mediated mechanism of immediate resistance to AURKA inhibitors. These findings could bear significant implications for the application and the success of anti-AURKA approaches that have already entered phase-II clinical trials for human melanoma. PMID:26962685

  13. 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

  14. 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

  15. Investigational drugs to treat methicillin-resistant Staphylococcus aureus

    PubMed Central

    Vuong, Cuong; Yeh, Anthony J; Cheung, Gordon YC; Otto, Michael

    2016-01-01

    Introduction Staphylococcus aureus remains one of the leading causes of morbidity and mortality worldwide. This is to a large extent due to antibiotic-resistant strains, in particular methicillin-resistant S. aureus (MRSA). While the toll of invasive MRSA infections appears to decrease in U.S. hospitals, the rate of community-associated MRSA infections remains constant and there is a surge of MRSA in many other countries. This situation calls for continuing if not increased efforts to find novel strategies to combat MRSA infections. Areas covered This review will provide an overview of current investigational antibiotics in clinical development (up to phase II), and of therapeutic antibodies and alternative drugs against S. aureus in preclinical and clinical development, including a short description of the mechanism of action and a presentation of microbiological and clinical data. Expert opinion Increased recent antibiotic development efforts and results from pathogenesis research have led to several new antibiotics and alternative drugs, as well as a more informed selection of targets for vaccination efforts against MRSA. This developing portfolio of novel anti-staphylococcal drugs will hopefully provide us with additional and more efficient ways to combat MRSA infections in the near future and prevent us from running out of treatment options, even if new resistances arise. PMID:26536498

  16. 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

  17. [In vitro activity of tigecycline against multiple resistant Acinetobacter baumannii and carbapenem resistant Klebsiella pneumoniae isolates].

    PubMed

    Arikan Akan, Ozay; Uysal, Sevil

    2008-04-01

    In order to detect the in vitro activity of tigecycline against multiple resistant gram-negative bacilli isolated in our hospital, tigecycline susceptibilities of clinical isolates of multiple and/or panresistant 100 Acinetobacter baumannii isolates, and 38 carbapenem resistant Klebsiella pneumoniae (17 of which were panresistant), obtained between January 2005 and August 2007, were evaluated by using E-test (AB Biodisc, Sweden). Carbapenem resistance rate was found to be 59% for A.baumannii, using Vitek2 Compact System (Bio-Merieux, France) which is present in our laboratory for routine use. Minimal inhibitory concentration (MIC) levels for tigecycline were < or =2 mcg/ml in 93% of the isolates while the MIC level was 3 mcg/ml for 7% of the isolates. Tigecycline MIC50 and MIC 90 values were 1.5 and 2 mcg/ml, respectively. Among K. pneumoniae the least resistance was detected against amikacin (52.6% resistant) while tigecycline MIC levels were between 0.13 mcg/ml and 2 mcg/ml. All of the K.pneumoniae strains were susceptible to tigecycline, and the MIC50 ve MIC90 values of these isolates were 1 mcg/ml and 1.5 mcg/ml, respectively. The in vitro susceptibility rates of tigecycline against multiple and/or panresistant A. baumannii and K. pneumoniae isolates are found to be promising for use in therapy. PMID:18697418

  18. Mutation detection in the drug-resistant hepatitis B virus polymerase gene using nanostructured reverse micelles.

    PubMed

    Park, Lian-Chun; Maruyama, Tatsuo; Kamiya, Noriho; Goto, Masahiro; Kuma, Hiroyuki; Hamasaki, Naotaka

    2004-11-01

    The emergence of drug-resistant hepatitis B virus (HBV) has been reported in patients with prolonged administration of lamivudine, which is a potent drug for the prevention of HBV infection. Lamivudine-resistant HBV has several types of mutations at the YMDD motif of its DNA polymerase. We successfully demonstrated that monitoring the hybridization behavior in nanostructured reverse micelles enables us to detect single nucleotide polymorphisms (SNPs). With the aid of reverse micelles, a model 40-mer oligonucleotide containing a single-base substitution was clearly distinguished from the normal, complementary oligonucleotide. In addition, we extended this technique to a high-throughput analysis. The results obtained with a 96-well micro-plate reader indicated the possibility of SNPs detection toward multiple samples of patients. PMID:15566158

  19. Drug Resistance Mechanisms of Mycoplasma pneumoniae to Macrolide Antibiotics

    PubMed Central

    Liu, Xijie; Jiang, Yue; Chen, Xiaogeng; Li, Jing; Shi, Dawei; Xin, Deli

    2014-01-01

    Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae) infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC) around 32–512 mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive) were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance. PMID:24592385

  20. 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

    2016-01-01

    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

  1. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing

    PubMed Central

    Rhee, Soo-Yon; Jordan, Michael R.; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U.; Mukui, Irene; Hosseinipour, Mina C.; Frenkel, Lisa M.; Ndembi, Nicaise; Hamers, Raph L.; Rinke de Wit, Tobias F.; Wallis, Carole L.; Gupta, Ravindra K.; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M.; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F.; De Oliveira, Tulio; Wensing, Annemarie M. J.; Gallant, Joel E.; Wainberg, Mark A.; Richman, Douglas D.; Fitzgibbon, Joseph E.; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W.

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  2. HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing.

    PubMed

    Rhee, Soo-Yon; Jordan, Michael R; Raizes, Elliot; Chua, Arlene; Parkin, Neil; Kantor, Rami; Van Zyl, Gert U; Mukui, Irene; Hosseinipour, Mina C; Frenkel, Lisa M; Ndembi, Nicaise; Hamers, Raph L; Rinke de Wit, Tobias F; Wallis, Carole L; Gupta, Ravindra K; Fokam, Joseph; Zeh, Clement; Schapiro, Jonathan M; Carmona, Sergio; Katzenstein, David; Tang, Michele; Aghokeng, Avelin F; De Oliveira, Tulio; Wensing, Annemarie M J; Gallant, Joel E; Wainberg, Mark A; Richman, Douglas D; Fitzgibbon, Joseph E; Schito, Marco; Bertagnolio, Silvia; Yang, Chunfu; Shafer, Robert W

    2015-01-01

    The increasing prevalence of acquired and transmitted HIV-1 drug resistance is an obstacle to successful antiretroviral therapy (ART) in the low- and middle-income countries (LMICs) hardest hit by the HIV-1 pandemic. Genotypic drug resistance testing could facilitate the choice of initial ART in areas with rising transmitted drug resistance (TDR) and enable care-providers to determine which individuals with virological failure (VF) on a first- or second-line ART regimen require a change in treatment. An inexpensive near point-of-care (POC) genotypic resistance test would be useful in settings where the resources, capacity, and infrastructure to perform standard genotypic drug resistance testing are limited. Such a test would be particularly useful in conjunction with the POC HIV-1 viral load tests that are currently being introduced in LMICs. A POC genotypic resistance test is likely to involve the use of allele-specific point mutation assays for detecting drug-resistance mutations (DRMs). This study proposes that two major nucleoside reverse transcriptase inhibitor (NRTI)-associated DRMs (M184V and K65R) and four major NNRTI-associated DRMs (K103N, Y181C, G190A, and V106M) would be the most useful for POC genotypic resistance testing in LMIC settings. One or more of these six DRMs was present in 61.2% of analyzed virus sequences from ART-naïve individuals with intermediate or high-level TDR and 98.8% of analyzed virus sequences from individuals on a first-line NRTI/NNRTI-containing regimen with intermediate or high-level acquired drug resistance. The detection of one or more of these DRMs in an ART-naïve individual or in a individual with VF on a first-line NRTI/NNRTI-containing regimen may be considered an indication for a protease inhibitor (PI)-containing regimen or closer virological monitoring based on cost-effectiveness or country policy. PMID:26717411

  3. 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

  4. Exosomes in development, metastasis and drug resistance of breast cancer.

    PubMed

    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

    2015-08-01

    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

  5. Drug Resistance Strategies and Substance Use among Adolescents in Monterrey, Mexico

    PubMed Central

    Marsiglia, Flavio Francisco; Castillo, Jason; Becerra, David; Nieri, Tanya

    2011-01-01

    This study examined drug resistance strategies and substance use among adolescents from Monterrey, Mexico. The focus was strategies that U.S. adolescents use most often to resist using substances, including refuse (saying no), explain (declining with an explanation), avoid (staying away from situations where drugs are offered), and leave (exiting situations where drugs are offered). Using self-administered questionnaire data from a convenience sample of 327 Mexican students enrolled at two secondary schools (preparatorias), we tested whether frequent use of particular drug resistance strategies predicted actual substance use. Multiple regression results showed that different strategies were effective for different substances, that some effects were mediated by number of offers received, and that certain effects were stronger for females than for males. Students using the refuse strategy reported less cigarette use and less binge drinking; those using the avoid strategy reported less alcohol and cigarette use; and those using the leave strategy reported less binge drinking and, for females only, less marijuana use. Use of the explain strategy was not significantly related to substance use after controlling for use of other strategies. Findings are discussed in terms of Mexican cultural values and their implications for the design of prevention programs for Mexican youth. PMID:18365314

