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1

Building a Morbidostat: An automated continuous-culture device for studying bacterial drug resistance under dynamically sustained drug inhibition  

PubMed Central

We present a protocol for building and operating an automated fluidic system for continuous culture that we call the “morbidostat”. The morbidostat is used to follow evolution of microbial drug resistance in real time. Instead of exposing bacteria to predetermined drug environments, the morbidostat constantly measures the growth rates of evolving microbial populations and dynamically adjusts drug concentrations inside culture vials in order to maintain a constant drug induced inhibition. The growth rate measurements are done using an optical detection system that is based on measuring the intensity of back-scattered light from bacterial cells suspended in the liquid culture. The morbidostat can additionally be used as a chemostat or a turbidostat. The whole system can be built from readily available components within two to three weeks, by biologists with some electronics experience or engineers familiar with basic microbiology. PMID:23429717

Toprak, Erdal; Veres, Adrian; Yildiz, Sadik; Pedraza, Juan M.; Chait, Remy; Paulsson, Johan; Kishony, Roy

2013-01-01

2

Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs  

PubMed Central

Antibiotics are important adjuncts in the treatment of infectious diseases, including periodontitis. The most severe criticisms to the indiscriminate use of these drugs are their side effects and, especially, the development of bacterial resistance. The knowledge of the biological mechanisms involved with the antibiotic usage would help the medical and dental communities to overcome these two problems. Therefore, the aim of this manuscript was to review the mechanisms of action of the antibiotics most commonly used in the periodontal treatment (i.e. penicillin, tetracycline, macrolide and metronidazole) and the main mechanisms of bacterial resistance to these drugs. Antimicrobial resistance can be classified into three groups: intrinsic, mutational and acquired. Penicillin, tetracycline and erythromycin are broad-spectrum drugs, effective against gram-positive and gram-negative microorganisms. Bacterial resistance to penicillin may occur due to diminished permeability of the bacterial cell to the antibiotic; alteration of the penicillin-binding proteins, or production of ?-lactamases. However, a very small proportion of the subgingival microbiota is resistant to penicillins. Bacteria become resistant to tetracyclines or macrolides by limiting their access to the cell, by altering the ribosome in order to prevent effective binding of the drug, or by producing tetracycline/macrolide-inactivating enzymes. Periodontal pathogens may become resistant to these drugs. Finally, metronidazole can be considered a prodrug in the sense that it requires metabolic activation by strict anaerobe microorganisms. Acquired resistance to this drug has rarely been reported. Due to these low rates of resistance and to its high activity against the gram-negative anaerobic bacterial species, metronidazole is a promising drug for treating periodontal infections. PMID:22858695

SOARES, Geisla Mary Silva; FIGUEIREDO, Luciene Cristina; FAVERI, Marcelo; CORTELLI, Sheila Cavalca; DUARTE, Poliana Mendes; FERES, Magda

2012-01-01

3

Drug Resistance  

MedlinePLUS

... every day and exactly as prescribed. What is drug resistance? Once a person becomes infected with HIV, ... does poor medication adherence increase the risk of drug resistance? Medication adherence means taking HIV medicines every ...

4

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

PubMed

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

Gemmell, C G

1996-01-01

5

Hierarchical nested trial design (HNTD) for demonstrating treatment efficacy of new antibacterial drugs in patient populations with emerging bacterial resistance.  

PubMed

In the last decade or so, pharmaceutical drug development activities in the area of new antibacterial drugs for treating serious bacterial diseases have declined, and at the same time, there are worries that the increased prevalence of antibiotic-resistant bacterial infections, especially the increase in drug-resistant Gram-negative infections, limits available treatment options . A recent CDC report, 'Antibiotic Resistance Threats in the United States', indicates that antimicrobial resistance is one of our most serious health threats. However, recently, new ideas have been proposed to change this situation. An idea proposed in this regard is to conduct randomized clinical trials in which some patients, on the basis of a diagnostic test, may show presence of bacterial pathogens that are resistant to the control treatment, whereas remaining patients would show pathogens that are susceptible to the control. The control treatment in such trials can be the standard of care or the best available therapy approved for the disease. Patients in the control arm with resistant pathogens can have the option for rescue therapies if their clinical signs and symptoms worsen. A statistical proposal for such patient populations is to use a hierarchical noninferiority-superiority nested trial design that is informative and allows for treatment-to-control comparisons for the two subpopulations without any statistical penalty. This design can achieve in the same trial dual objectives: (i) to show that the new drug is effective for patients with susceptible pathogens on the basis of a noninferiority test and (ii) to show that it is superior to the control in patients with resistant pathogens. This paper addresses statistical considerations and methods for achieving these two objectives for this design. Published 2014. This article is a U.S. Government work and is in the public domain in the USA. PMID:24957660

Huque, Mohammad F; Valappil, Thamban; Soon, Guoxing Greg

2014-11-10

6

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

PubMed

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

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

2013-04-01

7

[Resistance to antituberculous drugs].  

PubMed

Mycobacteria responsible for tuberculosis (M. tuberculosis, M. bovis, M. africanum) are susceptible to a very small number of antibiotics. As soon as these drugs were used in humans all gave rise to the selection of resistant mycobacteria. Study of the mechanisms of acquired resistance, with the help of the genetics of mycobacteria, led to a more accurate understanding of the mode of action of antituberculous drugs. The antibiotics isoniazid, pyrazinamide, ethionamide and ethambutol are mycobacteria-specific because they inhibit the synthesis of mycolic acids, which are specific constituants of the bacterial wall. Mutations responsible for resistance to these drugs affect genes coding for activator enzymes (katg for isoniazid, pncA for pyrazinamide) or genes coding for their target (inhA for isoniazid/ethionamide, embB for ethambutol). With rifamycins, aminosides and quinolones, mechanisms of action and resistance are the same for mycobacteria as for non-mycobacterial organisms. No plasmid or resistance transposon has been described in M. tuberculosis. Currently a test for the quick detection of resistance to rifampicin is widely available but in the future DNA chips may allow the simultaneous detection of multiple resistances. Monitoring of antituberculous drugs shows that in France the prevalence of multiresistance ( resistance to both isoniazid and rifampicin) is 0.5%, primary resistance (before treatment) is 9%, and secondary resistance (after treatment) is 16%. PMID:16129320

Veziris, N; Cambau, E; Sougakoff, W; Robert, J; Jarlier, V

2005-08-01

8

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

PubMed Central

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

2014-01-01

9

Bacterial Resistance in Acne  

Microsoft Academic Search

Antibiotics play a major role in acne therapy. Physicians base treatment choices on personal perceptions of efficacy, cost-effectiveness or risk-benefit ratios and rarely take bacterial resistance into account. It is well documented that resistant strains of coagulase-negative staphylococci within the resident skin flora increase in both prevalence and population density as duration of therapy increases. Acne patients represent a considerable

E. A. Eady

1998-01-01

10

Recent trends on bacterial resistance to antibiotics.  

PubMed

Antimicrobial resistance has become a major medical and public health problem. The main factor responsible for development and spread of bacterial resistance is injudicious use of antimicrobial agents which has resulted in most gram positive and gram negative bacteria continuously developing resistance to the antimicrobials in regular use at different time periods. In East Africa, among E. coli in urinary tract infections, more than 80% are currently resistant to ampicillin, cotrimoxazole and tetracycline while more than 80% of the isolates are still susceptible to nitrofurantoin, gentamicin and third generation cephalosporins. Penicillin G resistant strains of pneumococci were first reported in 1967 but had gradually increased to about 20% in 1991. Among group A streptococci, all natural strains are still sensitive to penicillin G while resistance to tetracycline has reached alarming proportions. In Tanzania, more than 65% of N. gonorrhoeae isolates are beta-lactamase producers, however, spectinomycin, second and third generation cephalosporins and ciprofloxacin are effective against most strains. Vibrio cholerae 01 strains resistant to multiple antibiotics are widely spread globally, however, there are recent reports indicating that withdrawal of the drugs can lead to loss of the antibiotic resistance factors. Despite varied susceptibility of N. meningitidis strains world wide, isolates in Tanzania are still susceptible to commonly available drugs including penicillin G and chloramphenicol. Available methods for control of spread of bacterial resistance include rational use of antimicrobial agents including control in animal husbandry, change to newer antimicrobials, rotational use of drugs and constant surveillance for emerging bacterial resistance. PMID:9185405

Urassa, W; Lyamuya, E; Mhalu, F

1997-03-01

11

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

PubMed

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

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

2014-11-01

12

Targeting bacterial central metabolism for drug development.  

PubMed

Current antibiotics, derived mainly from natural sources, inhibit a narrow spectrum of cellular processes, namely DNA replication, protein synthesis, and cell wall biosynthesis. With the worldwide explosion of drug resistance, there is renewed interest in the investigation of alternate essential cellular processes, including bacterial central metabolic pathways, as a drug target space for the next generation of antibiotics. However, the validation of targets in central metabolism is more complex, as essentiality of such targets can be conditional and/or contextual. Bearing in mind our enhanced understanding of prokaryotic central metabolism, a key question arises: can central metabolism be bacteria's Achilles' heel and a therapeutic target for the development of new classes of antibiotics? In this review, we draw lessons from oncology and attempt to address some of the open questions related to feasibility of targeting bacterial central metabolism as a strategy for developing new antibacterial drugs. PMID:25442374

Murima, Paul; McKinney, John D; Pethe, Kevin

2014-11-20

13

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

PubMed Central

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

2014-01-01

14

Antimicrobial (Drug) Resistance  

MedlinePLUS

... Drug) Resistance Top Banner Content Area Skip Content Marketing Share this: Main Content Area Microbes, collectively, include ... on how microbes develop resistance, new and faster diagnostics, and clinical trials designed to find new vaccines ...

15

Drug-resistant Diarrheogenic Escherichia coli, Mexico  

PubMed Central

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

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

2005-01-01

16

Ethics and drug resistance.  

PubMed

This paper reviews the dynamics behind, and ethical issues associated with, the phenomenon of drug resistance. Drug resistance is an important ethical issue partly because of the severe consequences likely to result from the increase in drug resistant pathogens if more is not done to control them. Drug resistance is also an ethical issue because, rather than being a mere quirk of nature, the problem is largely a product of drug distribution. Drug resistance results from the over-consumption of antibiotics by the wealthy; and it, ironically, results from the under-consumption of antibiotics, usually by the poor or otherwise marginalized. In both kinds of cases the phenomenon of drug resistance illustrates why health (care)--at least in the context of infectious disease--should be treated as a (global) public good. The point is that drug resistance involves 'externalities' affecting third parties. When one patient develops a resistant strain of disease because of her over- or under-consumption of medication, this more dangerous malady poses increased risk to others. The propriety of free-market distribution of goods subject to externalities is famously dubious--given that the 'efficiency' rationale behind markets assumes an absence of externalities. Market failure in the context of drug resistance is partly revealed by the fact that no new classes of antibiotics have been developed since 1970. I conclude by arguing that the case of drug resistance reveals additional reasons--to those traditionally appealed to by bioethicists--for treating health care as something special when making policy decisions about its distribution. PMID:17845480

Selgelid, Michael J

2007-05-01

17

Influence of First-Line Antibiotics on the Antibacterial Activities of Acetone Stem Bark Extract of Acacia mearnsii De Wild. against Drug-Resistant Bacterial Isolates  

PubMed Central

Background. This study was aimed at evaluating the antibacterial activity of the acetone extract of A. mearnsii and its interactions with antibiotics against some resistant bacterial strains. Methods. The antibacterial susceptibility testing was determined by agar diffusion and macrobroth dilution methods while the checkerboard method was used for the determination of synergy between the antibiotics and the extract. Results. The results showed that the susceptibility of the different bacterial isolates was concentration dependent for the extract and the different antibiotics. With the exception of S. marcescens, the inhibition zones of the extract produced by 20?mg/mL ranged between 18 and 32?mm. While metronidazole did not inhibit any of the bacterial isolates, all the antibiotics and their combinations, except for ciprofloxacin and its combination, did not inhibit Enterococcus faecalis. The antibacterial combinations were more of being antagonistic than of being synergistic in the agar diffusion assay. From the macrobroth dilution, the extract and the antibiotics exerted a varied degree of inhibitory effect on the test organisms. The MIC values of the acetone extract which are in mg/mL are lower than those of the different antibiotics which are in ?g/mL. From the checkerboard assay, the antibacterial combinations showed varied degrees of interactions including synergism, additive, indifference, and antagonism interactions. While antagonistic and additive interactions were 14.44%, indifference interaction was 22.22% and synergistic interaction was 37.78% of the antibacterial combinations against the test isolates. While the additivity/indifference interactions indicated no interactions, the antagonistic interaction may be considered as a negative interaction that could result in toxicity and suboptimal bioactivity. Conclusion. The synergistic effects of the herbal-drug combinations may be harnessed for the discovery and development of more rational evidence-based drug combinations with optimized efficiency in the prevention of multidrug resistance and therapy of multifactorial diseases. PMID:25101132

Olajuyigbe, Olufunmiso O.; Coopoosamy, Roger M.

2014-01-01

18

Influence of First-Line Antibiotics on the Antibacterial Activities of Acetone Stem Bark Extract of Acacia mearnsii De Wild. against Drug-Resistant Bacterial Isolates.  

PubMed

Background. This study was aimed at evaluating the antibacterial activity of the acetone extract of A. mearnsii and its interactions with antibiotics against some resistant bacterial strains. Methods. The antibacterial susceptibility testing was determined by agar diffusion and macrobroth dilution methods while the checkerboard method was used for the determination of synergy between the antibiotics and the extract. Results. The results showed that the susceptibility of the different bacterial isolates was concentration dependent for the extract and the different antibiotics. With the exception of S. marcescens, the inhibition zones of the extract produced by 20?mg/mL ranged between 18 and 32?mm. While metronidazole did not inhibit any of the bacterial isolates, all the antibiotics and their combinations, except for ciprofloxacin and its combination, did not inhibit Enterococcus faecalis. The antibacterial combinations were more of being antagonistic than of being synergistic in the agar diffusion assay. From the macrobroth dilution, the extract and the antibiotics exerted a varied degree of inhibitory effect on the test organisms. The MIC values of the acetone extract which are in mg/mL are lower than those of the different antibiotics which are in ?g/mL. From the checkerboard assay, the antibacterial combinations showed varied degrees of interactions including synergism, additive, indifference, and antagonism interactions. While antagonistic and additive interactions were 14.44%, indifference interaction was 22.22% and synergistic interaction was 37.78% of the antibacterial combinations against the test isolates. While the additivity/indifference interactions indicated no interactions, the antagonistic interaction may be considered as a negative interaction that could result in toxicity and suboptimal bioactivity. Conclusion. The synergistic effects of the herbal-drug combinations may be harnessed for the discovery and development of more rational evidence-based drug combinations with optimized efficiency in the prevention of multidrug resistance and therapy of multifactorial diseases. PMID:25101132

Olajuyigbe, Olufunmiso O; Coopoosamy, Roger M

2014-01-01

19

Regulation of Bacterial Drug Export Systems  

PubMed Central

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

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

2002-01-01

20

Bacterial cheating limits antibiotic resistance  

NASA Astrophysics Data System (ADS)

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

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

2012-02-01

21

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

SciTech Connect

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

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

2000-10-01

22

Resistance to Bacterial Pathogens in Plants  

E-print Network

). Disease symptoms caused by bacterial pathogens include wilts, galls, specks, spots, cankers and chlorosis in causing soft-rot diseases in- duced by bacteria in the Erwinia genus. Basal Defence against BacterialResistance to Bacterial Pathogens in Plants Jules Ade, Indiana University, Bloomington, Indiana

Innes, Roger

23

Bacteremia and Antimicrobial Drug Resistance over Time, Ghana  

PubMed Central

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

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

2011-01-01

24

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

PubMed Central

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

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

2015-01-01

25

Comparative proteomics to evaluate multi drug resistance in Escherichia coli.  

PubMed

Drug resistance in food-borne bacterial pathogens is an almost inevitable consequence of the use of antimicrobial drugs, used either therapeutically or to avoid infections in food-producing animals. In the past decades, the spread and inappropriate use of antibiotics have caused a considerable increase of antibiotics to which bacteria have developed resistance and, moreover, bacteria are becoming resistant to more than one antibiotic simultaneously. Understanding mechanisms at the molecular level is extremely important to control multi-resistant strains and to develop new therapeutic strategies. In the present study, comparative proteomics was applied to characterize membrane and cytosolic proteome in order to investigate the regulation of protein expression in multi-resistance E. coli isolated from young never vaccinated water buffalo. Results highlighted differentially expressed proteins under multi drug resistance conditions giving new insights about mechanisms involved in resistance, as quorum sensing mechanisms, and suggesting possible novel bacterial targets to develop alternative antibiotic drugs. PMID:22120138

Piras, Cristian; Soggiu, Alessio; Bonizzi, Luigi; Gaviraghi, Alessandro; Deriu, Francesca; De Martino, Luisa; Iovane, Giuseppe; Amoresano, Angela; Roncada, Paola

2012-04-01

26

Bacterial resistance: how to detect three types.  

PubMed

Antimicrobial susceptibility testing in the clinical laboratory is becoming more complex. We can no longer be concerned with simply determining accurate susceptibilities. Microbiologists must now possess knowledge of bacterial-resistance mechanisms and implement procedures to reliably detect them. The traditional susceptibility test will most likely need to be supplemented with testing methods and software that allow for phenotypic identification of resistance mechanisms. Resistance mechanisms can be present in apparently susceptible bacterial populations. Accurate identification of these mechanisms will help to control emergence of new resistance by encouraging use of the most appropriate antibiotics. PMID:15119053

Shima, Susan M; Donahoe, Lawrence W

2004-04-01

27

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

PubMed

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

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

2015-05-01

28

Antibiotics and Bacterial Resistance in the 21st Century  

PubMed Central

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

Fair, Richard J; Tor, Yitzhak

2014-01-01

29

Communicating trends in resistance using a drug resistance index  

PubMed Central

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

Klugman, Keith P

2011-01-01

30

In vitro antibiotic resistance in bacterial keratitis in London  

PubMed Central

AIM—To document changes in the profile of bacterial isolates from cases of keratitis and changes in their susceptibility to first line antibiotic therapies.?METHODS—A retrospective review was performed of all bacterial isolates from cases of keratitis seen between 1984 and 1999. In vitro laboratory susceptibilities to antibiotics were determined by the Kirby-Bauer disc diffusion method. The number of isolates, changes in the proportion of bacterial types, and the number that were fully resistant to monotherapy (ofloxacin), dual therapy (gentamicin and cefuroxime), and prophylactic treatment (chloramphenicol) were calculated.?RESULTS—There were 1312 bacterial isolates over 16 years. Gram positive bacteria accounted for 54.7% of isolates and Staphylococcus species (33.4%) were the most frequently isolated organisms. During the study period there has been an increase in the proportion of Pseudomonas species isolates but no overall increase in the proportion of Gram negative isolates. There has not been an increase in the proportion of isolates resistant to ofloxacin since 1995 or an increase in resistance to the combination of gentamicin and cefuroxime. However, since 1984 there has been a significant increase in proportion of Gram negative organisms resistant to chloramphenicol (p=0.0019).?CONCLUSIONS—An increase in the in vitro resistance of organisms to first line therapies for bacterial keratitis has not been observed. An increased resistance to chloramphenicol indicates that this drug is unlikely to provide prophylactic cover when Gram negative infection is a risk. Continued monitoring for the emergence of antibiotic resistance is recommended.?? PMID:10873974

Tuft, S.; Matheson, M.

2000-01-01

31

Combination Approaches to Combat Multi-Drug Resistant Bacteria  

PubMed Central

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 ?-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

Worthington, Roberta J.; Melander, Christian

2013-01-01

32

Antibacterial Mechanisms of Polymyxin and Bacterial Resistance  

PubMed Central

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

Qin, Wangrong; Fang, Shisong; Qiu, Juanping

2015-01-01

33

Drug resistance and DNA repair  

Microsoft Academic Search

DNA repair confers resistance to anticancer drugs which kill cells by reacting with DNA. A review of our current information on the topic will be presented here. Our understanding of the molecular biology of repair of 06-alkylguanine adducts in DNA has advanced as a result of the molecular cloning of the E. coli ada gene but the precise role of

Margaret Fox; John J. Roberts

1987-01-01

34

Colourful parrot feathers resist bacterial degradation  

PubMed Central

The brilliant red, orange and yellow colours of parrot feathers are the product of psittacofulvins, which are synthetic pigments known only from parrots. Recent evidence suggests that some pigments in bird feathers function not just as colour generators, but also preserve plumage integrity by increasing the resistance of feather keratin to bacterial degradation. We exposed a variety of colourful parrot feathers to feather-degrading Bacillus licheniformis and found that feathers with red psittacofulvins degraded at about the same rate as those with melanin and more slowly than white feathers, which lack pigments. Blue feathers, in which colour is based on the microstructural arrangement of keratin, air and melanin granules, and green feathers, which combine structural blue with yellow psittacofulvins, degraded at a rate similar to that of red and black feathers. These differences in resistance to bacterial degradation of differently coloured feathers suggest that colour patterns within the Psittaciformes may have evolved to resist bacterial degradation, in addition to their role in communication and camouflage. PMID:20926430

Burtt, Edward H.; Schroeder, Max R.; Smith, Lauren A.; Sroka, Jenna E.; McGraw, Kevin J.

2011-01-01

35

Drug Resistance in Cancer: An Overview  

PubMed Central

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

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

2014-01-01

36

Determination of Bacterial Antibiotic Resistance Based on Osmotic Shock Response  

E-print Network

Determination of Bacterial Antibiotic Resistance Based on Osmotic Shock Response Scott M. Knudsen. This behavior can be used to differentiate between an antibiotic-resistant and an antibiotic-susceptible strain- sion of the SMR for rapid detection of antibiotic resistance. The buoyant densities of bacterial cells

Manalis, Scott

37

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

PubMed Central

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

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

1999-01-01

38

Bacterial Volatiles Induce Systemic Resistance in Arabidopsis1  

E-print Network

and Bacillus amyloliquefaciens IN937a, disease severity by the bacterial pathogen Erwinia carotovora subspBacterial Volatiles Induce Systemic Resistance in Arabidopsis1 Choong-Min Ryu2,3 , Mohamed A. Farag ISR. In Arabidopsis seedlings exposed to bacterial volatile blends from Bacillus subtilis GB03

Paré, Paul W.

39

Understanding drug resistance in human intestinal protozoa.  

PubMed

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

El-Taweel, Hend Aly

2015-05-01

40

Clinical Management of HIV Drug Resistance  

PubMed Central

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

Cortez, Karoll J.; Maldarelli, Frank

2011-01-01

41

Bacterial Carbonic Anhydrases as Drug Targets: Toward Novel Antibiotics?  

PubMed Central

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

Supuran, Claudiu T.

2011-01-01

42

77 FR 60126 - Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability  

Federal Register 2010, 2011, 2012, 2013, 2014

...for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability...industry entitled ``Acute Bacterial Otitis Media: Developing Drugs for Treatment...the treatment of acute bacterial otitis media (ABOM). This guidance finalizes...

2012-10-02

43

Bacterial and archaeal resistance to ionizing radiation  

NASA Astrophysics Data System (ADS)

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

Confalonieri, F.; Sommer, S.

2011-01-01

44

Pyrrolidine bis-cyclic guanidines with antimicrobial activity against drug-resistant Gram-positive pathogens  

E-print Network

, vancomycin-resistant Enterococcus faecalis (VRE), and two Gram-negative bacterial species. At least 20- resistant isolates of Enterococcus species (VRE), nosoco- mial pathogenic species with frequent multi-drug resistance to other agents such as ampicillin and amino- glycosides. Over 28% of Enterococcus spp

Nizet, Victor

45

Bacterial histidine kinases as novel antibacterial drug targets.  

PubMed

Bacterial histidine kinases (HKs) are promising targets for novel antibacterials. Bacterial HKs are part of bacterial two-component systems (TCSs), the main signal transduction pathways in bacteria, regulating various processes including virulence, secretion systems and antibiotic resistance. In this review, we discuss the biological importance of TCSs and bacterial HKs for the discovery of novel antibacterials, as well as published TCS and HK inhibitors that can be used as a starting point for structure-based approaches to develop novel antibacterials. PMID:25436989

Bem, Agnieszka E; Velikova, Nadya; Pellicer, M Teresa; Baarlen, Peter van; Marina, Alberto; Wells, Jerry M

2015-01-16

46

A model of antibiotic-resistant bacterial epidemics in hospitals  

E-print Network

A model of antibiotic-resistant bacterial epidemics in hospitals Glenn F. Webb , Erika M. C. D environments and to provide understanding of mea- sures to avoid the endemicity of resistant antibiotic strains human vectors. These bacteria also serve as a reservoir of antibiotic-resistance plasmids

Ruan, Shigui

47

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

PubMed Central

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

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

2015-01-01

48

Recovery and identification of bacterial DNA from illicit drugs.  

PubMed

Bacterial infections, including Bacillus anthracis (anthrax), are a common risk associated with illicit drug use, particularly among injecting drug users. There is, therefore, an urgent need to survey illicit drugs used for injection for the presence of bacteria and provide valuable information to health and forensic authorities. The objectives of this study were to develop a method for the extraction of bacterial DNA from illicit drugs and conduct a metagenomic survey of heroin and methamphetamine seized in the Australian Capital Territory during 2002-2011 for the presence of pathogens. Trends or patterns in drug contamination and their health implications for injecting drug users were also investigated. Methods based on the ChargeSwitch(®)gDNA mini kit (Invitrogen), QIAamp DNA extraction mini kit (QIAGEN) with and without bead-beating, and an organic phenol/chloroform extraction with ethanol precipitation were assessed for the recovery efficiency of both free and cellular bacterial DNA. Bacteria were identified using polymerase chain reaction and electrospray ionization-mass spectrometry (PCR/ESI-MS). An isopropanol pre-wash to remove traces of the drug and diluents, followed by a modified ChargeSwitch(®) method, was found to efficiently lyse cells and extract free and cellular DNA from Gram-positive and Gram-negative bacteria in heroin and methamphetamine which could then be identified by PCR/ESI-MS. Analysis of 12 heroin samples revealed the presence of DNA from species of Comamonas, Weissella, Bacillus, Streptococcus and Arthrobacter. No organisms were detected in the nine methamphetamine samples analysed. This study develops a method to extract and identify Gram-positive and Gram-negative bacteria from illicit drugs and demonstrates the presence of a range of bacterial pathogens in seized drug samples. These results will prove valuable for future work investigating trends or patterns in drug contamination and their health implications for injecting drug users as well as enabling forensic links between seizures to be examined. PMID:24447454

Cho, Kaymann T; Richardson, Michelle M; Kirkbride, K Paul; McNevin, Dennis; Nelson, Michelle; Pianca, Dennis; Roffey, Paul; Gahan, Michelle E

2014-02-01

49

MRSA, Clostridium difficile and Other Drug Resistant Bacteria Information for Patients and Families What is Drug Resistant Bacteria?  

E-print Network

MRSA, Clostridium difficile and Other Drug Resistant Bacteria Information for Patients and Families What is Drug Resistant Bacteria? Drug Resistant Bacteria also referred to as Multi Drug Resistant Bacteria? Drug Resistant Bacteria are germs that can not be treated by some antibiotics often used to treat

Oliver, Douglas L.

50

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...

51

SCREENING OF TRANSGENIC ANTHURIUMS FOR BACTERIAL BLIGHT AND NEMATODE RESISTANCE  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

52

Antituberculous drug resistance in central Haiti.  