  6. Impact of mitochondrial telomerase over-expression on drug resistance of hepatocellular carcinoma

    PubMed Central

    Yan, Jing; Zhou, Yuan; Chen, Daixing; Li, Lili; Yang, Xin; You, Yang; Ling, Xianlong

    2015-01-01

    Background: The efficacy of chemotherapy in patients with hepatocellular carcinomas still poor due to multidrug resistance. This study aimed to investigate the impact of the over-expressed mitochondrial human telomerase reverse transcriptase on multidrug resistance of hepatocellular carcinomas. Methods: HepG2 and SK-Hep1 cell lines were used. And sensitivity to chemotherapeutic drugs was detected. Results: Mitochondrial human telomerase reverse transcriptase over-expression in hepatocellular carcinomas cells could significantly reduce its sensitivity to multiple chemotherapeutic drugs in vitro and in vivo. Hepatocellular carcinomas cells over-expressing mitochondrial human telomerase reverse transcriptase showed a significantly higher mitochondrial membrane potential, a markedly lower activated caspase-3 after drug treatment, and an increased mtDNA copy number, which explained the drastically decreased drug-induced apoptosis of hepatocellular carcinomas cells with mitochondrial human telomerase reverse transcriptase over-expression. Conclusion: Over-expressed mitochondrial human telomerase reverse transcriptase may increase the mtDNA copy number and inhibit the activation of mitochondrial apoptotic pathway to contribute to the multidrug resistance of hepatocellular carcinomas cells. PMID:25755831

  7. Doxorubicin loaded Polymeric Nanoparticulate Delivery System to overcome drug resistance in osteosarcoma

    PubMed Central

    2009-01-01

    Background Drug resistance is a primary hindrance for the efficiency of chemotherapy against osteosarcoma. Although chemotherapy has improved the prognosis of osteosarcoma patients dramatically after introduction of neo-adjuvant therapy in the early 1980's, the outcome has since reached plateau at approximately 70% for 5 year survival. The remaining 30% of the patients eventually develop resistance to multiple types of chemotherapy. In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure incurred from multidrug resistant (MDR) tumor cells, we explored the possibility of loading doxorubicin onto biocompatible, lipid-modified dextran-based polymeric nanoparticles and evaluated the efficacy. Methods Doxorubicin was loaded onto a lipid-modified dextran based polymeric nano-system. The effect of various concentrations of doxorubicin alone or nanoparticle loaded doxorubicin on KHOS, KHOSR2, U-2OS, and U-2OSR2 cells was analyzed. Effects on drug retention, immunofluorescence, Pgp expression, and induction of apoptosis were also analyzed. Results Dextran nanoparticles loaded with doxorubicin had a curative effect on multidrug resistant osteosarcoma cell lines by increasing the amount of drug accumulation in the nucleus via Pgp independent pathway. Nanoparticles loaded with doxorubicin also showed increased apoptosis in osteosarcoma cells as compared with doxorubicin alone. Conclusion Lipid-modified dextran nanoparticles loaded with doxorubicin showed pronounced anti-proliferative effects against osteosarcoma cell lines. These findings may lead to new treatment options for MDR osteosarcoma. PMID:19917123

  8. Device-Based Therapy for Drug-Resistant Hypertension: An Update.

    PubMed

    Li, Ping; Nader, Mark; Arunagiri, Kousalya; Papademetriou, Vasilios

    2016-08-01

    Drug-resistant hypertension (RH) remains a significant and common cardiovascular risk despite the availability of multiple potent antihypertensive medications. Uncontrolled resistant hypertension contributes substantially to excessive cardiovascular and renal morbidity and mortality. Clinical and experimental evidence suggest that sympathetic nervous system over-activity is the main culprit for the development and maintenance of drug-resistant hypertension. Both medical and interventional strategies, targeting the sympathetic over-activation, have been designed in patients with hypertension over the past few decades. Minimally invasive, catheter-based, renal sympathetic denervation (RDN) and carotid baroreceptor activation therapy (BAT) have been extensively evaluated in patients with RH in clinical trials. Current trial outcomes, though at times impressive, have been mostly uncontrolled trials in need of validation. Device-based therapy for drug-resistant hypertension has the potential to provide alternative treatment options to certain groups of patients who are refractory or intolerant to current antihypertensive medications. However, more research is needed to prove its efficacy in both animal models and in humans. In this article, we will review the evidence from recent renal denervation, carotid baroreceptor stimulation therapy, and newly emerged central arteriovenous anastomosis trials to pinpoint the weak links, and speculate on potential alternative approaches. PMID:27402013

  9. Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase

    SciTech Connect

    Yun, Mi-Kyung; Wu, Yinan; Li, Zhenmei; Zhao, Ying; Waddell, M. Brett; Ferreira, Antonio M.; Lee, Richard E.; Bashford, Donald; White, Stephen W.

    2013-04-08

    The sulfonamide antibiotics inhibit dihydropteroate synthase (DHPS), a key enzyme in the folate pathway of bacteria and primitive eukaryotes. However, resistance mutations have severely compromised the usefulness of these drugs. We report structural, computational, and mutagenesis studies on the catalytic and resistance mechanisms of DHPS. By performing the enzyme-catalyzed reaction in crystalline DHPS, we have structurally characterized key intermediates along the reaction pathway. Results support an S{sub N}1 reaction mechanism via formation of a novel cationic pterin intermediate. We also show that two conserved loops generate a substructure during catalysis that creates a specific binding pocket for p-aminobenzoic acid, one of the two DHPS substrates. This substructure, together with the pterin-binding pocket, explains the roles of the conserved active-site residues and reveals how sulfonamide resistance arises.

  10. [Occurrence and drug-resistance of beta-hemolytic streptococci].

    PubMed

    Mikołajczyk, Dorota; Budzyńska, Anna; Kaczmarek, Agnieszka; Gospodarek, Eugenia

    2007-01-01

    The aim of this study was the analysis of drug-resistance and frequency appearance of beta-hemolytic streptococci strains which were isolated in 2003-2005 in the University Hospital at the L. Rydygier Collegium Medicum in Bydgoszcz University of Nicolaus Copernicus in Toruń. Among investigeted beta-hemolytic streptococci the most frequency isolated species was S. agalactiae. All isolates examined in our study were susceptible to penicillin, the higest rate of resistance was found for tetracycline. The rates of resistence to macrolide-lincosamide-streptogramin B (phenotyp MLS(B)) were as follows: S. agalactiae (18.7%), S. pyogenes (10.1%), group G streptococci (10.6%) and group C streptococci (8.0%). In our study we presented also a special case patient from which in investigeted period S. agalactiae was isolated twenty eight times. For ten chromosomal DNA isolated from this patient three different PFGE profiles were obtained. PMID:18416122

  11. Catalysis and sulfa drug resistance in dihydropteroate synthase.

    PubMed

    Yun, Mi-Kyung; Wu, Yinan; Li, Zhenmei; Zhao, Ying; Waddell, M Brett; Ferreira, Antonio M; Lee, Richard E; Bashford, Donald; White, Stephen W

    2012-03-01

    The sulfonamide antibiotics inhibit dihydropteroate synthase (DHPS), a key enzyme in the folate pathway of bacteria and primitive eukaryotes. However, resistance mutations have severely compromised the usefulness of these drugs. We report structural, computational, and mutagenesis studies on the catalytic and resistance mechanisms of DHPS. By performing the enzyme-catalyzed reaction in crystalline DHPS, we have structurally characterized key intermediates along the reaction pathway. Results support an S(N)1 reaction mechanism via formation of a novel cationic pterin intermediate. We also show that two conserved loops generate a substructure during catalysis that creates a specific binding pocket for p-aminobenzoic acid, one of the two DHPS substrates. This substructure, together with the pterin-binding pocket, explains the roles of the conserved active-site residues and reveals how sulfonamide resistance arises. PMID:22383850

  12. Prevalence of Primary HIV Drug Resistance in Thailand Detected by Short Reverse Transcriptase Genotypic Resistance Assay

    PubMed Central

    Kiertiburanakul, Sasisopin; Pinsai, Subencha; Chantratita, Wasun; Pasomsub, Ekawat; Leechawengwongs, Manoon; Thipmontree, Wilawan; Siriyakorn, Nirada; Sungkanuparph, Somnuek