PubMed

To determine the prevalence of antituberculous drug resistance in Haiti, we conducted a 1-yr survey in a central district. From a bacillary positive (smear and/or culture positive) case rate of 80/100,000, there were 282 patients from whom Mycobacterium tuberculosis was cultured. Each isolate was packaged and delivered to Canada where speciation and drug susceptibility testing were performed. Reported resistances are those using the proportions method (Laboratory Center for Disease Control, Ottawa, Canada). Resistance to one or more drugs was found in 22% of isolates. Age was the most important predictor of resistance in Haiti; resistance rates for age groups less than 14, 14 to 29, 30 to 44, greater than or equal to 45 were 8, 19, 22, and 31%, respectively. In patients not known to have received antituberculous drugs in the past, resistances were isoniazid (19%), streptomycin (5%), ethambutol (2%), ethionamide (2%), rifampin (1%). We conclude that antituberculous drug resistance is prevalent in Haiti, especially in older age groups, and that in persons with no known antituberculous drug use in the past, resistance to isoniazid is significant. PMID:2117870

Scalcini, M; Carré, G; Jean-Baptiste, M; Hershfield, E; Parker, S; Wolfe, J; Nelz, K; Long, R

1990-09-01

53

HIV-1 drug-resistance and drug-dependence  

PubMed Central

In this review, we will describe several recent HIV-1 studies in which a drug-dependent virus variant was selected. A common evolutionary route to the drug-dependence phenotype is proposed. First, the selection of a drug-resistance mutation that also affects the function of the targeted viral protein. Second, a compensatory mutation that repairs the protein function, but in the presence of the drug, which becomes an intrinsic part of the mechanism. The clinical relevance of drug-dependent HIV-1 variants is also discussed. PMID:17961213

Baldwin, Chris; Berkhout, Ben

2007-01-01

54

Emerging pathogens: Dynamics, mutation and drug resistance  

SciTech Connect

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.

Perelson, A.S.; Goldstein, B.; Korber, B.T. [and others

1997-10-01

55

A database of antimalarial drug resistance.  

PubMed

A large investment is required to develop, license and deploy a new antimalarial drug. Too often, that investment has been rapidly devalued by the selection of parasite populations resistant to the drug action. To understand the mechanisms of selection, detailed information on the patterns of drug use in a variety of environments, and the geographic and temporal patterns of resistance is needed. Currently, there is no publically-accessible central database that contains information on the levels of resistance to antimalaria drugs. This paper outlines the resources that are available and the steps that might be taken to create a dynamic, open access database that would include current and historical data on clinical efficacy, in vitro responses and molecular markers related to drug resistance in Plasmodium falciparum and Plasmodium vivax. The goal is to include historical and current data on resistance to commonly used drugs, like chloroquine and sulfadoxine-pyrimethamine, and on the many combinations that are now being tested in different settings. The database will be accessible to all on the Web. The information in such a database will inform optimal utilization of current drugs and sustain the longest possible therapeutic life of newly introduced drugs and combinations. The database will protect the valuable investment represented by the development and deployment of novel therapies for malaria. PMID:16774688

Sibley, Carol Hopkins; Ringwald, Pascal

2006-01-01

56

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

PubMed

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

Jung, Carina M

2014-01-01

57

Antibiotic Adjuvants: Diverse Strategies for Controlling Drug-Resistant Pathogens  

PubMed Central

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

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

2015-01-01

58

Elucidating drug resistance in human fungal pathogens.  

PubMed

Fungal pathogens cause life-threatening infections in immunocompetent and immunocompromised individuals. Millions of people die each year due to fungal infections, comparable to the mortality attributable to tuberculosis or malaria. The three most prevalent fungal pathogens are Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. Fungi are eukaryotes like their human host, making it challenging to identify fungal-specific therapeutics. There is a limited repertoire of antifungals in clinical use, and drug resistance and host toxicity compromise the clinical utility. The three classes of antifungals for treatment of invasive infections are the polyenes, azoles and echinocandins. Understanding mechanisms of resistance to these antifungals has been accelerated by global and targeted approaches, which have revealed that antifungal drug resistance is a complex phenomenon involving multiple mechanisms. Development of novel strategies to block the emergence of drug resistance and render resistant pathogens responsive to antifungals will be critical to treating life-threatening fungal infections. PMID:24810351

Xie, Jinglin Lucy; Polvi, Elizabeth J; Shekhar-Guturja, Tanvi; Cowen, Leah E

2014-01-01

59

Overcoming Drug Resistance in Pancreatic Cancer  

PubMed Central

Introduction Pancreatic cancer has the worst survival rate of all cancers. The current standard care for metastatic pancreatic cancer is gemcitabine, however, the success of this treatment is poor and overall survival has not improved for decades. Drug resistance (both intrinsic and acquired) is thought to be a major reason for the limited benefit of most pancreatic cancer therapies. Areas covered Previous studies have indicated various mechanisms of drug resistance in pancreatic cancer, including changes in individual genes or signaling pathways, the influence of the tumor microenvironment, and the presence of highly resistant stem cells. This review summarizes recent advances in the mechanisms of drug resistance in pancreatic cancer, and potential strategies to overcome this. Expert Opinion Increasing drug delivery efficiency and decreasing drug resistance is the current aim in pancreatic cancer treatment, and will also benefit the treatment of other cancers. Understanding the molecular and cellular basis of drug resistance in pancreatic cancer will lead to the development of novel therapeutic strategies with the potential to sensitize pancreatic cancer to chemotherapy, and to increase the efficacy of current treatments in a wide variety of human cancers. PMID:21391891

Long, Jiang; Zhang, Yuqing; Yu, Xianjun; Yang, Jingxuan; LeBrun, Drake; Chen, Changyi; Yao, Qizhi; Li, Min

2011-01-01

60

Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme  

SciTech Connect

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

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

2011-08-12

61

Introduction Treatment resistance in antidepressant drug therapy  

E-print Network

Introduction Treatment resistance in antidepressant drug therapy Major depressive disorder (MDD of Pharmacogenetic Diagnostics in Antidepressant Drug Treatment of Major Depressive Disorders J. Kirchheiner1 L-system for bedside-genotyping. Key words Major depressive disorder ´ antidepressants ´ pharmacogenetics

62

Bacterial Cheating Limits the Evolution of Antibiotic Resistance  

NASA Astrophysics Data System (ADS)

The emergence of antibiotic resistance in bacteria is a significant health concern. Bacteria can gain resistance to the antibiotic ampicillin by acquiring a plasmid carrying the gene beta-lactamase, which inactivates the antibiotic. This inactivation may represent a cooperative behavior, as the entire bacterial population benefits from removal of the antibiotic. The presence of a cooperative mechanism of resistance suggests that a cheater strain - which does not contribute to breaking down the antibiotic - may be able to take advantage of resistant cells. We find experimentally that a ``sensitive'' bacterial strain lacking the plasmid conferring resistance can invade a population of resistant bacteria, even in antibiotic concentrations that should kill the sensitive strain. We use a simple model in conjunction with difference equations to explain the observed population dynamics as a function of cell density and antibiotic concentration. Our experimental difference equations resemble the logistic map, raising the possibility of oscillations or even chaotic dynamics.

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

2012-02-01

63

Antiretroviral Drug Resistance and Routine Therapy, Cameroon  

PubMed Central

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

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

2006-01-01

64

Bacterial-Resistant Infections in Resource-Limited Countries  

Microsoft Academic Search

\\u000a Considering that antibiotics play a crucial role in reducing morbidity and mortality due to bacterial infections, antibiotic\\u000a resistance is a major problem in resource-limited countries (RLCs) where there is a high burden of infectious diseases, resistance\\u000a rates are even higher than in industrialized countries, and therapeutical options are often unavailable or too expensive.\\u000a Multidrug-resistant organisms – e.g. Streptococcus pneumoniae, Salmonella

Alessandro Bartoloni; Eduardo Gotuzzo

65

NOTE: Dielectrophoretic assay of bacterial resistance to antibiotics  

NASA Astrophysics Data System (ADS)

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

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

2003-07-01

66

DNA sequence analysis of bacterial toxic heavy metal resistances  

Microsoft Academic Search

Bacterial plasmids have genes that confer highly specific resistances to As, Bi, Cd, Cu, Cr, Hg, Pb, Te, Zn, and other toxic\\u000a heavy metals. For each toxic cation or anion, generally a different resistance system exists, and these systems may be “linked”\\u000a together on multiple resistance plasmids. For Cd2+, AsO2\\u000a ?, AsO4\\u000a 3?, Hg2+, and organomercurials, DNA sequence analysis has

Simon Silver; Tapan K. Misra; Richard A. Laddaga

1989-01-01

67

The Prevalence of Resistant Bacterial Colonization in Chronic Hemodialysis Patients  

Microsoft Academic Search

Backgound: Hospitalized dialysis patients are at increased risk for colonization and infection with resistant bacterial strains. Methods: We performed a cross-sectional analysis of the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) colonization in 198 hemodialysis outpatients, 75 of whom had longitudinal screening data from prior hospitalization. Nasal specimens for MRSA, perirectal specimens for VRE, and permanent catheter

Alexander C. Hadley; Tobi B. Karchmer; Gregory B. Russell; Debra G. McBride; Barry I. Freedman

2007-01-01

68

Bioinformatics approach to predicting HIV drug resistance.  

PubMed

The emergence of drug resistance remains one of the most challenging issues in the treatment of HIV-1 infection. The extreme replication dynamics of HIV facilitates its escape from the selective pressure exerted by the human immune system and by the applied combination drug therapy. This article reviews computational methods whose combined use can support the design of optimal antiretroviral therapies based on viral genotypic and phenotypic data. Genotypic assays are based on the analysis of mutations associated with reduced drug susceptibility, but are difficult to interpret due to the numerous mutations and mutational patterns that confer drug resistance. Phenotypic resistance or susceptibility can be experimentally evaluated by measuring the inhibition of the viral replication in cell culture assays. However, this procedure is expensive and time consuming. PMID:16512780

Cordes, Frank; Kaiser, Rolf; Selbig, Joachim

2006-03-01

69

Mechanisms of Drug-Resistance in Kinases  

PubMed Central

Introduction Because of their important roles in disease and excellent “druggability”, kinases have become the second-largest drug target family. The great success of the BCR-ABL inhibitor imatinib in treating CML illustrates the high potential of kinase inhibitor (KI) therapeutics, but also unveiled a major limitation: the development of drug-resistance. This is a significant concern as KIs reach large patient populations for an expanding array of indications. Areas covered We provide an up-to-date understanding of the mechanisms through which KIs function, and through which cells can become KI-resistant. We review current and future approaches to overcome KI-resistance, focussing on currently approved KIs and KIs in clinical trials. We then discuss approaches to improve KI efficacy and overcome drug-resistance and novel approaches to develop less drug-resistance prone KI-therapeutics. Expert opinion Although drug-resistance is a concern for current KI-therapeutics, recent progress in our understanding of the underlying mechanisms and promising technological advances may overcome this limitation and provide powerful new therapeutics. PMID:21235428

Barouch-Bentov, Rina; Sauer, Karsten

2010-01-01

70

Beef carcass contamination in a slaughterhouse and prevalence of resistance to antimicrobial drugs in isolates of selected microbial species  

Microsoft Academic Search

Meat contaminating bacteria may be the direct cause of foodborne diseases and represent a potential cause for the drug resistance of human pathogenic agents. The prevalence and resistance to 17 antimicrobial drugs of isolates of selected bacterial species were investigated in 70 swabs of beef carcasses and 70 subsequent samples of beef meat. Molecular techniques (coagulase gene typing Staphylococcus aureus

J Schlegelová; E Nápravn??ková; M Dendis; R Horváth; J Bened??k; V Babák; E Kl??mová; P Navrátilová; A Šustá?ková

2004-01-01

71

Coinfection and the evolution of drug resistance.  

PubMed

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

Hansen, J; Day, T

2014-12-01

72

The Pharmacology of HIV Drug Resistance  

PubMed Central

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

Zdanowicz, Martin M.

2006-01-01

73

Antimalarial drug resistance and combination chemotherapy.  

PubMed Central

Antimarial drug resistance develops when spontaneously occurring parasite mutants with reduced susceptibility are selected, and are then transmitted. Drugs for which a single point mutation confers a marked reduction in susceptibility are particularly vulnerable. Low clearance and a shallow concentration-effect relationship increase the chance of selection. Use of combinations of antimalarials that do not share the same resistance mechanisms will reduce the chance of selection because the chance of a resistant mutant surviving is the product of the per parasite mutation rates for the individual drugs, multiplied by the number of parasites in an infection that are exposed to the drugs. Artemisinin derivatives are particularly effective combination partners because (i) they are very active antimalarials, producing up to 10,000-fold reductions in parasite biomass per asexual cycle; (ii) they reduce malaria transmissibility; and (iii) no resistance to these drugs has been reported yet. There are good arguments for no longer using antimalarial drugs alone in treatment, and instead always using a combination with artemisinin or one of its derivatives. PMID:10365399

White, N

1999-01-01

74

Antiviral drug resistance of human cytomegalovirus.  

PubMed

The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance. PMID:20930070

Lurain, Nell S; Chou, Sunwen

2010-10-01

75

Antiviral Drug Resistance of Human Cytomegalovirus  

PubMed Central

Summary: The study of human cytomegalovirus (HCMV) antiviral drug resistance has enhanced knowledge of the virological targets and the mechanisms of antiviral activity. The currently approved drugs, ganciclovir (GCV), foscarnet (FOS), and cidofovir (CDV), target the viral DNA polymerase. GCV anabolism also requires phosphorylation by the virus-encoded UL97 kinase. GCV resistance mutations have been identified in both genes, while FOS and CDV mutations occur only in the DNA polymerase gene. Confirmation of resistance mutations requires phenotypic analysis; however, phenotypic assays are too time-consuming for diagnostic purposes. Genotypic assays based on sequencing provide more rapid results but are dependent on prior validation by phenotypic methods. Reports from many laboratories have produced an evolving list of confirmed resistance mutations, although differences in interpretation have led to some confusion. Recombinant phenotyping methods performed in a few research laboratories have resolved some of the conflicting results. Treatment options for drug-resistant HCMV infections are complex and have not been subjected to controlled clinical trials, although consensus guidelines have been proposed. This review summarizes the virological and clinical data pertaining to HCMV antiviral drug resistance. PMID:20930070

Lurain, Nell S.; Chou, Sunwen

2010-01-01

76

Molecular evolution of bacterial ?-lactam resistance  

Microsoft Academic Search

Background: Two groups of penicillin-destroying enzymes, the class A and class C ?-lactamases, may have evolved from bacterial transpeptidases that transfer x-d-Ala-d-Ala peptides to the growing peptidoglycan during cell wall synthesis. Both the transpeptidases and the ?-lactamases are acylated by ?-lactam antibiotics such as penicillin, which mimic the peptide, but breakdown and removal of the antibiotic is much faster in

James R. Knox; Paul C. Moews; Jean-Marie Frere

1996-01-01

77

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

PubMed

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

Bektöre, Bayhan; Haznedaro?lu, Tunçer; Baylan, Orhan; Ozyurt, Mustafa; Ozkütük, Nuri; Satana, Dilek; Cavu?o?lu, Cengiz; Seber, Engin

2013-01-01

78

Drug resistance in trypanosomes; cross-resistance analyses  

PubMed Central

Eight strains of Trypanosoma rhodesiense, made resistant respectively to atoxyl, butarsen, acriflavine, stilbamidine, Surfen C, suramin, and pontamine sky blue 5BX, have been examined for cross-resistance to representatives of nine structurally dissimilar groups of trypanocide. On the basis of their predominant ionic form at blood pH, these groups are considered in three main classes: (a) feebly ionized (neutral aromatic arsenicals), (b) ionized as cations (melaminyl arsenicals and antimonials, acridine derivatives, diguanidines and diamidines, 6-aminoquinoline and 6-aminocinnoline derivatives, phenanthridinium derivatives, triphenylmethane dyes), and (c) ionized as anions (carboxylated aromatic arsenicals and sulphonated naphthylamine derivatives). The results are discussed in relation to those of other workers and to possible modes of trypanocidal drug action. Cross-resistance behaviour is not wholly explicable on an ionic basis; the results suggest that stereospecific structural changes associated with initial drug uptake occur in resistant trypanosomes. PMID:13844958

Williamson, J.; Rollo, I. M.

1959-01-01

79

Evaluation of Gene Mutations Involved in Drug Resistance in Mycobacterium Tuberculosis Strains Derived from Tuberculosis Patients in Mazandaran, Iran, 2013  

PubMed Central

Drug resistance (especially multiple drug resistance) in Mycobacterium tuberculosis makes global concerns in treatment and control of tuberculosis. Rapid diagnosis of drug resistant strains of the bacteria has vital importance in the prognosis of the disease. The aim of this study was to identify the mutations responsible for drug resistance in Mycobacterium tuberculosis strains derived from patients with tuberculosis using line probe assay (LPA) method which rapidly detect drug resistant strains and respective mutations. Sputum samples from tuberculosis patients were collected and cultured on Lowenstein– Jensen medium, and then the colonies of Mycobacterium tuberculosis from cultures of 54 bacterial positive cases were randomly chosen for DNA extraction. Bacterial DNA was extracted using standard Cetyl Trimethyl Ammonium Bromide (CTAB) method. In order to identify drug resistant strains and related mutations, LPA method was applied. Three subjects out of 54 investigated cases were resistant to quinolone (5.5%), and resistance to kanamycin/ amikacin, streptomycin, rifampin, and isoniazid were observed in 3 (5.5%), 4 (7.4%), 3 (5.5%), and 2 (3.7%) of the Mycobacterium tuberculosis strains, respectively. In the present study, 4 cases (7.4%) were detected to be resistant to more than one drug. Since LPA is a rapid method that simultaneously detects mutations involved in drug resistance, applying this method in the prediction of drug resistance and selecting appropriate treatment in tuberculosis patients is recommended. PMID:25317406

Babamahmoodi, Farhang; Mahdavi, Mohammad Reza; Jalali, Hossein; Talebi, Bita; Roshan, Payam; Mahdavi, Mehrad

2014-01-01

80

Aedesin: structure and antimicrobial activity against multidrug resistant bacterial strains.  

PubMed

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

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

2014-01-01

81

Aedesin: Structure and Antimicrobial Activity against Multidrug Resistant Bacterial Strains  

PubMed Central

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

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

2014-01-01

82

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

PubMed Central

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

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

2014-01-01

83

Plant pathology A new source of resistance to bacterial wilt  

E-print Network

Plant pathology A new source of resistance to bacterial wilt of eggplants obtained from a cross'Amélioration des Plantes, BP 1232, 97184 Pointe-à-Pitre Cedex; 2 INRA, station d'Amélioration des Plantes such as hot season planting (July- August) (Bereau and Messiaen, 1975) or plant- ing in poorly drained fields

Paris-Sud XI, Université de

84

Extensively drug-resistant tuberculosis, Pakistan.  

PubMed

Frequency of extensively drug-resistant tuberculosis in Pakistan increased from 1.5% in 2006 to 4.5% in 2009 (p<0.01). To understand the epidemiology, we genotyped selected strains by using spoligotyping, mycobacterial interspersed repetitive units-variable number of tandem repeats, and IS6110 restriction fragment length polymorphism analysis. PMID:20735937

Hasan, Rumina; Jabeen, Kauser; Ali, Asho; Rafiq, Yasraba; Laiq, Rabia; Malik, Babar; Tanveer, Mahnaz; Groenheit, Ramona; Ghebremichael, Solomon; Hoffner, Sven; Hasan, Zahra

2010-09-01

85

Mechanisms of Drug Resistance in Cancer Chemotherapy  

Microsoft Academic Search

The management of cancer involves procedures, which include surgery, radiotherapy and chemotherapy. Development of chemoresistance is a persistent problem during the treatment of local and disseminated disease. A plethora of cytotoxic drugs that selectively, but not exclusively, target actively proliferating cells include such diverse groups as DNA alkylating agents, antimetabolites, intercalating agents and mitotic inhibitors. Resistance constitutes a lack of

Y. A. Luqmani

2005-01-01

86

Antibiotic Resistance of Bacterial Litter Isolates  

Microsoft Academic Search

Use of antibiotics in subtherapeutic doses as growth-promoting feed additives for animal produc- tion is widespread in the U.S. and throughout the world. Previous studies by our research group concluded that size fractionation of poultry (broiler) litter followed by storage facilitated reutilization of litter as a soil amend- ment or bedding supplement. However, litter microbial contamination, including antibiotic-resistant popula- tions,

TIMOTHY R. KELLEY; O. C. PANCORBO; W. C. MERKA; H. M. BARNHART

87

Mechanisms of bacterial resistance to macrolide antibiotics  

Microsoft Academic Search

Macrolides have been used in the treatment of infectious diseases since the late 1950s. Since that time, a finding of antagonistic\\u000a action between erythromycin and spiramycin in clinical isolates1 led to evidence of the biochemical mechanism and to the current understanding of inducible or constitutive resistance to\\u000a macrolides mediated by erm genes containing, respectively, the functional regulation mechanism or constitutively

Yoshinori Nakajima

1999-01-01

88

Resistance to antibiotics targeted to the bacterial cell wall  

PubMed Central

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

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

2014-01-01

89

Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance  

NASA Astrophysics Data System (ADS)

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

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

2011-03-01

90

White Paper: Recommendations on the Conduct of Superiority and Organism-Specific Clinical Trials of Antibacterial Agents for the Treatment of Infections Caused by Drug-Resistant Bacterial Pathogens  

PubMed Central

There is a critical need for new pathways to develop antibacterial agents to treat life-threatening infections caused by highly resistant bacteria. Traditionally, antibacterial agents have been studied in noninferiority clinical trials that focus on one site of infection (eg, pneumonia, intra-abdominal infection). Conduct of superiority trials for infections caused by highly antibiotic-resistant bacteria represents a new, and as yet, untested paradigm for antibacterial drug development. We sought to define feasible trial designs of antibacterial agents that could enable conduct of superiority and organism-specific clinical trials. These recommendations are the results of several years of active dialogue among the white paper's drafters as well as external collaborators and regulatory officials. Our goal is to facilitate conduct of new types of antibacterial clinical trials to enable development and ultimately approval of critically needed new antibacterial agents. PMID:22891041

2012-01-01

91

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

SciTech Connect

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

Hoelzel, Christina S., E-mail: Christina.Hoelzel@wzw.tum.de [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany); Mueller, Christa [Institute for Agroecology, Organic Farming and Soil Protection, Bavarian State Research Center for Agriculture (LfL), Lange Point 12, 85354 Freising (Germany)] [Institute for Agroecology, Organic Farming and Soil Protection, Bavarian State Research Center for Agriculture (LfL), Lange Point 12, 85354 Freising (Germany); Harms, Katrin S. [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)] [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany); Mikolajewski, Sabine [Department for Quality Assurance and Analytics, Bavarian State Research Center for Agriculture (LfL), Lange Point 4, 85354 Freising (Germany)] [Department for Quality Assurance and Analytics, Bavarian State Research Center for Agriculture (LfL), Lange Point 4, 85354 Freising (Germany); Schaefer, Stefanie; Schwaiger, Karin; Bauer, Johann [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)] [Chair of Animal Hygiene, Technische Universitaet Muenchen, Weihenstephaner Berg 3, 85354 Freising (Germany)

2012-02-15

92

Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants.  

PubMed

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

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

2014-01-01

93

Antimicrobial Drug Resistance in Pathogens Causing Nosocomial Infections at a University Hospital in Taiwan, 1981-1999  

Microsoft Academic Search

To determine the distribution and antimicrobial drug resistance in bacterial pathogens causing nosocomial infections, surveillance data on nosocomial infections documented from 1981 to 1999 at National Taiwan Uni- versity Hospital were analyzed. During this period, 35,580 bacterial pathogens causing nosocomial infections were identified. Candida species increased considerably, ranking first by 1999 in the incidence of pathogens causing all nosocomial infections,

Po-Ren Hsueh; Mei-Ling Chen; Chun-Chuan Sun; Wen-Hwei Chen; Hui-Ju Pan; Li-Seh Yang; Shan-Chwen Chang; Shen-Wu Ho; Chin-Yu Lee; Wei-Chuan Hsieh; Kwen-Tay Luh

2002-01-01

94

Essential oils, a new horizon in combating bacterial antibiotic resistance.  

PubMed

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

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

2014-01-01

95

Essential Oils, A New Horizon in Combating Bacterial Antibiotic Resistance  

PubMed Central

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

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

2014-01-01

96

Current Perspectives on HIV-1 Antiretroviral Drug Resistance  

PubMed Central

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

Iyidogan, Pinar; Anderson, Karen S.

2014-01-01

97

Management of antiviral drug resistance in chronic hepatitis B.  

PubMed

Rescue antiviral treatment for patients with resistance to preexisting nucleos(t)ide analogues remains a clinical challenge. The correct choice of a first-line treatment of high potency and with a high genetic barrier to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and the emergence of drug resistance. The management of treatment failure and drug resistance requires a precise and accurate clinical and virologic monitoring. Combination treatment with antiviral drugs that belong to different groups is associated with a lower chance of developing resistance to rescue drugs. To guarantee better control of viral replication in patients with drug resistance, the addition of another drug without a cross resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. Long-term surveillance for treatment efficacy and possible emergence of drug resistance should be continued to prevent the emergence of multidrug-resistant strains. PMID:25206270

Bang, Ki Bae; Kim, Hong Joo

2014-09-01

98

Management of antiviral drug resistance in chronic hepatitis B  

PubMed Central

Rescue antiviral treatment for patients with resistance to preexisting nucleos(t)ide analogues remains a clinical challenge. The correct choice of a first-line treatment of high potency and with a high genetic barrier to achieve sustained long-term suppression of viral replication provides the best chance of preventing treatment failure and the emergence of drug resistance. The management of treatment failure and drug resistance requires a precise and accurate clinical and virologic monitoring. Combination treatment with antiviral drugs that belong to different groups is associated with a lower chance of developing resistance to rescue drugs. To guarantee better control of viral replication in patients with drug resistance, the addition of another drug without a cross resistance profile should be given as early as possible, preferably at the time when genotypic resistance emerges. Long-term surveillance for treatment efficacy and possible emergence of drug resistance should be continued to prevent the emergence of multidrug-resistant strains. PMID:25206270

Bang, Ki Bae; Kim, Hong Joo

2014-01-01

99

Challenges of drug-resistant malaria  

PubMed Central

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

Sinha, Shweta; Medhi, Bikash; Sehgal, Rakesh

2014-01-01

100

Genetic dissection of drug resistance in trypanosomes.  

PubMed

The trypanosomes cause two neglected tropical diseases, Chagas disease in the Americas and African trypanosomiasis in sub-Saharan Africa. Over recent years a raft of molecular tools have been developed enabling the genetic dissection of many aspects of trypanosome biology, including the mechanisms underlying resistance to some of the current clinical and veterinary drugs. This has led to the identification and characterization of key resistance determinants, including transporters for the anti-Trypanosoma brucei drugs, melarsoprol, pentamidine and eflornithine, and the activator of nifurtimox-benznidazole, the anti-Trypanosoma cruzi drugs. More recently, advances in sequencing technology, combined with the development of RNA interference libraries in the clinically relevant bloodstream form of T. brucei have led to an exponential increase in the number of proteins known to interact either directly or indirectly with the anti-trypanosomal drugs. In this review, we discuss these findings and the technological developments that are set to further revolutionise our understanding of drug-trypanosome interactions. The new knowledge gained should inform the development of novel interventions against the devastating diseases caused by these parasites. PMID:23552488

Alsford, Sam; Kelly, John M; Baker, Nicola; Horn, David

2013-10-01

101

The sociomicrobiology of antivirulence drug resistance: a proof of concept.  

PubMed

Antivirulence drugs disarm rather than kill pathogens and are thought to alleviate the problem of resistance, although there is no evidence to support this notion. Quorum sensing (QS) often controls cooperative virulence factor production and is therefore an attractive antivirulence target, for which inhibitors (QSI) have been developed. We designed a proof-of-principle experiment to investigate the impact of bacterial social interactions on the evolution of QSI resistance. We cocultured Pseudomonas aeruginosa QS-deficient mutants with small proportions of the QS-proficient wild type, which in the absence of QSI mimic QSI-sensitive and -resistant variants, respectively. We employed two different QS-dependent nutrients that are degraded by extracellular (public) and cell-associated (private) enzymes. QS mutants (QSI-sensitive mimics) behaved as social cheaters that delayed population growth and prevented enrichment of wild-type cooperators (QSI-resistant mimics) only when nutrient acquisition was public, suggesting that QSI resistance would not spread. This highlights the potential for antivirulence strategies that target cooperative behaviors and provides a conceptual framework for future studies. PMID:21990612

Mellbye, Brett; Schuster, Martin

2011-01-01

102

Drug Resistant Fetal Arrhythmia in Obstetric Cholestasis  

PubMed Central

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.