    2016-01-01

    Background HIV drug resistance (HIVDR) is the major cause of treatment failure after scaling up of antiretroviral therapy (ART). HIVDR testing prior to ART initiation is not routinely performed in resource-limited settings. We aimed to assess the prevalence of primary HIVDR by short reverse transcriptase (RT) genotypic resistance assay and evaluate of the impact of the mutations on the treatment outcomes. Methods A prospective cohort study was conducted in treatment-naïve HIV-infected patients. Fourteen major mutations of codon 99–191 on the RT gene were selected (K103N, V106A/M, V108I, Q151M, Y181C/I, M184V/I, Y188C/L/H, and G190S/A) at a cost of testing of 35 USD. The association between the presence of primary HIVDR and undetectable HIV RNA (<50 copies/mL) after 6 months of ART was determined. Results A total of 265 HIV-infected patients were included, with a median age of 35.2 (range, 16.8–75.2) years; 62.6% were males. The median (interquartile range) CD4 cell count at ART initiation was 216 (77–381) cells/mm3. The overall prevalence of primary HIVDR was 7.9%. The prevalence of each HIVDR mutation were K103N 6.0%, V106I 1.1%, V108I 0.4%, Y181C 2.3%, Y181I 0.7%, Y181V 0.4%, M184V 3.0%, M184I 1.5%, and G190A 2.3%. No associated factor of having primary HIVDR was determined. By multiple stepwise logistic regression, factors associated with undetectable HIV RNA after 6 months of ART were: having M184V/I (odds ratio [OR] 0.11; 95% confidence interval [CI] 0.02–0.62, p = 0.013), condom use (OR 2.38; 95% CI 1.12–5.06, p = 0.024), and adherence per 5% increase (OR 1.16; 95% CI 1.00–1.35, p = 0.044). Conclusions The prevalence of primary HIVDR is approximately 8%; it is associated with detectable HIV RNA at 6 months after ART initiation. Routine “short RT” genotypic resistance assay should be considered in resource-limited settings to maximize treatment outcome. PMID:26828876

  13. Using MALDI-TOF Mass Spectrometry to Identify Drug Resistant Staphylococcal Isolates from Nonhospital Environments in Brunei Darussalam.

    PubMed

    Chong, Ko S; Shazali, Siti A; Xu, Zhen; Cutler, Ronald R; Idris, Adi

    2016-01-01

    Drug resistant bacteria have been a growing threat to the community and hospitals due to the misuse of antibiotics by humans, industrialization, and lack of novel antimicrobials currently available. Little is known about the prevalence of drug resistant bacteria in nonhealthcare environments in Brunei Darussalam and about how antibiotic resistant genes are transferred within these environments. Human contact points from different types of environments in Brunei Darussalam, varying from urban to jungle settings, were swabbed and cultured onto selective media to isolate staphylococci bacteria before performing antimicrobial susceptibility testing on the isolates. The identity of the isolates was determined using MALDI-TOF mass spectrometry (MS). Staphylococci isolates resistant to oxacillin were further tested for their minimum inhibitory concentration (MIC). PCR analysis of the mecA gene, a gene that confers resistance to oxacillin, is done to determine the level of resistance to oxacillin. Ten different staphylococcal species were identified by MALDI-TOF-MS analysis. Out of the 36 staphylococci isolates, 24 were resistant to multiple antibiotics including two isolates which were oxacillin resistant. Some staphylococci isolates had similar antibiotic resistance profiles to other staphylococci isolates of different species in the same location. This work provides the first-ever evidence of drug resistant staphylococci in the nonhospital environment in Brunei Darussalam. PMID:27127505

  14. Using MALDI-TOF Mass Spectrometry to Identify Drug Resistant Staphylococcal Isolates from Nonhospital Environments in Brunei Darussalam

    PubMed Central

    Chong, Ko S.; Shazali, Siti A.; Xu, Zhen; Cutler, Ronald R.; Idris, Adi

    2016-01-01

    Drug resistant bacteria have been a growing threat to the community and hospitals due to the misuse of antibiotics by humans, industrialization, and lack of novel antimicrobials currently available. Little is known about the prevalence of drug resistant bacteria in nonhealthcare environments in Brunei Darussalam and about how antibiotic resistant genes are transferred within these environments. Human contact points from different types of environments in Brunei Darussalam, varying from urban to jungle settings, were swabbed and cultured onto selective media to isolate staphylococci bacteria before performing antimicrobial susceptibility testing on the isolates. The identity of the isolates was determined using MALDI-TOF mass spectrometry (MS). Staphylococci isolates resistant to oxacillin were further tested for their minimum inhibitory concentration (MIC). PCR analysis of the mecA gene, a gene that confers resistance to oxacillin, is done to determine the level of resistance to oxacillin. Ten different staphylococcal species were identified by MALDI-TOF-MS analysis. Out of the 36 staphylococci isolates, 24 were resistant to multiple antibiotics including two isolates which were oxacillin resistant. Some staphylococci isolates had similar antibiotic resistance profiles to other staphylococci isolates of different species in the same location. This work provides the first-ever evidence of drug resistant staphylococci in the nonhospital environment in Brunei Darussalam. PMID:27127505

  15. Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease

    PubMed Central

    Shapiro, Rebecca S.; Robbins, Nicole; Cowen, Leah E.

    2011-01-01

    Summary: Pathogenic fungi have become a leading cause of human mortality due to the increasing frequency of fungal infections in immunocompromised populations and the limited armamentarium of clinically useful antifungal drugs. Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus are the leading causes of opportunistic fungal infections. In these diverse pathogenic fungi, complex signal transduction cascades are critical for sensing environmental changes and mediating appropriate cellular responses. For C. albicans, several environmental cues regulate a morphogenetic switch from yeast to filamentous growth, a reversible transition important for virulence. Many of the signaling cascades regulating morphogenesis are also required for cells to adapt and survive the cellular stresses imposed by antifungal drugs. Many of these signaling networks are conserved in C. neoformans and A. fumigatus, which undergo distinct morphogenetic programs during specific phases of their life cycles. Furthermore, the key mechanisms of fungal drug resistance, including alterations of the drug target, overexpression of drug efflux transporters, and alteration of cellular stress responses, are conserved between these species. This review focuses on the circuitry regulating fungal morphogenesis and drug resistance and the impact of these pathways on virulence. Although the three human-pathogenic fungi highlighted in this review are those most frequently encountered in the clinic, they represent a minute fraction of fungal diversity. Exploration of the conservation and divergence of core signal transduction pathways across C. albicans, C. neoformans, and A. fumigatus provides a foundation for the study of a broader diversity of pathogenic fungi and a platform for the development of new therapeutic strategies for fungal disease. PMID:21646428

  16. Best-bet integrated strategies for containing drug-resistant trypanosomes in cattle

    PubMed Central

    2012-01-01

    Background African animal trypanosomosis is a major constraint to the rearing of productive livestock in the sub-humid Sudan-Sahel zone of West Africa where cotton is grown. Trypanosomosis is mainly controlled using trypanocidal drugs, but the effective use of drugs is threatened by the development of widespread resistance. This study tested integrated best-bet strategies for containment and/ or reversal of trypanocide resistance in villages in south-east Mali where resistance has been reported. Methods Four sentinel villages each from an intervention area (along the road from Mali to Burkina Faso) and a control area (along the road from Mali to Côte d’Ivoire) were selected for the study. Tsetse control was based on deltamethrin-treated stationary attractive devices and targeted cattle spraying between March 2008 and November 2009. Trypanosome-positive cattle were selectively treated with 3.5 mg/kg diminazene aceturate. Strategic helminth control using 10 mg/kg albendazole was also undertaken. During the intervention, tsetse densities along drainage lines, trypanosome infections and faecal egg counts in risk cattle (3 to 12 months of age) were monitored. Results Catch reductions of 66.5 % in Glossina palpalis gambiensis and 90 % in G. tachinoides were observed in the intervention area. Trypanosome prevalence was significantly (p < 0.05) lower in the intervention area (2.3 %; 1.3-3.6 %) compared to the control area (17.3 %; 14.8-20.1 %). Albendazole treatment resulted in a faecal egg count reduction of 55.6 % and reduced trypanosome infection risk (2.9 times lower than in the placebo group) although not significantly (p > 0.05). Further studies are required before confirming the existence of albendazole resistant strongyles in the study area. Conclusion Integration of best-bet strategies in areas of multiple drug-resistance is expected to reduce trypanosome infection risk thus contributing to containment of trypanocidal drug resistance

  17. Paradoxical resistance of multiple myeloma to proteasome inhibitors by decreased levels of 19S proteasomal subunits

    PubMed Central

    Acosta-Alvear, Diego; Cho, Min Y; Wild, Thomas; Buchholz, Tonia J; Lerner, Alana G; Simakova, Olga; Hahn, Jamie; Korde, Neha; Landgren, Ola; Maric, Irina; Choudhary, Chunaram; Walter, Peter; Weissman, Jonathan S; Kampmann, Martin

    2015-01-01

    Hallmarks of cancer, including rapid growth and aneuploidy, can result in non-oncogene addiction to the proteostasis network that can be exploited clinically. The defining example is the exquisite sensitivity of multiple myeloma (MM) to 20S proteasome inhibitors, such as carfilzomib. However, MM patients invariably acquire resistance to these drugs. Using a next-generation shRNA platform, we found that proteostasis factors, including chaperones and stress-response regulators, controlled the response to carfilzomib. Paradoxically, 19S proteasome regulator knockdown induced resistance to carfilzomib in MM and non-MM cells. 19S subunit knockdown did not affect the activity of the 20S subunits targeted by carfilzomib nor their inhibition by the drug, suggesting an alternative mechanism, such as the selective accumulation of protective factors. In MM patients, lower 19S levels predicted a diminished response to carfilzomib-based therapies. Together, our findings suggest that an understanding of network rewiring can inform development of new combination therapies to overcome drug resistance. DOI: http://dx.doi.org/10.7554/eLife.08153.001 PMID:26327694

  18. First report of multiple anthelmintic resistance in nematodes of sheep in Colombia.

    PubMed

    Gárcia, Carlos M B; Sprenger, Lew K; Ortiz, Efraín B; Molento, Marcelo B

    2016-03-01

    This study aimed to report the presence of parasites resistant to the most used anthelmintic drugs in sheep in Colombia. Four farms (denominated farm 1, 2, 3 and 4) were selected where the animals were not treated with anthelmintics for two months before the trial. Animals with faecal egg count (FEC) above 150 and of different ages were allocated into six groups, each consisting of at least 5 animals. The drugs and dosages used were: ivermectin 1% (0.2 mg/kg), albendazole 25% (5 mg/kg), fenbendazole 10% (5 mg/kg), levamisole 10% (5 mg/kg), and moxidectin 1% (0.2 mg/kg). Anthelmintic efficacy was determined by the FEC reduction test (FECRT) with a second sampling 14 days post-treatment. The efficacy of albendazole and fenbendazole at farm 1 was above 95%, which was different from the others farms. The FECRT indicated the presence of multidrug resistance in the other farms where no tested drugs showed activity higher than 79% (albendazole: 0 to 55%, fenbendazole: 51.4 to 76.6%, ivermectin: 67.3 to 93.1%, levamisole: 0 to 78.1%, and moxidectin: 49.2 to 64.1%).Haemonchus contortus was the predominant (96%) species, followed by a small presence of Trichostrongylus sp. (3%) andCooperia sp. (1%). Therefore, we report for the first time the existence of multiple anthelmintic resistance in gastrointestinal nematodes of sheep in Colombia. PMID:26871489

  19. A Method for Amplicon Deep Sequencing of Drug Resistance Genes in Plasmodium falciparum Clinical Isolates from India

    PubMed Central

    Rao, Pavitra N.; Uplekar, Swapna; Kayal, Sriti; Mallick, Prashant K.; Bandyopadhyay, Nabamita; Kale, Sonal; Singh, Om P.; Mohanty, Akshaya; Mohanty, Sanjib; Wassmer, Samuel C.

    2016-01-01

    A major challenge to global malaria control and elimination is early detection and containment of emerging drug resistance. Next-generation sequencing (NGS) methods provide the resolution, scalability, and sensitivity required for high-throughput surveillance of molecular markers of drug resistance. We have developed an amplicon sequencing method on the Ion Torrent PGM platform for targeted resequencing of a panel of six Plasmodium falciparum genes implicated in resistance to first-line antimalarial therapy, including artemisinin combination therapy, chloroquine, and sulfadoxine-pyrimethamine. The protocol was optimized using 12 geographically diverse P. falciparum reference strains and successfully applied to multiplexed sequencing of 16 clinical isolates from India. The sequencing results from the reference strains showed 100% concordance with previously reported drug resistance-associated mutations. Single-nucleotide polymorphisms (SNPs) in clinical isolates revealed a number of known resistance-associated mutations and other nonsynonymous mutations that have not been implicated in drug resistance. SNP positions containing multiple allelic variants were used to identify three clinical samples containing mixed genotypes indicative of multiclonal infections. The amplicon sequencing protocol has been designed for the benchtop Ion Torrent PGM platform and can be operated with minimal bioinformatics infrastructure, making it ideal for use in countries that are endemic for the disease to facilitate routine large-scale surveillance of the emergence of drug resistance and to ensure continued success of the malaria treatment policy. PMID:27008882

  20. A Method for Amplicon Deep Sequencing of Drug Resistance Genes in Plasmodium falciparum Clinical Isolates from India.

    PubMed

    Rao, Pavitra N; Uplekar, Swapna; Kayal, Sriti; Mallick, Prashant K; Bandyopadhyay, Nabamita; Kale, Sonal; Singh, Om P; Mohanty, Akshaya; Mohanty, Sanjib; Wassmer, Samuel C; Carlton, Jane M

    2016-06-01

    A major challenge to global malaria control and elimination is early detection and containment of emerging drug resistance. Next-generation sequencing (NGS) methods provide the resolution, scalability, and sensitivity required for high-throughput surveillance of molecular markers of drug resistance. We have developed an amplicon sequencing method on the Ion Torrent PGM platform for targeted resequencing of a panel of six Plasmodium falciparum genes implicated in resistance to first-line antimalarial therapy, including artemisinin combination therapy, chloroquine, and sulfadoxine-pyrimethamine. The protocol was optimized using 12 geographically diverse P. falciparum reference strains and successfully applied to multiplexed sequencing of 16 clinical isolates from India. The sequencing results from the reference strains showed 100% concordance with previously reported drug resistance-associated mutations. Single-nucleotide polymorphisms (SNPs) in clinical isolates revealed a number of known resistance-associated mutations and other nonsynonymous mutations that have not been implicated in drug resistance. SNP positions containing multiple allelic variants were used to identify three clinical samples containing mixed genotypes indicative of multiclonal infections. The amplicon sequencing protocol has been designed for the benchtop Ion Torrent PGM platform and can be operated with minimal bioinformatics infrastructure, making it ideal for use in countries that are endemic for the disease to facilitate routine large-scale surveillance of the emergence of drug resistance and to ensure continued success of the malaria treatment policy. PMID:27008882

  1. Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects

    PubMed Central

    Florea, Ana-Maria; Büsselberg, Dietrich

    2011-01-01

    Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects. PMID:24212665

  2. First-Line Treatment for Tuberculosis (TB), Drug Resistant TB -- A Visual Tour

    MedlinePlus

    ... Skip Content Marketing Share this: Main Content Area Tuberculosis Drugs First-Line Treatment of TB for Drug- ... ago. See how these drugs work . Multidrug-Resistant Tuberculosis (MDR TB) and Second-Line Treatments MDR TB ...

  3. Indirect Selection for Antibiotic Resistance in Multiple Stream Microhabitats

    NASA Astrophysics Data System (ADS)

    Wright, M. S.; Peltier, G. L.; McArthur, J.

    2005-05-01

    One aspect challenging public health efforts to minimize the spread of antibiotic resistance (AR) is the prevalence of resistant bacteria in the environment. Anthropogenic-derived sources of selection are typically implicated as mechanisms for maintaining AR in the environment. Here we report an additional mechanism for maintaining AR in the environment through co- or cross-resistance to heavy metals. Using culture-independent techniques, bacteria isolated from heavy-metal contaminated sites were more tolerant of antibiotics and metals compared to those bacteria from a reference site. This evidence supports our hypothesis that metal contamination directly selects for metal tolerant bacteria while indirectly selecting for antibiotic tolerant bacteria. Additionally, to assess how antibiotic- and metal-tolerance may be transported through a stream network, we studied antibiotic and metal-tolerance patterns over four months in bacteria collected from multiple stream microhabitats including water column, biofilm, sediment, and Corbicula fluminea (Asiatic clam) digestive tracts. Sediment bacteria were the most tolerant to antibiotics and metals, while bacteria from Corbicula were the least tolerant. Differences between these microhabitats may be important for predicting antibiotic resistance transfer and transport in stream environments. Further, temporal dynamics suggest that tolerance patterns within microhabitats are linked to physico-chemical characteristics of the stream.