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

2015-01-01

103

Mining complex genotypic features for predicting HIV1 drug resistance  

Microsoft Academic Search

Motivation: Human immunodeficiency virus type 1 (HIV-1) evolves in human body, and its exposure to a drug often causes mutations that enhance the resistance against the drug. To design an effective pharmacotherapy for an individual patient, it is important to accurately predict the drug resistance based on genotype data. Notably, the resistance is not just the simple sum of the

Hiroto Saigo; Takeaki Uno; Koji Tsuda

2007-01-01

104

Marine bacterial communities are resistant to elevated carbon dioxide levels.  

PubMed

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

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

2014-12-01

105

Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery.  

PubMed

The increase in drug-resistant pathogenic bacteria has created an urgent demand for new antibiotics. Among the more attractive targets for the development of new antibacterial compounds are the enzymes of fatty acid biosynthesis. Although a number of potent inhibitors of microbial fatty acid biosynthesis have been discovered, few of these are clinically useful drugs. Several of these fatty acid biosynthesis inhibitors have potential as lead compounds in the development of new antibacterials. This review encompasses the known inhibitors and prospective targets for new antibacterials. PMID:11544358

Campbell, J W; Cronan, J E

2001-01-01

106

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

PubMed Central

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

Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

2013-01-01

107

Determination of Bacterial Antibiotic Resistance Based on Osmotic Shock Response  

PubMed Central

We investigate the buoyant mass of bacterial cells in real time with the suspended microchannel resonator (SMR) as the population recovers from an osmotic shock. The density of the culture medium is chosen such that the bacteria initially have a positive buoyant mass which becomes negative as they recover from the hyperosmotic stress. This behavior can be used to differentiate between an antibiotic-resistant and an antibiotic-susceptible strain of the pathogenic bacteria Citrobacter rodentium, and we propose a general approach for exploiting the high precision of the SMR for rapid detection of antibiotic resistance. PMID:20337387

Knudsen, Scott M.; von Muhlen, Marcio G.; Schauer, David B.; Manalis, Scott R.

2014-01-01

108

Engaging resistant adolescents in drug abuse treatment  

Microsoft Academic Search

In the first phase of a two-part treatment development study, families with a treatment-resistant drug-abusing adolescent (n = 42) were offered 12 sessions of Community Reinforcement and Family Training (CRAFT). This parent-focused intervention was designed to help parents facilitate their adolescents' entry into treatment, to support adolescents' subsequent behavior change, and to improve parent and family functioning. In the second

Holly Barrett Waldron; Sheryl Kern-Jones; Charles W. Turner; Thomas R. Peterson; Timothy J. Ozechowski

2007-01-01

109

What should be considered in the treatment of bacterial infections by multi-drug therapies: a mathematical perspective?  

PubMed

Bacterial infections are a global health concern with high levels of mortality and morbidity associated. The resistance of pathogens to drugs is one leading cause of this problem, being common the administration of multiple drugs to improve the therapeutic effects. This review critically explores diverse aspects involved in the treatment of bacterial infections through multi-drug therapies, from a mathematical and within-host perspectives. Five recent models were selected and are reviewed. These models fall into the following question: which drugs to select, the respective dose, the administration period to effectively eradicate the infection in the shortest period of time and with reduced side effects? In this analysis, three groups of variables were considered: pharmacokinetics, pharmacodynamics and disturbance variables. To date, there is no model that fully answers to this issue for a living organism and it is questionable whether this would be possible for any case of infection. PMID:25156320

Pimenta, Francisco; Abreu, Ana Cristina; Simões, Lúcia Chaves; Simões, Manuel

2014-07-01

110

Insect peptides with improved protease-resistance protect mice against bacterial infection.  

PubMed Central

At a time of the emergence of drug-resistant bacterial strains, the development of antimicrobial compounds with novel mechanisms of action is of considerable interest. Perhaps the most promising among these is a family of antibacterial peptides originally isolated from insects. These were shown to act in a stereospecific manner on an as-yet unidentified target bacterial protein. One of these peptides, drosocin, is inactive in vivo due to the rapid decomposition in mammalian sera. However, another family member, pyrrhocoricin, is significantly more stable, has increased in vitro efficacy against gram-negative bacterial strains, and if administered alone, as we show here, is devoid of in vitro or in vivo toxicity. At low doses, pyrrhocoricin protected mice against Escherichia coli infection, but at a higher dose augmented the infection of compromised animals. Analogs of pyrrhocoricin were, therefore, synthesized to further improve protease resistance and reduce toxicity. A linear derivative containing unnatural amino acids at both termini showed high potency and lack of toxicity in vivo and an expanded cyclic analog displayed broad activity spectrum in vitro. The bioactive conformation of native pyrrhocoricin was determined by nuclear magnetic resonance spectroscopy, and similar to drosocin, reverse turns were identified as pharmacologically important elements at the termini, bridged by an extended peptide domain. Knowledge of the primary and secondary structural requirements for in vivo activity of these peptides allows the design of novel antibacterial drug leads. PMID:10794416

Otvos, L.; Bokonyi, K.; Varga, I.; Otvos, B. I.; Hoffmann, R.; Ertl, H. C.; Wade, J. D.; McManus, A. M.; Craik, D. J.; Bulet, P.

2000-01-01

111

Overcoming drug resistance in multi-drug resistant cancers and microorganisms  

PubMed Central

Resistance development against multiple drugs is a common feature among many pathogens—including bacteria such as Pseudomonas aeruginosa, viruses, and parasites—and also among cancers. The reasons are two-fold. Most commonly-used rationally-designed small molecule drugs or monoclonal antibodies, as well as antibiotics, strongly inhibit a key single step in the growth and proliferation of the pathogen or cancer cells. The disease agents quickly change or switch off this single target, or activate the efflux mechanisms to pump out the drug, thereby becoming resistant to the drug. A second problem is the way drugs are designed. The pharmaceutical industry chooses to use, by high-throughput screening, compounds that are maximally inhibitory to the key single step in the growth of the pathogen or cancer, thereby promoting selective pressure. An ideal drug would be one that inhibits multiple steps in the disease progression pathways with less stringency in these steps. Low levels of inhibition at multiple steps provide cumulative strong inhibitory effect, but little incentives or ability on the part of the pathogen/cancer to develop resistance. Such intelligent drug design involving multiple less stringent inhibitory steps is beyond the scope of the drug industry and requires evolutionary wisdom commonly possessed by bacteria. This review surveys assessments of the current clinical situation with regard to drug resistance in P. aeruginosa, and examines tools currently employed to limit this trend. We then provide a conceptual framework in which we explore the similarities between multi-drug resistance in pathogens and in cancers. We summarize promising work on anti-cancer drugs derived from the evolutionary wisdom of bacteria such as P. aeruginosa, and how such strategies can be the basis for how to look for candidate protein/peptide antibiotic drugs from bioengineered bugs. Such multi-domain proteins, unlike diffusible antibiotics, are not diffusible because of their large size and are often released only on contact with the perceived competitor. Thus, multi-domain proteins are missed during traditional methods of looking for growth zone inhibition of susceptible bacteria as demonstrated by antibiotics, but may represent the weapons of the future in the fights against both drug-resistant cancers and pathogens such as P. aeruginosa. PMID:22750915

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

2012-01-01

112

Drug resistance beyond extensively drug-resistant tuberculosis: individual patient data meta-analysis.  

PubMed

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95% CI 0.2-0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB. PMID:23060633

Migliori, Giovanni Battista; Sotgiu, Giovanni; Gandhi, Neel R; Falzon, Dennis; DeRiemer, Kathryn; Centis, Rosella; Hollm-Delgado, Maria-Graciela; Palmero, Domingo; Pérez-Guzmán, Carlos; Vargas, Mario H; D'Ambrosio, Lia; Spanevello, Antonio; Bauer, Melissa; Chan, Edward D; Schaaf, H Simon; Keshavjee, Salmaan; Holtz, Timothy H; Menzies, Dick

2013-07-01

113

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

PubMed

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

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

2013-11-01

114

Exploiting Nanotechnology to Overcome Tumor Drug Resistance: Challenges and Opportunities  

PubMed Central

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

Kirtane, Ameya; Kalscheuer, Stephen; Panyam, Jayanth

2013-01-01

115

Bacterial cheating limits the evolution of antibiotic resistance  

NASA Astrophysics Data System (ADS)

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

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

2011-03-01

116

Capsule Polysaccharide Mediates Bacterial Resistance to Antimicrobial Peptides  

PubMed Central

The innate immune system plays a critical role in the defense of areas exposed to microorganisms. There is an increasing body of evidence indicating that antimicrobial peptides and proteins (APs) are one of the most important weapons of this system and that they make up the protective front for the respiratory tract. On the other hand, it is known that pathogenic organisms have developed countermeasures to resist these agents such as reducing the net negative charge of the bacterial membranes. Here we report the characterization of a novel mechanism of resistance to APs that is dependent on the bacterial capsule polysaccharide (CPS). Klebsiella pneumoniae CPS mutant was more sensitive than the wild type to human neutrophil defensin 1, ?-defensin 1, lactoferrin, protamine sulfate, and polymyxin B. K. pneumoniae lipopolysaccharide O antigen did not play an important role in AP resistance, and CPS was the only factor conferring protection against polymyxin B in strains lacking O antigen. In addition, we found a significant correlation between the amount of CPS expressed by a given strain and the resistance to polymyxin B. We also showed that K. pneumoniae CPS mutant bound more polymyxin B than the wild-type strain with a concomitant increased in the self-promoted pathway. Taken together, our results suggest that CPS protects bacteria by limiting the interaction of APs with the surface. Finally, we report that K. pneumoniae increased the amount of CPS and upregulated cps transcription when grown in the presence of polymyxin B and lactoferrin. PMID:15557634

Campos, Miguel A.; Vargas, Miguel A.; Regueiro, Verónica; Llompart, Catalina M.; Albertí, Sebastián; Bengoechea, José A.

2004-01-01

117

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

PubMed Central

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

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

2003-01-01

118

Worldwide Emergence of Extensively Drug-resistant Tuberculosis  

Microsoft Academic Search

Mycobacterium tuberculosis strains that are resistant to an increasing number of second-line drugs used to treat multidrug-resistant tuberculosis (MDR TB) are becoming a threat to public health worldwide. We surveyed the Network of Supranational Reference Laboratories for M. tuberculo- sis isolates that were resistant to second-line anti-TB drugs during 2000-2004. We defined extensively drug-resistant TB (XDR TB) as MDR TB

N. Sarita Shah; Abigail Wright; Gill-Han Bai; Lucia Barrera; Fadila Boulahbal; Nuria Martín-Casabona; Francis Drobniewski; Chris Gilpin; Marta Havelková; Rosario Lepe; Richard Lumb; Beverly Metchock; Françoise Portaels; Maria Filomena Rodrigues; Sabine Rüsch-Gerdes; Armand Van Deun; Veronique Vincent; Kayla Laserson; Charles Wells; J. Peter Cegielski

2007-01-01

119

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

PubMed

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

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

2015-01-01

120

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

PubMed Central

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

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

2015-01-01

121

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

PubMed

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

Dey, Diganta; Ray, Ratnamala; Hazra, Banasri

2014-07-01

122

Drug resistance in Sudanese Trypanosoma evansi.  

PubMed

The drug sensitivities of 16 Trypanosoma evansi isolates from Sudan were examined using two different in vitro assays and rodent models. IC50 values (concentration which inhibited incorporation of 3H-hypoxanthine by 50%) obtained in a 40 h assay indicate that most of the isolates were resistant to suramin, a drug which has not been used in Sudan since 1975. Sensitivities for suramin in a 10-day-in vitro assay varied within a 124-fold range. The in vitro results were confirmed by infection/treatment experiments in mice. Sensitivities in vitro for quinapyramine varied within a 166-fold range. In mice, the least sensitive isolates were not cured with dosages up to 10 mg/kg quinapyramine. Based on in vitro results, all isolates appeared to be susceptible to isometamidium. PMID:9950334

El Rayah, I E; Kaminsky, R; Schmid, C; El Malik, K H

1999-01-28

123

Mycobacterium tuberculosis mutation rate estimates from different lineages predict substantial differences in the emergence of drug resistant tuberculosis  

PubMed Central

A critical question in tuberculosis control is why some strains of Mycobacterium tuberculosis are preferentially associated with multiple drug resistances. We demonstrate that M. tuberculosis strains from Lineage 2 (East Asian lineage and Beijing sublineage) acquire drug resistances in vitro more rapidly than M. tuberculosis strains from Lineage 4 (Euro-American lineage) and that this higher rate can be attributed to a higher mutation rate. Moreover, the in vitro mutation rate correlates well with the bacterial mutation rate in humans as determined by whole genome sequencing of clinical isolates. Finally, using a stochastic mathematical model, we demonstrate that the observed differences in mutation rate predict a substantially higher probability that patients infected with a drug susceptible Lineage 2 strain will harbor multidrug resistant bacteria at the time of diagnosis. These data suggest that interventions to prevent the emergence of drug resistant tuberculosis should target bacterial as well as treatment-related risk factors. PMID:23749189

Ford, Christopher B.; Shah, Rupal R.; Maeda, Midori Kato; Gagneux, Sebastien; Murray, Megan B.; Cohen, Ted; Johnston, James C.; Gardy, Jennifer; Lipsitch, Marc; Fortune, Sarah M.

2013-01-01

124

Multidrug-resistant bacterial isolates in infected wounds at Jimma University Specialized Hospital, Ethiopia  

PubMed Central

Background The term ’Multidrug-resistant’ (MDR) applies to a bacterium that is simultaneously resistant to a number of antimicrobials belonging to different chemical classes. The effectiveness of currently available antmicrobial drugs is decreasing due to the increasing number of resistant strains causing infections so that available therapeutic options for such organisms are severely limited. Objective The aim of this study was to determine multidrug-resistance rate of bacterial isolates that caused wound infections. Methods A Hospital based cross-sectional study was conducted on 322 wound samples taken from consecutive patients seen at inpatient and outpatient department of Jimma University Specialized Hospital from June to December 2011. Swabs from surgical incisions, burns, abscess and traumatic wounds were collected aseptically using Levine’s technique. Bacteriological culture and examination was done following standard microbiological techniques. Multidrug-resistance test was performed by disk diffusion method against 10 classes of antimicrobials. The data was analyzed for descriptive statistics using SPSS version 16 and Microsoft Excel. Results The overall MDR among gram positive and gram negative bacterial isolates were (77%) and (59.3%) respectively. About, 86.2%?S.aureus and 28.6% of Coagulase negative Staphylococci became MDR. Nearly 30.1% of S.aureus was resistant to six classes of antimicrobials. The average MDR rate of Proteus, Klebsiella, and Providencia species was 74.8%, 69.6% and 75% in that order. Nearly, 30.8% of Proteus sp, 32.6% of Klebsiella sp and 61% of Citrobacter sp were resistance to 4 classes each. Surprisingly, the average MDR rate for Citrobacter sp was 100%. About (76.7%) of S.aureus was Oxacillin/Methicillin resistant while (16.4%) were Vancomycin resistant. Proteus species was the predominant isolates (27.9%) followed by P.aeruginosa and S.aureus (19.3%) and (19%) respectively. Conclusion This study indicated that, the overall rate of MDR bacterial pathogens that caused wound infection was very high and many of the isolates were also identified as resistant to three or more classes of antimicrobials. Such widespread resistance to antimicrobial classes is something serious because a few treatment options remain for patients with wound infections. Periodic monitoring of etiology and antimicrobial susceptibility in areas where there is no culture facility is essential to assists physician in selection of chemotherapy. PMID:23879886

2013-01-01

125

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

ERIC Educational Resources Information Center

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…

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

2011-01-01

126

Rural Adolescent Perceptions of Alcohol and Other Drug Resistance.  

ERIC Educational Resources Information Center

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…

Jenkins, Jeanne E.

2001-01-01

127

Characterization of Novel HIV Drug Resistance Mutations Using Clustering, Multidimensional  

E-print Network

for each of the 19 drugs currently available for anti-HIV therapy, by using mutation lists annually updatedCharacterization of Novel HIV Drug Resistance Mutations Using Clustering, Multidimensional Scaling of clinically relevant domain knowledge in the field of HIV drug resistance. Novel mutations in the HIV genome

128

Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis  

PubMed Central

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

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

129

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

PubMed Central

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

Fernández, Lucía

2012-01-01

130

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

PubMed Central

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

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

2003-01-01

131

Drug-Resistant Leptomonas: Cross-Resistance in Trypanocide-Resistant Clones  

PubMed Central

A Leptomonas of insect origin was highly susceptible to several standard trypanocides and leishmanicides in vitro. Resistance was induced to some of these drugs; clones were isolated from each strain. Cross-resistance patterns of the clones were derived for diamidines, quinapyramine (Antrycide), acriflavin, phenanthridines, and other drugs active against trypanosomes and leishmanias. Clones tested included two each that were resistant to acriflavin, Antrycide, diminazene aceturate (Berenil), and pentamidine and one that was resistant to stilbamidine. Appreciable cross-resistance was evident for all clones. Differences were observed between clones from the same parent strain. Collateral susceptibility towards isometamidium and oxophenarsine was detected in most clone-derived populations. In clones passaged without drug to test for drug fastness, acriflavin and pentamidine clones lost resistance within 10 transfers, whereas Berenil and Antrycide clones retained considerable resistance after 20 to 30 subcultures without drug. Considerations of differences in life cycles suggest that the clone collection may be useful in screening for agents effective against leishmanias and stercorarian trypanosomes rather than against salivary trypanosomes. PMID:1211922

Bacchi, C. J.; Lambros, C.; Ellenbogen, B. B.; Penkovsky, L. N.; Sullivan, W.; Eyinna, E. E.; Hutner, S. H.

1975-01-01

132

The evolution and spread of antibiotic resistance in bacterial pathogens is a grow-  

E-print Network

The evolution and spread of antibiotic resistance in bacterial pathogens is a grow- ing threat to public health. The frequency of antibiotic resistance in many bacterial pathogens is increasing around rate of novel antibiotic dis- covery and by the likelihood that pathogens will evolve resistance

Kishony, Roy

133

Identification of DNA markers of tobacco linked to bacterial wilt resistance  

Microsoft Academic Search

Bacterial wilt caused by Ralstonia solanacearum is one of the most destructive soil-borne diseases in the world. Breeding resistant commercial varieties of tobacco is difficult because most donor candidates' resistance is controlled by polygenes. In this paper, we demonstrate the identification of useful DNA markers for bacterial wilt-resistant tobacco breeding. One hundred and seventeen markers were identified by the amplified

T. Nishi; T. Tajima; S. Noguchi; H. Ajisaka; H. Negishi

2003-01-01

134

SCREENING OF POTATO CLONES FOR FIELD RESISTANCE TO BACTERIAL WILT ( Pseudomonas solanacearum )  

Microsoft Academic Search

In order to develop new varieties with good levels of resistance to bacterial wilt as well as good agronomic characteristics and acceptable culinary traits, breeding for resistance to this disease has until recently continued at the International Potato Center (CIP) as well as various national potato research programs. CIP has produced a set of potentially bacterial wilt resistant potato clones

Sudjoko Sahat; Peter Schmiediche

135

[Multidrug-resistant tuberculosis. 2. Mechanisms of drug-resistance in Mycobacterium tuberculosis--genetic mechanisms of drug-resistance].  

PubMed

Multidrug-resistant Mycobacterium tuberculosis infection is now world wide health problem. However, according to the recent advances of molecular biological technics, some of the genetic mechanisms of drug-resistance of M. tuberculosis has been uncovered. Generally, drug-resistance of M. tuberculosis was caused by point mutations in chromosomal gene. In isoniazid (INH) resistant M. tuberculosis, mutations and genetic deletions in catalase-peroxidase gene (katG), inhA gene, or alkyl hydroperoxide reductase gene were reported. We also found that about 15% of INH-resistant M. tuberculosis isolates lacked katG gene, and these isolates showed highly resistance to INH with MIC > or = 64 micrograms/ml. On the other hand, mutations and other genetic alterations in RNA polymerase beta subunit gene (rpoB) were the major mechanisms of resistance to rifampicin (RFP) with high frequencies of 90% or more. Our evaluation of the relationship between RFP susceptibility and genetic alteration in rpoB gene also showed that 95% of RFP-resistant M. tuberculosis isolates involved genetic alterations in 69 bp core region of rpoB gene. Moreover, these genetic alterations in rpoB gene were suspected as the resistant mechanism to other rifamycin antituberculosis drugs, such as rifabutin and KRM-1648. In addition, it was reported that point mutations in 16S rRNA gene (rrs) and ribosomal protein S12 gene (rpsL) induced M. tuberculosis as streptomycin (SM) resistant phenotype. We analyzed genetic alternations in rpsL gene of clinically isolates of M. tuberculosis, about 60% of SM resistant isolates were shown point mutation in this gene ant they were all high SM-resistant with MIC > or = 256 micrograms/ml. Furthermore, nicotinamidase (pncA) gene, DNA gyrase A subunit (gyrA) gene, and embB gene were reported as the responsible gene to pyrazinamide-, quinolone- and ethambutol-resistance, respectively. Although all mechanisms of drug-resistance were still unclear, these informations are very useful and helpful for development of rapid diagnosis system of drug-resistant M. tuberculosis. PMID:9866928

Ohno, H; Koga, H; Kohno, S

1998-11-01

136

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

Federal Register 2010, 2011, 2012, 2013, 2014

...FDA-2013-D-1181] Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment...of a guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for...

2013-10-23

137

Nanomedicine therapeutic approaches to overcome cancer drug resistance.  

PubMed

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

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

2013-11-01

138

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 ...

139

Transmitted drug resistance in French HIV-2-infected patients.  

PubMed

We report the first transmitted drug resistance survey study in HIV-2-infected patients living in France. The prevalence of transmitted drug resistance was 5.0% (95% confidence interval, 0.1-9.9) with mutations detected only in protease, not in reverse transcriptase. In this series, 10% of patients displayed X4/dual-mixed viruses. These findings classified the rate of transmitted drug resistance in the HIV-2 French Cohort as low prevalence. PMID:23595155

Charpentier, Charlotte; Visseaux, Benoit; Bénard, Antoine; Peytavin, Gilles; Damond, Florence; Roy, Céline; Taieb, Audrey; Chêne, Geneviève; Matheron, Sophie; Brun-Vézinet, Françoise; Descamps, Diane

2013-06-19

140

Harnessing the potential of bacterial ghost for the effective delivery of drugs and biotherapeutics  

PubMed Central

It seems to be a necessary need to develop an effective drug carrier system for targeted delivery of pharmaceuticals. Bacterial ghosts are emerging drug delivery platform that are capable of delivery of proteins, antigens, nucleic acids, and pharmaceuticals. Bacterial ghosts are generally produced by lysis of gram-negative bacteria. Pharmaceutically, these ghosts could be utilized to deliver proteins peptides, vaccines, drugs effectively. However, this technology is at initial stage and systematic studies are required to implement such system over humans. PMID:24678455

Ganeshpurkar, Aditya; Ganeshpurkar, Ankit; Pandey, Vikas; Agnihotri, Abhishek; Bansal, Divya; Dubey, Nazneen

2014-01-01

141

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

PubMed Central

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

2014-01-01

142

New approaches for understanding mechanisms of drug resistance in schistosomes  

PubMed Central

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

GREENBERG, ROBERT M.

2013-01-01

143

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic Sensitivity  

E-print Network

Methicillin-resistant Staphylococcus aureus Bacterial Nitric-oxide Synthase Affects Antibiotic of Medicine, New York, New York 10016 Background: Methicillin-resistant Staphylococcus aureus (MRSA) generates activities to reduce MRSA pathology and increase antibiotic effectiveness. Staphylococcus aureus infections

Nizet, Victor

144

Molecular genetics of drug resistance in Mycobacterium tuberculosis.  

PubMed

Tuberculosis (TB) is the single largest killer among infectious diseases. The recent resurgence of TB together with outbreaks of multidrug resistant tuberculosis has focused attention on understanding the mechanisms of such drug resistance. Because of the relative neglect of TB research in the past and late arrival of mycobacterial genetic tools, the molecular mechanisms of drug resistance in TB remained largely unknown until very recently. In this paper we review recent progress on the mechanisms of resistance to three major anti-TB drugs; isoniazid, rifampicin and streptomycin. While the resistance mechanisms for rifampicin and streptomycin are similar to those found in other bacteria, isoniazid susceptibility and resistance is unique to Mycobacterium tuberculosis. So far, mutations in two chromosomal loci, katG and inhA have been found to be involved in isoniazid resistance in TB. Identification and characterization of mutations responsible for resistance opens up new possibilities for rapid detection of drug resistant strains. Molecular understanding of drug resistance and drug action in M. tuberculosis may eventually lead to rational design of new anti-TB drugs. PMID:7829406

Zhang, Y; Young, D

1994-09-01

145

Pyramiding of bacterial blight resistance genes in rice: marker-assisted selection using RFLP and PCR  

Microsoft Academic Search

DNA marker-assisted selection was used to pyramid four bacterial blight resistance genes, Xa-4, xa-5, xa-13 and Xa-21. Breeding lines with two, three and four resistance genes were developed and tested for resistance to the bacterial blight\\u000a pathogen (Xanthomonas oryzae pv. oryzae). The pyramid lines showed a wider spectrum and a higher level of resistance than lines with only a single

N. Huang; E. R. Angeles; J. Domingo; G. Magpantay; S. Singh; G. Zhang; N. Kumaravadivel; J. Bennett; G. S. Khush

1997-01-01

146

Engaging resistant adolescents in drug abuse treatment.  

PubMed

In the first phase of a two-part treatment development study, families with a treatment-resistant drug-abusing adolescent (n = 42) were offered 12 sessions of Community Reinforcement and Family Training (CRAFT). This parent-focused intervention was designed to help parents facilitate their adolescents' entry into treatment, to support adolescents' subsequent behavior change, and to improve parent and family functioning. In the second phase, successfully engaged adolescents (n = 30) were offered 12 sessions of a multicomponent individual cognitive-behavioral therapy (CBT) targeting substance use and related problem behaviors. For parents and adolescents, measures were collected on pretreatment and posttreatment, with an additional follow-up assessment for parents at 3 months after treatment. Parents on CRAFT intervention experienced a significant reduction in negative symptoms, and 71% of parents were successful in engaging their resistant youths in treatment. The CBT intervention for engaged youths was associated with a statistically significant, but not clinically significant, reduction in marijuana use. PMID:17306722

Waldron, Holly Barrett; Kern-Jones, Sheryl; Turner, Charles W; Peterson, Thomas R; Ozechowski, Timothy J

2007-03-01

147

Packaging protein drugs as bacterial inclusion bodies for therapeutic applications  

PubMed Central

A growing number of insights on the biology of bacterial inclusion bodies (IBs) have revealed intriguing utilities of these protein particles. Since they combine mechanical stability and protein functionality, IBs have been already exploited in biocatalysis and explored for bottom-up topographical modification in tissue engineering. Being fully biocompatible and with tuneable bio-physical properties, IBs are currently emerging as agents for protein delivery into mammalian cells in protein-replacement cell therapies. So far, IBs formed by chaperones (heat shock protein 70, Hsp70), enzymes (catalase and dihydrofolate reductase), grow factors (leukemia inhibitory factor, LIF) and structural proteins (the cytoskeleton keratin 14) have been shown to rescue exposed cells from a spectrum of stresses and restore cell functions in absence of cytotoxicity. The natural penetrability of IBs into mammalian cells (reaching both cytoplasm and nucleus) empowers them as an unexpected platform for the controlled delivery of essentially any therapeutic polypeptide. Production of protein drugs by biopharma has been traditionally challenged by IB formation. However, a time might have arrived in which recombinant bacteria are to be engineered for the controlled packaging of therapeutic proteins as nanoparticulate materials (nanopills), for their extra- or intra-cellular release in medicine and cosmetics. PMID:22686540

2012-01-01

148

Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens  

E-print Network

Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens Silvie Huijben1¤a *, Andrew S University, University Park, Pennsylvania, United States of America, 2 Departments of Mathematics, Statistics, National Institutes of Health, Bethesda, Maryland, United States of America Abstract Drug resistant

Day, Troy

149

Recent highlights in antimalarial drug resistance and chemotherapy research  

E-print Network

Recent highlights in antimalarial drug resistance and chemotherapy research David A. Fidock1 investigations into anti- malarial drug resistance and chemotherapy, including reports of some of the many meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we

Symington, Lorraine S.