  4. Reversing Cancer Multidrug Resistance in Xenograft Models via Orchestrating Multiple Actions of Functional Mesoporous Silica Nanoparticles.

    PubMed

    Yang, Debin; Wang, Tingfang; Su, Zhigui; Xue, Lingjing; Mo, Ran; Zhang, Can

    2016-08-31

    A multistimuli responsive drug delivery system (DDS) based on sulfhydryl and amino-cofunctionalized mesoporous silica nanoparticles (SH/NH2-MSNs) has been developed, in which the multifunctional hyaluronic acid (HA) derivatives were grafted onto the SH/NH2-MSNs by disulfide bonds for targeting delivery, controlling drug release and reversing multidrug resistance (MDR). The doxorubicin (Dox) loaded multifunctional HA derivatives modified mesoporous silica nanoparticles (Dox/HHS-MSNs) were enzyme and redox sensitive, which could respond to the intracellular stimuli of hyaluronidase (HAase) and glutathione (GSH) successively and prevent drug leakage before reaching the tumor tissues. The cellular uptake experiments showed that Dox/HHS-MSNs were vulnerable to be endocytosed into the Dox-resistant human breast adenocarcinoma (MCF-7/ADR) cells, efficiently realized the endolysosomal escape and remained in the cytoplasm. Because of orchestrating multiple actions above including active targeting, endolysosomal escape and efficient multilevel drug release, Dox/HHS-MSNs could induce the strongest apoptosis and cytotoxicity of MCF-7/ADR cells. Furthermore, a series of in vivo studies on MCF-7/ADR tumor-bearing xenograft mouse models demonstrated that Dox/HHS-MSNs possessed the enhanced tumor-targeting capacity and the best therapeutic efficacy to reverse cancer MDR. PMID:27420116

  5. Resistance profile and risk factors of drug resistant tuberculosis in the Baltic countries.

    PubMed

    Ignatyeva, Olga; Balabanova, Yanina; Nikolayevskyy, Vladyslav; Koshkarova, Ekaterina; Radiulyte, Birute; Davidaviciene, Edita; Riekstina, Vija; Jaama, Kadri; Danilovits, Manfred; Popa, Cristina M; Drobniewski, Francis A

    2015-09-01

    The rates of multi- and extensively drug-resistant tuberculosis (X/MDRTB) in the Baltic countries are the highest within the European Union hampering recent achievements of national TB control programmes. We included all consecutive culture-confirmed X/MDRTB patients registered for treatment in 2009 in Latvia, Lithuania and Estonia into this multicenter case-control study. Cases were compared with randomly selected controls with non-MDRTB registered for treatment in the same year across these sites. Of 495 MDRTB patients, 243 (49.7%) showed resistance to at least one second-line drug, 206 (42.1%) had pre-XDRTB (i.e. MDRTB with additional resistance to a second-line injectable or fluoroquinolones) and 64 (13.1%) had XDRTB. Younger age, male gender and known contact with an MDRTB case were associated with increased risk of primary infection with X/MDRTB strains. Previous treatment and alcohol abuse were strong predictors for MDRTB acquisition; defaults and failures in the past triggered XDRTB development. All patients received appropriate therapy; less than half of the patients were fully adherent. An erroneous treatment strategy is unlikely to drive resistance development. Increasing patients' compliance, addressing issues of social support, rapid detection of drug resistance and improving infection control is crucial for prevention of further spread of X/MDRTB and achieving higher cure rates. PMID:26164355

  6. Informatics tools to monitor progress and outcomes of patients with drug resistant tuberculosis in Peru.

    PubMed

    Fraser, Hamish S F; Jazayeri, Darius; Mitnick, Carole D; Mukherjee, Joia S; Bayona, Jaime

    2002-01-01

    Multi-drug resistant tuberculosis (MDR-TB) is an important and growing problem in many developing countries. New strategies have been developed to combat the disease but require complex treatment regimens and close monitoring of patients' bacteriology results. We describe a web-based medical record system deployed in Peru to support the management of MDR-TB. Web-based analyses have been developed to track drug sensitivity test results, patterns of sputum smear and culture results and time to conversion from positive to negative cultures. Individual and aggregate drug requirements can also be monitored in real time. Multiple analyses can be linked together and data can be graphed or downloaded to spreadsheets. Over 1200 patients are currently in the system. We argue that such a web-based clinical and epidemiological management system is an important component for successful implementation of complex health interventions in resource poor areas. PMID:12463829

  7. 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

  8. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux operon.

    PubMed Central

    Poole, K; Krebes, K; McNally, C; Neshat, S

    1993-01-01

    An outer membrane protein of 50 kDa (OprK) was overproduced in a siderophore-deficient mutant of Pseudomonas aeruginosa capable of growth on iron-deficient minimal medium containing 2,2'-dipyridyl (0.5 mM). The expression of OprK in the mutant (strain K385) was associated with enhanced resistance to a number of antimicrobial agents, including ciprofloxacin, nalidixic acid, tetracycline, chloramphenicol, and streptonigrin. OprK was inducible in the parent strain by growth under severe iron limitation, as provided, for example, by the addition of dipyridyl or ZnSO4 to the growth medium. The gene encoding OprK (previously identified as ORFC) forms part of an operon composed of three genes (ORFABC) implicated in the secretion of the siderophore pyoverdine. Mutants defective in ORFA, ORFB, or ORFC exhibited enhanced susceptibility to tetracycline, chloramphenicol, ciprofloxacin, streptonigrin, and dipyridyl, consistent with a role for the ORFABC operon in multiple antibiotic resistance in P. aeruginosa. Sequence analysis of ORFC (oprK) revealed that its product is homologous to a class of outer membrane proteins involved in export. Similarly, the products of ORFA and ORFB exhibit homology to previously described bacterial export proteins located in the cytoplasmic membrane. These data suggest that ORFA-ORFB-oprK (ORFC)-dependent drug efflux contributes to multiple antibiotic resistance in P. aeruginosa. We propose, therefore, the designation mexAB (multiple efflux) for ORFAB. Images PMID:8226684

  9. Comparative genomics of drug resistance in Trypanosoma brucei rhodesiense.

    PubMed

    Graf, Fabrice E; Ludin, Philipp; Arquint, Christian; Schmidt, Remo S; Schaub, Nadia; Kunz Renggli, Christina; Munday, Jane C; Krezdorn, Jessica; Baker, Nicola; Horn, David; Balmer, Oliver; Caccone, Adalgisa; de Koning, Harry P; Mäser, Pascal

    2016-09-01

    Trypanosoma brucei rhodesiense is one of the causative agents of human sleeping sickness, a fatal disease that is transmitted by tsetse flies and restricted to Sub-Saharan Africa. Here we investigate two independent lines of T. b. rhodesiense that have been selected with the drugs melarsoprol and pentamidine over the course of 2 years, until they exhibited stable cross-resistance to an unprecedented degree. We apply comparative genomics and transcriptomics to identify the underlying mutations. Only few mutations have become fixed during selection. Three genes were affected by mutations in both lines: the aminopurine transporter AT1, the aquaporin AQP2, and the RNA-binding protein UBP1. The melarsoprol-selected line carried a large deletion including the adenosine transporter gene AT1, whereas the pentamidine-selected line carried a heterozygous point mutation in AT1, G430R, which rendered the transporter non-functional. Both resistant lines had lost AQP2, and both lines carried the same point mutation, R131L, in the RNA-binding motif of UBP1. The finding that concomitant deletion of the known resistance genes AT1 and AQP2 in T. b. brucei failed to phenocopy the high levels of resistance of the T. b. rhodesiense mutants indicated a possible role of UBP1 in melarsoprol-pentamidine cross-resistance. However, homozygous in situ expression of UBP1-Leu(131) in T. b. brucei did not affect the sensitivity to melarsoprol or pentamidine. PMID:26973180

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

    PubMed Central

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

    2015-01-01

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

  11. Cisplatin Resistance: A Cellular Self-Defense Mechanism Resulting from Multiple Epigenetic and Genetic Changes

    PubMed Central

    Shen, Ding-Wu; Pouliot, Lynn M.; Hall, Matthew D.