150

Cancer Treatment Using Multiple Chemotheraputic Agents Subject to Drug Resistance  

E-print Network

Cancer Treatment Using Multiple Chemotheraputic Agents Subject to Drug Resistance J. J. Westman-7045 USA Abstract A compartment model for the evolution of cancer subject to multiple chemotherapeutic agents is presented. The formulation accounts for the heterogeneous nature of cancer and drug resistance

Hanson, Floyd B.

151

A Logical Framework for Detecting Anomalies in Drug Resistance Algorithms  

E-print Network

of such an endeavor is the re- search tackling anti-HIV treatment problems [7] conducted within the Virolab projectA Logical Framework for Detecting Anomalies in Drug Resistance Algorithms L. Caroprese Dipartimento that facil- itates medical knowledge discovery and decision support for HIV drug resistance. Large, high

Amsterdam, Universiteit van

152

The de novo selection of drug-resistant malaria parasites.  

PubMed Central

Antimalarial drug resistance emerges de novo predominantly in areas of low malaria transmission. Because of the logarithmic distribution of parasite numbers in human malaria infections, inadequately treated high biomass infections are a major source of de novo antimalarial resistance, whereas use of antimalarial prophylaxis provides a low resistance selection risk. Slowly eliminated antimalarials encourage resistance largely by providing a selective filter for resistant parasites acquired from others, and not by selecting resistance de novo. The de novo emergence of resistance can be prevented by use of antimalarial combinations. Artemisinin derivative combinations are particularly effective. Ensuring adequate treatment of the relatively few heavily infected patients would slow the emergence of resistance. PMID:12641911

White, N J; Pongtavornpinyo, W

2003-01-01

153

Inheritance and identification of SCAR marker linked to bacterial wilt-resistance in eggplant  

Microsoft Academic Search

In the present work, the combinations (F1) were crossed between highly resistant and susceptible to bacterial wilt eggplant parents and its F2, BC1 segregation population plants were inoculated with race1 of Ralstonia solanacearum in greenhouse. In this paper, we reported that the inheritance of bacterial wilt resistance in eggplant was controlled by a single dominant gene showing Mendelian inheritance model.

Cao Bi-hao; Lei Jian-jun; Wang Yong; Chen Guo-ju

2009-01-01

154

Targeting xa13 , a recessive gene for bacterial blight resistance in rice  

Microsoft Academic Search

Bacterial blight, caused by Xanthomonas oryzae pv. oryzae (Xoo), is one of the most serious diseases of rice worldwide. Thirty bacterial blight resistance (R) genes (21 dominant genes and 9 recessive genes) in rice have been identified. They are the main sources for the genetic\\u000a improvement of rice for resistance to Xoo. However, little is known about the recessive R

Zhaohui Chu; Binying Fu; Hong Yang; Caiguo Xu; Zhikang Li; A. Sanchez; Y. J. Park; J. L. Bennetzen; Qifa Zhang; Shiping Wang

2006-01-01

155

Meditation improves clinicoelectroencephalographic measures in drug-resistant epileptics  

Microsoft Academic Search

Eleven adults suffering from drug-resistant epilepsies were given meditation practice, while another nine adults acted as waiting list controls. All patients were on antiepileptic drugs and their serum drug levels were monitored regularly. Patients in the intervention group were given training in meditation, and they practiced meditation 20 minutes a day for one year. They showed a significant reduction in

K. K. Deepak; S. K. Manchanda; M. C. Maheshwari

1994-01-01

156

Efflux-Mediated Drug Resistance in Bacteria: an Update  

PubMed Central

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

Li, Xian-Zhi; Nikaido, Hiroshi

2010-01-01

157

Drug resistance and the microenvironment: nature and nurture  

Microsoft Academic Search

Drug resistance remains a major obstacle to the successful use of chemotherapeutic drugs for cancer therapy. It is well documented that cancer cells can adapt to the presence of chemotherapeutic agents through mutations or expression changes of key genes that control drug metabolism or response to damage. In addition, it is becoming increasingly apparent that the tumor microenvironment can have

Patrice J Morin

2003-01-01

158

Cancer stem cells and drug resistance: the potential of nanomedicine  

PubMed Central

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

Vinogradov, Serguei; Wei, Xin

2012-01-01

159

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

NASA Astrophysics Data System (ADS)

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.

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

2013-03-01

160

Overcoming multiple drug resistance mechanisms in medulloblastoma  

PubMed Central

Introduction Medulloblastoma (MB) is the most common malignant paediatric brain tumour. Recurrence and progression of disease occurs in 15-20% of standard risk and 30-40% of high risk patients. We analysed whether circumvention of chemoresistance pathways (drug export, DNA repair and apoptotic inhibition) can restore chemotherapeutic efficacy in a panel of MB cell lines. Results We demonstrate, by immunohistochemistry in patient tissue microarrays, that ABCB1 is expressed in 43% of tumours and is significantly associated with high-risk. We show that ABCB1, O6-methylguanine-DNA-methyltransferase (MGMT) and BCL2 family members are differentially expressed (by quantitative reverse transcription polymerase chain reaction, Western blotting and flow cytometry) in MB cell lines. Based on these findings, each pathway was then inhibited or circumvented and cell survival assessed using clonogenic assays. Inhibition of ABCB1 using vardenafil or verapamil resulted in a significant increase in sensitivity to etoposide in ABCB1-expressing MB cell lines. Sensitivity to temozolomide (TMZ) was MGMT-dependent, but two novel imidazotetrazine derivatives (N-3 sulfoxide and N-3 propargyl TMZ analogues) demonstrated ?7 fold and ?3 fold more potent cytotoxicity respectively compared to TMZ in MGMT-expressing MB cell lines. Activity of the BAD mimetic ABT-737 was BCL2A1 and ABCB1 dependent, whereas the pan-BCL2 inhibitor obatoclax was effective as a single cytotoxic agent irrespective of MCL1, BCL2, BCL2A1, or ABCB1 expression. Conclusions ABCB1 is associated with high-risk MB; hence, inhibition of ABCB1 by vardenafil may represent a valid approach in these patients. Imidazotetrazine analogues of TMZ and the BH3 mimetic obatoclax are promising clinical candidates in drug resistant MB tumours expressing MGMT and BCL2 anti-apoptotic members respectively. PMID:24887326

2014-01-01

161

Totally drug-resistant tuberculosis and adjunct therapies.  

PubMed

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

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

162

Drug resistance of Mycobacterium tuberculosis in Karachi, Pakistan.  

PubMed

We determined the primary and secondary resistance of isolates of M. tuberculosis to the standard antituberculous drugs in Karachi (Pakistan). Primary resistance to one or more anti-tuberculous drugs was found in 17% of 123 isolates of M. tuberculosis (obtained from patients with no history of previous treatment for tuberculosis). Secondary resistance was found in 36% of 33 isolates (obtained from individuals who had received anti-tuberculous treatment in the past). The drug to which organisms were most commonly resistant was isoniazid (11% primary resistance, 30% secondary resistance). Fifteen per cent of isolates obtained from previously-studied patients showed secondary resistance to rifampicin. We discuss the importance of these findings for tuberculosis treatment and control. PMID:8438507

Khan, J; Islam, N; Ajanee, N; Jafri, W

1993-01-01

163

Drug resistant tuberculosis in prisons in Azerbaijan: case study  

PubMed Central

Objectives: To document the existence of drug resistance in a tuberculosis treatment programme that adheres strictly to the DOTS principles (directly observed treatment, short course) and to determine the extent of drug resistance in a prison setting in one of the republics of the former Soviet Union. Design: Case study. Setting: Central Penitentiary Hospital in Baku, the referral centre for tuberculosis patients from all prisons in Azerbaijan. Subjects: Prisoners with tuberculosis: 28 selected patients not responding clinically or bacteriologically to the standard treatment (group 1) and 38 consecutive patients at admission to the programme (group 2). Main outcome measures: Drug resistance of Mycobacterium tuberculosis strains grown from sputum. Results: All the non-responding patients (group 1) had strains resistant to at least one drug. 25 (89%) of the non-responding patients and nine (24%) of the consecutive patients had M tuberculosis strains resistant to both rifampicin and isoniazid. A further 17 patients in group 2 had strains resistant to one or more first line drugs. Conclusions: Drug resistant M tuberculosis strains are common in prisons in Azerbaijan. Tuberculosis problems tend to be worse in prisons, but prisoners and former prisoners may have an important role in the transmission of tuberculosis, particularly of drug resistant forms, in the community. National programmes to control tuberculosis will have to take into account and address the problems in prisons to ensure their success. Key messages Tuberculosis is an important problem in prisons in Azerbaijan Multidrug resistant tuberculosis was common and an important cause of non-response to standard treatment National tuberculosis control programmes must include prisons and take account of drug resistance Unless WHO recommended treatment protocols are followed the problem of multidrug resistant tuberculosis may result in untreatable tuberculosis which will spread to the general community PMID:9572751

Coninx, R; Pfyffer, G E; Mathieu, C; Savina, D; Debacker, M; Jafarov, F; Jabrailov, I; Ismailov, A; Mirzoev, F; de Haller, R; Portaels, F

1998-01-01

164

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

PubMed

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

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

2014-10-01

165

Antibiotic resistance pattern among common bacterial uropathogens with a special reference to ciprofloxacin resistant Escherichia coli  

PubMed Central

Background & objectives: The resistance of bacteria causing urinary tract infection (UTI) to commonly prescribed antibiotics is increasing both in developing as well as in developed countries. Resistance has emerged even to more potent antimicrobial agents. The present study was undertaken to report the current antibiotic resistance pattern among common bacterial uropathogens isolated in a tertiary care hospital in south India, with a special reference to ciprofloxacin. Methods: A total of 19,050 consecutive urine samples were cultured and pathogens isolated were identified by standard methods. Antibiotic susceptibility was done by Kirby Bauer disk diffusion method. The clinical and demographic profile of the patients was noted. Results: Of the 19,050 samples, 62 per cent were sterile, 26.01 per cent showed significant growth, 2.3 per cent showed insignificant growth and 9.6 per cent were found contaminated. Significant association (P<0.001) of prior use of antibiotics in males, UTI in adults, gynaecological surgery in females, obstructive uropathy in males and complicated UTI in females with the occurrence of UTI with ciprofloxacin resistant Escherichia coli was noted. Significant association was noted in females with prior antibiotics, with prior urological surgery and in males with prior complicated UTI. There was no significant association with diabetes mellitus with the occurrence of UTI with ciprofloxacin resistant E. coli. Fluoroquinolone resistance was found to increase with age. Interpretations & conclusions: Ciprofloxacin resistance has emerged due to its frequent use. This resistance was seen more in the in-patients, elderly males and females. Also the resistance to other antibiotics was also high. Increasing antibiotic resistance trends indicate that it is imperative to rationalize the use of antimicrobials in the community and also use these conservatively. PMID:23287133

Mandal, Jharna; Acharya, N. Srinivas; Buddhapriya, D.; Parija, Subhash Chandra

2012-01-01

166

[Prediction of a risk for drug resistance in the pathogen of pulmonary tuberculosis].  

PubMed

The authors studied the spread of drug resistance in Mycobacterium tuberculosis was studied in Armenia and its association with risk factors in 1114 patients with positive bacterial culture and developed a mathematical method for early detection of a risk of its developed, which had been tested in 210 patients. Over 3 years (2002-2004), there was a rise in multiple drug resistance from 8.83 to 10.03% and polyresistance from 5.61 to 7.67%, a reduction in monoresistance from 8.68 to 6.96%; among new cases, there was an increase in multiple resistance from 3.23 to 6.59%, polyresistance from 4.42 to 7.01% and a decrease in monoresistance from 8.73 to 6.74%. For estimation of the value of clinical, laboratory, and social risk factors, the authors complied a rapid diagnostic table (RDT) that reflected 16 signs. Fischer's angular transformation method and stage-by-stage computer-aided analysis were analyzed, by detecting the diagnostic coefficients and informative value of signs, which was based on Wald's analysis called a heterogeneous sequential statistical recognition procedure. Testing this procedure indicated that their data was concordant with the results of bacterial cultures. The use of the proposed procedure make is possible in any conditions to predict the possible development of drug resistance and to take measures of its prevention. PMID:19062571

Safarian, M D; Minasian, G R; Khachatrian, D G; Stamboltsian, E P

2008-01-01

167

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

Code of Federal Regulations, 2011 CFR

...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification . The in vitro HIV drug resistance genotype assay...

2011-04-01

168

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

Code of Federal Regulations, 2012 CFR

...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification . The in vitro HIV drug resistance genotype assay...

2012-04-01

169

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

Code of Federal Regulations, 2013 CFR

...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification . The in vitro HIV drug resistance genotype assay...

2013-04-01

170

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

Code of Federal Regulations, 2014 CFR

...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification. The in vitro HIV drug resistance genotype assay...

2014-04-01

171

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

Code of Federal Regulations, 2010 CFR

...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. 866...In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification . The in vitro HIV drug resistance genotype assay...

2010-04-01

172

Development of Extensively Drug-resistant Tuberculosis during Multidrug-resistant Tuberculosis Treatment  

E-print Network

Development of Extensively Drug-resistant Tuberculosis during Multidrug-resistant Tuberculosis of Public Health, Boston, Massachusetts; 6 Tomsk Oblast Tuberculosis Services, Tomsk, Russian Federation; 7 Siberia State Medical University, Tomsk, Russian Federation; 8 Tomsk Oblast Tuberculosis Hospital, Tomsk

Cohen, Ted

173

Low abundance drug resistance variants in transmitted HIV drug resistance surveillance specimens identified using tagged pooled pyrosequencing.  