    2012-01-01

    Cisplatin is one of the most effective broad-spectrum anticancer drugs. Its effectiveness seems to be due to the unique properties of cisplatin, which enters cells via multiple pathways and forms multiple different DNA-platinum adducts while initiating a cellular self-defense system by activating or silencing a variety of different genes, resulting in dramatic epigenetic and/or genetic alternations. As a result, the development of cisplatin resistance in human cancer cells in vivo and in vitro by necessity stems from bewilderingly complex genetic and epigenetic changes in gene expression and alterations in protein localization. Extensive published evidence has demonstrated that pleiotropic alterations are frequently detected during development of resistance to this toxic metal compound. Changes occur in almost every mechanism supporting cell survival, including cell growth-promoting pathways, apoptosis, developmental pathways, DNA damage repair, and endocytosis. In general, dozens of genes are affected in cisplatin-resistant cells, including pathways involved in copper metabolism as well as transcription pathways that alter the cytoskeleton, change cell surface presentation of proteins, and regulate epithelial-to-mesenchymal transition. Decreased accumulation is one of the most common features resulting in cisplatin resistance. This seems to be a consequence of numerous epigenetic and genetic changes leading to the loss of cell-surface binding sites and/or transporters for cisplatin, and decreased fluid phase endocytosis. PMID:22659329

  12. HIV drug resistance testing by high-multiplex "wide" sequencing on the MiSeq instrument.

    PubMed

    Lapointe, H R; Dong, W; Lee, G Q; Bangsberg, D R; Martin, J N; Mocello, A R; Boum, Y; Karakas, A; Kirkby, D; Poon, A F Y; Harrigan, P R; Brumme, C J

    2015-11-01

    Limited access to HIV drug resistance testing in low- and middle-income countries impedes clinical decision-making at the individual patient level. An efficient protocol to address this issue must be established to minimize negative therapeutic outcomes for HIV-1-infected individuals in such settings. This is an observational study to ascertain the potential of newer genomic sequencing platforms, such as the Illumina MiSeq instrument, to provide accurate HIV drug resistance genotypes for hundreds of samples simultaneously. Plasma samples were collected from Canadian patients during routine drug resistance testing (n = 759) and from a Ugandan study cohort (n = 349). Amplicons spanning HIV reverse transcriptase codons 90 to 234 were sequenced with both MiSeq sequencing and conventional Sanger sequencing methods. Sequences were evaluated for nucleotide concordance between methods, using coverage and mixture parameters for quality control. Consensus sequences were also analyzed for disparities in the identification of drug resistance mutations. Sanger and MiSeq sequencing was successful for 881 samples (80%) and 892 samples (81%), respectively, with 832 samples having results from both methods. Most failures were for samples with viral loads of <3.0 log10 HIV RNA copies/ml. Overall, 99.3% nucleotide concordance between methods was observed. MiSeq sequencing achieved 97.4% sensitivity and 99.3% specificity in detecting resistance mutations identified by Sanger sequencing. Findings suggest that the Illumina MiSeq platform can yield high-quality data with a high-multiplex "wide" sequencing approach. This strategy can be used for multiple HIV subtypes, demonstrating the potential for widespread individual testing and annual population surveillance in resource-limited settings. PMID:26282425

  13. Ceramide Glycosylation Catalyzed by Glucosylceramide Synthase and Cancer Drug Resistance

    PubMed Central

    Liu, Yong-Yu; Li, Yu-Teh

    2014-01-01

    Glucosylceramide synthase (GCS), converting ceramide to glucosylceramide, catalyzes the first reaction of ceramide glycosylation in sphingolipid metabolism. This glycosylation by GCS is a critical step regulating the modulation of cellular activities by controlling ceramide and glycosphingolipids (GSLs). An increase of ceramide in response to stresses, such as chemotherapy, drives cells to proliferation arrest and apoptosis or autophagy; however, ceramide glycosylation promptly eliminates ceramide and consequently, these induced processes, thus protecting cancer cells. Furthermore, persistently enhanced ceramide glycosylation can increase GSLs, participating in selecting cancer cells to drug resistance. GCS is overexpressed in diverse drug-resistant cancer cells and in tumors of breast, colon, and leukemia that display poor response to chemotherapy. As ceramide glycosylation by GCS is a rate-limiting step in GSL synthesis, inhibition of GCS sensitizes cancer cells to anticancer drugs and eradicates cancer stem cells. Mechanistic studies indicate that uncoupling ceramide glycosylation can modulate gene expression, decreasing MDR1 through the cSrc/β-catenin pathway and restoring p53 expression via RNA splicing. These studies not only expand our knowledge in understanding how ceramide glycosylation affects cancer cells, but also provide novel therapeutic approaches for targeting refractory tumors. PMID:23290777

  14. Map the gap: missing children with drug-resistant tuberculosis

    PubMed Central

    Yuen, C. M.; Rodriguez, C. A.; Keshavjee, S.

    2015-01-01

    Background: The lack of published information about children with multidrug-resistant tuberculosis (MDR-TB) is an obstacle to efforts to advocate for better diagnostics and treatment. Objective: To describe the lack of recognition in the published literature of MDR-TB and extensively drug-resistant TB (XDR-TB) in children. Design: We conducted a systematic search of the literature published in countries that reported any MDR- or XDR-TB case by 2012 to identify MDR- or XDR-TB cases in adults and in children. Results: Of 184 countries and territories that reported any case of MDR-TB during 2005–2012, we identified adult MDR-TB cases in the published literature in 143 (78%) countries and pediatric MDR-TB cases in 78 (42%) countries. Of the 92 countries that reported any case of XDR-TB, we identified adult XDR-TB cases in the published literature in 55 (60%) countries and pediatric XDR-TB cases for 9 (10%) countries. Conclusion: The absence of publications documenting child MDR- and XDR-TB cases in settings where MDR- and XDR-TB in adults have been reported indicates both exclusion of childhood disease from the public discourse on drug-resistant TB and likely underdetection of sick children. Our results highlight a large-scale lack of awareness about children with MDR- and XDR-TB. PMID:26400601

  15. Molecular pathways: mitogen-activated protein kinase pathway mutations and drug resistance.

    PubMed

    Pritchard, Antonia L; Hayward, Nicholas K

    2013-05-01

    Receptor tyrosine kinases are a diverse family of transmembrane proteins that can activate multiple pathways upon ligation of the receptor, one of which is the series of mitogen-activated protein kinase (MAPK) signaling cascades. The MAPK pathways play critical roles in a wide variety of cancer types, from hematologic malignancies to solid tumors. Aberrations include altered expression levels and activation states of pathway components, which can sometimes be attributable to mutations in individual members. The V600E mutation of BRAF was initially described in 2002 and has been found at particularly high frequency in melanoma and certain subtypes of colorectal cancer. In the relatively short time since this discovery, a family of drugs has been developed that specifically target this mutated BRAF isoform, which, after results from phase I/II and III clinical trials, was granted U.S. Food and Drug Administration approval in August 2011. Although these drugs produce clinically meaningful increases in progression-free and overall survival, due to acquired resistance they have not improved mortality rates. New drugs targeting other members of the MAPK pathways are in clinical trials or advanced stages of development. It is hoped that combination therapies of these new drugs in conjunction with BRAF inhibitors will counteract the mechanisms of resistance and provide cures. The clinical implementation of next-generation sequencing is leading to a greater understanding of the genetic architecture of tumors, along with acquired mechanisms of drug resistance, which will guide the development of tumor-specific inhibitors and combination therapies in the future. PMID:23406774

  16. In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.

    PubMed

    Neves, Bruno J; Braga, Rodolpho C; Bezerra, José C B; Cravo, Pedro V L; Andrade, Carolina H

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. PMID:25569258

  17. In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

    PubMed Central

    Neves, Bruno J.; Braga, Rodolpho C.; Bezerra, José C. B.; Cravo, Pedro V. L.; Andrade, Carolina H.

    2015-01-01

    Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes. PMID:25569258

  18. Pharmacogenetics of multiple sclerosis: personalized therapy with immunomodulatory drugs.

    PubMed

    Tsareva, Ekaterina; Kulakova, Olga; Boyko, Alexey; Favorova, Olga

    2016-03-01

    Pharmacogenetic (PG) studies aim to discover the individual genetic background that underlies the heterogeneity of treatment response, and thus find biomarkers for identification of individual patients who will benefit the most from the therapy administered or urgently require the alternate drug. Over the last decade, PG studies have made progress in terms of multiple sclerosis (MS), which is one of the most severe neurodegenerative diseases of the central nervous system. With the understanding of the role of the immune system in the pathogenesis of MS, a number of immunomodulatory drugs were developed for MS treatment management. However, clinical response to these disease-modifying therapies varies in individual patients. Interferon-β and glatiramer acetate showed the most reliable long-term safety and remain among the first-line disease-modifying therapies for MS worldwide. Here, we will review the results of interferon-β and glatiramer acetate PG studies with a detailed analysis of study design and approaches, their advantages and limitations, and future perspectives. PMID:26678572

  19. Salicylate intolerance: a masquerader of multiple adverse drug reactions

    PubMed Central

    Fernando, Suran Loshana; Clarke, Lesley R

    2009-01-01

    A female in her early 50s presented with a long-standing history of episodic urticaria and angioedema. She also reported urticarial reactions after ingestion of aspirin, prednisone and multiple antibiotics. These medications were all taken during upper respiratory tract infections. An elimination diet followed by a series of open challenges to food chemicals demonstrated an urticarial eruption following the ingestion of mints, which contain high levels of salicylates. A double-blinded placebo-controlled challenge to salicylate confirmed her sensitivity and explained her reaction to aspirin. The patient informed her treating physician of her copious ingestion of mints during upper respiratory tract infections. Drug hypersensitivity to antibiotics and prednisone was excluded on the basis of negative radioallergosorbent tests (RASTs) and/or absent skin-test responses and/or tolerance to oral challenges. This patient had a salicylate intolerance that caused her episodic urticaria and angioedema, and also masqueraded as a drug allergy due to the concurrent ingestion of mints. PMID:21918670

  20. A Platform for Rapid, Quantitative Assessment of Multiple Drug Combinations Simultaneously in Solid Tumors In Vivo

    PubMed Central

    Grenley, Marc O.; Casalini, Joseph R.; Tretyak, Ilona; Ditzler, Sally H.; Thirstrup, Derek J.; Frazier, Jason P.; Pierce, Daniel W.; Carleton, Michael; Klinghoffer, Richard A.

    2016-01-01

    While advances in high-throughput screening have resulted in increased ability to identify synergistic anti-cancer drug combinations, validation of drug synergy in the in vivo setting and prioritization of combinations for clinical development remain low-throughput and resource intensive. Furthermore, there is currently no viable method for prospectively assessing drug synergy directly in human patients in order to potentially tailor therapies. To address these issues we have employed the previously described CIVO platform and developed a quantitative approach for investigating multiple combination hypotheses simultaneously in single living tumors. This platform provides a rapid, quantitative and cost effective approach to compare and prioritize drug combinations based on evidence of synergistic tumor cell killing in the live tumor context. Using a gemcitabine resistant model of pancreatic cancer, we efficiently investigated nine rationally selected Abraxane-based combinations employing only 19 xenografted mice. Among the drugs tested, the BCL2/BCLxL inhibitor ABT-263 was identified as the one agent that synergized with Abraxane® to enhance acute induction of localized apoptosis in this model of human pancreatic cancer. Importantly, results obtained with CIVO accurately predicted the outcome of systemic dosing studies in the same model where superior tumor regression induced by the Abraxane/ABT-263 combination was observed compared to that induced by either single agent. This supports expanded use of CIVO as an in vivo platform for expedited in vivo drug combination validation and sets the stage for performing toxicity-sparing drug combination studies directly in cancer patients with solid malignancies. PMID:27359113

  1. Numerical modeling of the transmission dynamics of drug-sensitive and drug-resistant HSV-2

    NASA Astrophysics Data System (ADS)

    Gumel, A. B.

    2001-03-01

    A competitive finite-difference method will be constructed and used to solve a modified deterministic model for the spread of herpes simplex virus type-2 (HSV-2) within a given population. The model monitors the transmission dynamics and control of drug-sensitive and drug-resistant HSV-2. Unlike the fourth-order Runge-Kutta method (RK4), which fails when the discretization parameters exceed certain values, the novel numerical method to be developed in this paper gives convergent results for all parameter values.

  2. Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.

    PubMed

    Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A

    2015-01-23

    The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ≤0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. PMID:25502314

  3. Assessment of Microbiota and Their Drug Resistance in Chronic Fistulous Tracts

    PubMed Central

    Wu, Xiuwen; Li, Xiaoting; Liu, Song; Wu, Qin; Wang, Gefei; Gu, Guosheng; Ren, Huajian; Li, Jieshou

    2015-01-01

    Abstract Background: Bacteria colonizing an enterocutaneous fistula tract have not been clarified. The aims of this study were to investigate the pathogen spectra of fistulous tracts and their resistance to antibiotics in patients with chronic fistulas. Methods: We conducted a one-year prospective single-center study. In the absence of significant sepsis, consecutively stabilized patients with chronic enterocutaneous fistula were included. Microbiology and antimicrobial susceptibility of isolates from the tracts were analyzed. The correlations between the existence of bacteria and various clinical values were investigated further. Results: Forty-one patients were enrolled, of whom eight had a negative culture. A total of 48 bacterial strains were harvested, including 42 strains of gram-negative bacteria and six strains of gram-positive bacteria, most of which were multiple-drug-resistant. The three bacteria cultured most often were Escherichia coli (11 strains; 22.9%), Pseudomonas aeruginosa (eight strains; 16.7%), and Klebsiella pneumoniae (eight strains). Binary logistic regression analysis with forward (conditional) stepwise selection found that fistula length correlated with positive bacterial results (p=0.018). Other variables, namely entire length of hospitalization and fistula duration and location, were unrelated to the presence of micro-organisms in fistula tracts. Conclusions: Multiple-drug-resistant gram-negative bacteria were the main pathogens colonizing chronic fistula tracts. Fistula length was significantly associated with the presence of pathogens in a multivariable logistic regression model. PMID:25894837

  4. Candida Efflux ATPases and Antiporters in Clinical Drug Resistance.

    PubMed

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

    2016-01-01

    An enhanced expression of genes encoding ATP binding cassette (ABC) and major facilitator superfamily (MFS) transport proteins are known to contribute to the development of tolerance to antifungals in pathogenic yeasts. For example, the azole resistant (AR) clinical isolates of the opportunistic human fungal pathogen Candida albicans show an overexpression of CDR1 and/or CaMDR1 belonging to ABC and MFS, superfamilies, respectively. The reduced accumulation (due to rapid efflux) of drugs in AR isolates confirms the role of efflux pump proteins in the development of drug tolerance. Considering the importance of major multidrug transporters, the focus of recent research has been to understand the structure and function of these proteins which could help to design inhibitors/modulators of these pump proteins. This chapter focuses on some aspects of the structure and function of yeast transporter proteins particularly in relation to MDR in Candida. PMID:26721282

  5. Chrysin and its emerging role in cancer drug resistance.

    PubMed

    Kasala, Eshvendar Reddy; Bodduluru, Lakshmi Narendra; Barua, Chandana C; Gogoi, Ranadeep

    2015-07-01

    This letter illustrates the significant chemosensitizing effects of chrysin to resistance cancer cells and refers to the article on "Combination of chrysin and cisplatin promotes the apoptosis of Hep G2 cells by up-regulating p53" by Li et al., published in your journal recently. Recent studies have demonstrated that chrysin is able to sensitize or kill cancer cells which are resistant to chemotherapeutic drugs such as cisplatin, doxorubicin and adriamycin. Owing to its potential anti-cancer effects and devoid of toxicity to non-transformed cells, further research is required to completely explore its chemosensitizing effects in other cancers and also assess and evaluate its safety, before going for possible human application. PMID:25912556

  6. Role of integrated cancer nanomedicine in overcoming drug resistance.

    PubMed

    Iyer, Arun K; Singh, Amit; Ganta, Srinivas; Amiji, Mansoor M

    2013-11-01

    Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed. PMID:23880506

  7. 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

  8. Effects of pefloxacin in multi drug resistant typhoid Fever.

    PubMed

    Ullah, Zakir; Ahmed, Wilayat; Khan, Abdul Matin; Khan, M Farid; Qureshi, Ayaz Hussain; Khan, Ahmed

    2005-10-01

    In 28 children, with bacteriologically and/or serologically diagnosed typhoid fever treated at CMH, Rawalpindi in 2003, first one of the three recommended drugs (viz. chloramphenicol, amoxycillin or co-trimoxazole) was given for 7 days for defervescence to occur. In those who failed to respond a second trial of therapy with one of the other two drugs was initiated, after excluding the first drug. A second failure of therapy was taken as an indication to use pefloxacin singly. Finally, 18 (64.3%) cases responded to chloramphenicol or amoxycillin or co-trimoxazole. Pefloxacin was used in 10 (35.7%) cases. The failure rate of treatment with chloramphenicol was 50%, with amoxycillin 71.4% with co-trimoxazole 75% and 0% with pefloxacin. An analysis of the 28 cases revealed that apart from fever (in 100%), splenomegaly (in 82.1%) was the most important clinical indicator to diagnosis. along with absolute eosinopenia (in 71.4%). There were no major complications, except 2 cases with typhoid hepatitis that responded to choramphenicol and co-trimoxazole, respectively. Blood culture grew Salmonella typhi in 7 cases of which 5 (72%) were multi drug resistant S. typhi. PMID:16380360

  9. 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

  10. Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors

    PubMed Central

    Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

    2012-01-01

    The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

  11. Treatment Options for Carbapenem-Resistant and Extensively Drug-Resistant Acinetobacter baumannii Infections

    PubMed Central

    Viehman, J. Alexander; Nguyen, Minh-Hong; Doi, Yohei

    2014-01-01

    Acinetobacter baumannii is a leading cause of healthcare-associated infections worldwide. Due to various intrinsic and acquired mechanisms of resistance, most β-lactam agents are not effective against many strains, and carbapenems have played an important role in therapy. Recent trends show many infections are caused by carbapenem-resistant, or even extensively drug-resistant (XDR) strains, for which effective therapy is not well established. Evidence to date suggests that colistin constitutes the backbone of therapy, but the unique pharmacokinetic properties of colistin have led many to suggest the use of combination antimicrobial therapy. However, the combination of agents and dosing regimens that delivers the best clinical efficacy while minimizing toxicity is yet to be defined. Carbapenems, sulbactam, rifampin and tigecycline have been the most studied in the context of combination therapy. Most data regarding therapy for invasive, resistant A. baumannii infections come from uncontrolled case series and retrospective analyses, though some clinical trials have been completed and others are underway. Early institution of appropriate antimicrobial therapy is shown to consistently improve survival of patients with carbapenem-resistant and XDR A. baumannii infection, but the choice of empiric therapy in these infections remains an open question. This review summarizes the most current knowledge regarding the epidemiology, mechanisms of resistance, and treatment considerations of carbapenem-resistant and XDR A. baumannii. PMID:25091170

  12. Radiation induction of drug resistance in RIF-1: Correlation of tumor and cell culture results

    SciTech Connect

    Moulder, J.E.; Hopwood, L.E.; Volk, D.M.; Davies, B.M. )

    1991-02-01

    The RIF-1 tumor line contains cells that are resistant to various anti-neoplastic drugs, including 5-fluorouracil (5FU), methotrexate (MTX), adriamycin (ADR), and etoposide (VP16). The frequency of these drug-resistant cells is increased after irradiation. The frequency of drug-resistant cells and the magnitude of radiation-induced drug resistance are different in cell culture than in tumors. The dose-response and expression time relationships for radiation induction of drug resistance observed in RIF-1 tumors are unusual.We hypothesize that at high radiation doses in vivo, we are selecting for cells that are both drug resistant and radiation resistant due to microenvironmental factors, whereas at low radiation doses in vivo and all radiation doses in vitro, we are observing true mutants. These studies indicate that there can be significant differences in drug-resistance frequencies between tumors and their cell lines of origin, and that radiation induction of drug resistance depends significantly on whether the induction is done in tumors or in cell culture. These results imply that theories about the induction of drug resistance that are based on cell culture studies may be inapplicable to the induction of drug resistance in tumors.

  13. Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression

    PubMed Central

    Bourguignon, Lilly Y. W.

    2016-01-01

    Solid tumor invasion, metastasis and therapeutic drug resistance are the common causes for serious morbidity and cancer recurrence in patients. A number of research studies have searched for malignancy-related biomarkers and drug targets that are closely linked to tumor cell properties. One of the candidates is matrix hyaluronan (HA), which is known as one of the major extracellular matrix (ECM) components. HA serves as a physiological ligand for surface CD44 molecule and also functions as a bio-regulator. The binding of HA to CD44 has been shown to stimulate concomitant activation of a number of oncogenic pathways and abnormal cellular processes in cancer cells and cancer stem cells (CSCs). MicroRNAs (miRNAs) belong to a class of small RNAs containing ~20–25 nucleotides and are known to promote aberrant cellular functions in cancer cells. In this article, I have focused on the role of HA interaction with CD44 and several important signaling molecules in the regulation of unique miRNAs (e.g., miR-21, miR-302 and miR-10b) and their downstream targets leading to multiple tumor cell-specific functions (e.g., tumor cell growth, drug resistance and metastasis) and cancer progression. This new knowledge could provide the groundwork necessary for establishing new tumor markers and developing important, novel drugs targeted against HA/CD44-associated tumor progression, which can be utilized in the therapeutic treatment of metastatic cancer patients. PMID:27070574

  14. A Role for OCT4 in Tumor Initiation of Drug-Resistant Prostate Cancer Cells

    PubMed Central

    Linn, Douglas E.; Yang, Xi; Sun, Feng; Xie, Yingqiu; Chen, Hege; Jiang, Richeng; Chen, Hegang; Chumsri, Saranya; Burger, Angelika M.; Qiu, Yun

    2010-01-01

    Drug resistance remains a clinical challenge in cancer treatment due to poor understanding of underlying mechanisms. We have established several drug-resistant prostate cancer cell lines by long-term culture in medium containing chemotherapeutic drugs. These resistant lines displayed a significant increase in side population cells due to overexpression of drug efflux pumps including ABCG2/BCRP and MDR1/Pgp. To uncover potential mechanisms underlying drug resistance, we performed microarray analysis to identify differentially expressed genes in 2 drug-resistant lines. We observed that POU5F1/OCT4, a transcription factor key to regulating pluripotency in embryonic stem cells, was upregulated in drug-resistant lines and accompanied by transcriptional activation of a set of its known target genes. Upregulation of OCT4 in drug-resistant cells was validated by RT-PCR and sequencing of PCR products as well as confirmation by Western blot and specific shRNA knockdown. Analysis of the regulatory region of POU5F1/OCT4 revealed a reduction of methylation in drug-resistant cell lines. Furthermore, these drug-resistant cells exhibited a significant increase in tumorigenicity in vivo. Subcutaneous inoculation of as few as 10 drug-resistant cells could initiate tumor formation in SCID mice, whereas no detectable tumors were observed from the parental line under similar conditions, suggesting that these drug-resistant cells may be enriched for tumor-initiating cells. Knocking down OCT4 expression by specific shRNAs attenuated growth of drug-resistant cells. Our data suggest that OCT4 re-expression in cancer cells may play an important role in carcinogenesis and provide one possible mechanism by which cancer cells acquire/maintain a drug-resistant phenotype. PMID:21779471

  15. [Flunarizine in drug-resistant epilepsies of childhood and adolescence].

    PubMed

    Curatolo, P; Bruni, O; Brindesi, I; Pruna, D; Cusmai, R

    1986-01-01

    Therapeutic effects of flunarizine have been studied on 26 patients, aged from 9 months to 17 years, suffering for epilepsies resistant to common anticonvulsant treatment, despite proper plasmatic levels of drugs. All the cases were monitored with monthly clinical and EEG controls, neuropsychological evaluations and monitoring antiepileptic drugs plasmatic levels. At first, a study was performed on an intra-patient basis: after a basal observation during two months, an open clinical trial was started, using for three months flunarizine 5 mg a day in patients weighing over 10 kg, and 5 mg every two days in children weighing less than 10 kg. Later on, a simple blind clinical trial has been performed on 16 patients, using flunarizine or placebo for three months. The results, obtained in resistant epilepsy of children and adolescent, showed that flunarizine induced in 47.6% of cases a significant reduction of critical (stroke) frequency and intensity, together with normalization of sleeping-waking rhythm, and amelioration of attention performances (vigilance, reactivity, environmental participation). The only side-effect, noticed in 23.8% of cases, was a light diurnal sleepiness, spontaneously regressing after a few days of treatment. PMID:3086959

  16. Targeted drug-resistance testing strategy for multidrug-resistant tuberculosis detection, Lima, Peru, 2005-2008.

    PubMed

    Velásquez, Gustavo E; Yagui, Martin; Cegielski, J Peter; Asencios, Luis; Bayona, Jaime; Bonilla, Cesar; Jave, Hector O; Yale, Gloria; Suárez, Carmen; Atwood, Sidney; Contreras, Carmen C; Shin, Sonya S

    2011-03-01

    The Peruvian National Tuberculosis Control Program issued guidelines in 2006 specifying criteria for culture and drug-susceptibility testing (DST), including district-level rapid DST. All patients referred for culture and DST in 2 districts of Lima, Peru, during January 2005-November 2008 were monitored prospectively. Of 1,846 patients, 1,241 (67.2%) had complete DST results for isoniazid and rifampin; 419 (33.8%) patients had multidrug-resistant (MDR) TB at the time of referral. Among patients with new smear-positive TB, household contact and suspected category I failure were associated with MDR TB, compared with concurrent regional surveillance data. Among previously treated patients with smear-positive TB, adult household contact, suspected category II failure, early relapse after category I, and multiple previous TB treatments were associated with MDR TB, compared with concurrent regional surveillance data. The proportion of MDR TB detected by using guidelines was higher than that detected by a concurrent national drug-resistance survey, indicating that the strategy effectively identified patients for DST. PMID:21392434