PubMed

HIV drug resistance (DR) testing using Sanger sequencing (SS) is limited by the inability of the method to identify low abundance drug resistance variants. The application of tagged pooled pyrosequencing (TPP) for HIV DR surveillance is described and the results compared with SS. HIV(+) serum specimens were genotyped using both SS and TPP. Surveillance drug resistance mutations were identified using SS and TPP consensus reads at multiple mixed base identification thresholds (MBITs). Drug resistance patterns were highly concordant between SS and TPP when the MBIT was set at 20%. DR mutations were detected in 7.1% of the subjects, with 1.6% of individuals harboring resistance to NRTI, 3.3% NNRTI and 2.7% PI. Analyzing the TPP reads for each subject confirmed that drug resistance mutations with frequencies <20% were inconsistently detected by SS. Conversely, low abundance drug resistant variants were easily identified using TPP with mixed base identification threshold set at low value. In conclusion, at considerable savings when compared to commercial assays, TPP produces HIV DR profiles that are concordant with those from SS, furthermore, these same data can be used to identify low abundance drug resistant variants. PMID:23159670

Ji, Hezhao; Liang, Ben; Li, Yang; Van Domselaar, Gary; Graham, Morag; Tyler, Shaun; Merks, Harriet; Sandstrom, Paul; Brooks, James

2013-02-01

174

Drug Resistance among Pulmonary Tuberculosis Patients in Calabar, Nigeria  

PubMed Central

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

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

2013-01-01

175

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

PubMed

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

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

2015-03-17

176

Fitness of Leishmania donovani Parasites Resistant to Drug Combinations  

PubMed Central

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

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

2015-01-01

177

Fitness of Leishmania donovani Parasites Resistant to Drug Combinations.  

PubMed

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

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

2015-04-01

178

Combinatorial discovery of polymers resistant to bacterial attachment  

E-print Network

Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric ...

Hook, Andrew L

179

Inhibitory effect of Allium sativum and Zingiber officinale extracts on clinically important drug resistant pathogenic bacteria  

PubMed Central

Background Herbs and spices are very important and useful as therapeutic agent against many pathological infections. Increasing multidrug resistance of pathogens forces to find alternative compounds for treatment of infectious diseases. Methods In the present study the antimicrobial potency of garlic and ginger has been investigated against eight local clinical bacterial isolates. Three types of extracts of each garlic and ginger including aqueous extract, methanol extract and ethanol extract had been assayed separately against drug resistant Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, Klebsiella pneumoniae, Shigella sonnei, Staphylococcusepidermidis and Salmonella typhi. The antibacterial activity was determined by disc diffusion method. Results All tested bacterial strains were most susceptible to the garlic aqueous extract and showed poor susceptibility to the ginger aqueous extract. The (minimum inhibitory concentration) MIC of different bacterial species varied from 0.05?mg/ml to 1.0?mg/ml. Conclusion In the light of several socioeconomic factors of Pakistan mainly poverty and poor hygienic condition, present study encourages the use of spices as alternative or supplementary medicine to reduce the burden of high cost, side effects and progressively increasing drug resistance of pathogens. PMID:22540232

2012-01-01

180

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

PubMed

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

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

2015-05-01

181

The evolution of drug-resistant malaria: the role of drug elimination half-life.  

PubMed Central

This paper seeks to define and quantify the influence of drug elimination half-life on the evolution of antimalarial drug resistance. There are assumed to be three general classes of susceptibility of the malaria parasite Plasmodium falciparum to a drug: Res0, the original, susceptible wildtype; Res1, a group of intermediate levels of susceptibility that are more tolerant of the drug but still cleared by treatment; and Res2, which is completely resistant to the drug. Res1 and Res2 resistance both evolve much faster if the antimalarial drug has a long half-life. We show that previous models have significantly underestimated the rate of evolution of Res2 resistance by omitting the effects of drug half-life. The methodology has been extended to investigate (i) the effects of using drugs in combination, particularly when the components have differing half-lives, and (ii) the specific example of the development of resistance to the antimalarial pyrimethamine-sulphadoxine. An important detail of the model is the development of drug resistance in two separate phases. In phase A, Res1 is spreading and replacing the original sensitive forms while Res2 remains at a low level. Phase B starts once parasites are selected that can escape drug action (Res1 genotypes with borderline chemosensitivity, and Res2): these parasites are rapidly selected, a process that leads to widespread clinical failure. Drug treatment is clinically successful during phase A, and health workers may be unaware of the substantial changes in parasite population genetic structure that predicate the onset of phase B. Surveillance programs are essential, following the introduction of a new drug, to monitor effectively changes in treatment efficacy and thus provide advance warning of drug failure. The model is also applicable to the evolution of antibiotic resistance in bacteria: in particular, the need for these models to incorporate drug pharmacokinetics to avoid potentially large errors in their predictions. PMID:12028788

Hastings, Ian M; Watkins, William M; White, Nicholas J

2002-01-01

182

Bedaquiline for the treatment of drug-resistant tuberculosis.  

PubMed

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

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

2015-05-01

183

Drug-Resistant Candida glabrata Infection in Cancer Patients  

PubMed Central

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

Farmakiotis, Dimitrios; Tarrand, Jeffrey J.

2014-01-01

184

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

Microsoft Academic Search

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

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

2007-01-01

185

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

PubMed Central

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 ? 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.

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

2014-01-01

186

Diabetes drug points the way to overcoming drug resistance in melanoma  

Cancer.gov

Advanced metastatic melanoma is a disease that has proven difficult to eradicate. Despite the success of melanoma-targeting drugs, tumors inevitably become drug resistant and return, more aggressive than before. In the current issue of the journal Cancer Cell, researchers at The Wistar Institute describe how they increase the effectiveness of anti-melanoma drugs by combining anticancer therapies with diabetes drugs. Their studies, conducted in cell and animal models of melanoma, demonstrate that the combined therapy could destroy a subset of drug-resistant cells within a tumor.

187

Enhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria  

E-print Network

following Drug Treatment in Rodent Malaria. PLoS ONE 7(6): e37172. doi:10.1371/journal.pone.0037172 EditorEnhanced Transmission of Drug-Resistant Parasites to Mosquitoes following Drug Treatment in Rodent Malaria Andrew S. Bell1 , Silvie Huijben1 , Krijn P. Paaijmans1 , Derek G. Sim1 , Brian H. K. Chan1

Read, Andrew

188

An antibiotic protocol to minimize emergence of drug-resistant tuberculosis  

NASA Astrophysics Data System (ADS)

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

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

2014-04-01

189

Monopoly pricing of an antibiotic subject to bacterial resistance.  

PubMed

We develop a dynamic bio-economic model of bacterial resistance and disease transmission in which we characterize the pricing policy of a monopolist who is protected by a patent. After expiration, the monopolist behaves competitively in a generic industry having open access to the common pool of antibiotic efficacy and infection. The monopolist manages endogenously the levels of antibiotic efficacy as well as the infected population, which represent quality and market size respectively and achieves, at least temporarily, higher such levels than a hypothetically myopic monopolist who does not take into account the dynamic externalities. The pricing policy and the biological system is characterized by the turnpike property. Before the patent vanishes, the monopolist behaves more and more myopically, leading to a continuous decrease in the price of the antibiotic. Once the generic industry takes over, a discontinuous fall in price occurs. Whether a prolongation of the patent is socially desirable depends on the relative levels of antibiotic efficacy and infection. PMID:20015559

Herrmann, Markus

2010-01-01

190

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

MedlinePLUS

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

191

Relationship between resistance to bacterial wilt and nutrient uptake in tomato seedlings  

Microsoft Academic Search

Varietal differences in the resistance to bacterial wilt and nutrient uptake of tomato (Lycopersicon esculentum Mill.) seedlings were examined in pot experiments. Twenty-three tomato cultivars were classified into three groups based on the degree of resistance to the disease. Differences in nutrient uptake among cultivars were observed for all the elements tested, and highly resistant cultivars were characterized by a

Hiromichi Yamazaki; Osamu Ishizuka; Tsuguo Hoshina

1996-01-01

192

Calcium uptake and resistance to bacterial wilt of mutually grafted tomato seedlings  

Microsoft Academic Search

Bacterial wilt of tomato (Lycopersicon esculentum Mill.) caused by Ralstonia solanacearum Smith is a serious disease in Japan. We previously reported that calcium (Ca) nutrition in tomato significantly affected the resistance to the disease, and that highly resistant cultivars were characterized by a high Ca uptake. We examined the relationship between the Ca uptake and resistance using mutually grafted seedlings

Hiromichi Yamazaki; Sunao Kikuchi; Tsuguo Hoshina; Takeshi Kimura

2000-01-01

193

Bacterial resistance to antibiotics continues to pose a serious threat to human and animal  

E-print Network

Bacterial resistance to antibiotics continues to pose a serious threat to human and animal health. The relationship between antibiotic use and the development of resistance has been studied extensively, with some of this research aimed at identifying antibiotic treatment strategies that minimize the maintenance of resistance

Singer, Randall

194

A research-inspired laboratory sequence investigating acquired drug resistance  

E-print Network

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 ...

Taylor, Elizabeth Vogel

195

Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story  

PubMed Central

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

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

2013-01-01

196

Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia  

PubMed Central

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

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

197

Travelers Bringing Drug-Resistant Bacteria to United States  

MedlinePLUS

... enable JavaScript. Travelers Bringing Drug-Resistant Bacteria to United States Strain of Shigella is easily transmitted and causes ... bacteria that causes diarrhea is spreading in the United States, federal health officials warned Thursday. Travelers are bringing ...

198

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

NASA Astrophysics Data System (ADS)

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.

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

199

Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens  

PubMed Central

Drug resistant pathogens are one of the key public health challenges of the 21st century. There is a widespread belief that resistance is best managed by using drugs to rapidly eliminate target pathogens from patients so as to minimize the probability that pathogens acquire resistance de novo. Yet strong drug pressure imposes intense selection in favor of resistance through alleviation of competition with wild-type populations. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug resistance emergence. Identifying treatment regimens which best retard resistance evolution while maximizing health gains and minimizing disease transmission requires empirical analysis of resistance evolution in vivo in conjunction with measures of clinical outcomes and infectiousness. Using rodent malaria in laboratory mice, we found that less aggressive chemotherapeutic regimens substantially reduced the probability of onward transmission of resistance (by >150-fold), without compromising health outcomes. Our experiments suggest that there may be cases where resistance evolution can be managed more effectively with treatment regimens other than those which reduce pathogen burdens as fast as possible. PMID:24068922

Huijben, Silvie; Bell, Andrew S.; Sim, Derek G.; Tomasello, Danielle; Mideo, Nicole; Day, Troy; Read, Andrew F.

2013-01-01

200

Combined antiretroviral and anti-tuberculosis drug resistance following incarceration  

PubMed Central

We describe a case of HIV/tuberculosis (TB) co-infection from KwaZulu-Natal, South Africa, characterised by drug resistance in both pathogens. The development of drug resistance was linked temporally to two periods of incarceration. This highlights the urgent need for improved integration of HIV/TB control strategies within prison health systems and within the broader public health framework. PMID:24273475

Stott, K E; de Oliviera, T; Lessells, R J

2013-01-01

201

Increasing antimalarial drug resistance in Uganda and revision of the national drug policy  

Microsoft Academic Search

Summary Chloroquine (CQ) resistance was first documented in Uganda in 1988. Subsequent surveillance of antimalarial drug resistance, conducted by the Ugandan Ministry of Health and several research organizations, suggests that resistance to CQ is now widespread, reaching critical levels in many areas of the country. In June 2000, the Ministry of Health held a National Consensus Meeting to evaluate the

M. R. Kamya; N. N. Bakyaita; A. O. Talisuna; W. M. Were; S. G. Staedke

2002-01-01

202

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

PubMed

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

Joice, Regina; Lipsitch, Marc

2013-01-01

203

Using Aspergillus nidulans to identify antifungal drug resistance mutations.  

PubMed

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

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

2014-02-01

204

The medical and surgical treatment of drug-resistant tuberculosis  

PubMed Central

Multi drug-resistant tuberculosis (MDR-TB) and extensively drug-resistant TB (XDR-TB) are burgeoning global problems with high mortality which threaten to destabilise TB control programs in several parts of the world. Of alarming concern is the emergence, in large numbers, of patients with resistance beyond XDR-TB (totally drug-resistant TB; TDR-TB or extremely drug resistant TB; XXDR-TB). Given the burgeoning global phenomenon of MDR-TB, XDR-TB and TDR-TB, and increasing international migration and travel, healthcare workers, researchers, and policy makers in TB endemic and non-endemic countries should familiarise themselves with issues relevant to the management of these patients. Given the lack of novel TB drugs and limited access to existing drugs such as linezolid and bedaquiline in TB endemic countries, significant numbers of therapeutic failures are emerging from the ranks of those with XDR-TB. Given the lack of appropriate facilities in resource-limited settings, such patients are being discharged back into the community where there is likely ongoing disease spread. In the absence of effective drug regimens, in appropriate patients, surgery is a critical part of management. Here we review the diagnosis, medical and surgical management of MDR-TB and XDR-TB. PMID:24624282

Calligaro, Gregory L.; Moodley, Loven; Symons, Greg

2014-01-01

205

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

PubMed

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

Niero, Evandro Luís; Rocha-Sales, Bianca; Lauand, Camila; Cortez, Beatriz Araujo; de Souza, Marcelo Medina; Rezende-Teixeira, Paula; Urabayashi, Marcel Shiniti; Martens, Adam Arai; Neves, Jorge Henrique; Machado-Santelli, Gláucia Maria

2014-01-01

206

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

PubMed Central

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

2014-01-01

207

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

PubMed

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

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

2011-01-01

208

Knowledge-based Avoidance of Drug-Resistant HIV Mutants  

E-print Network

encode knowledge about sequence mutations in the HIV genome that have been found to result in drug is not in hand, but a number of speci c sequence mutations in the HIV genome have been described in the scienti cKnowledge-based Avoidance of Drug-Resistant HIV Mutants Richard H. Lathrop, Nicholas R. Ste en

Pazzani, Michael J.

209

MicroRNA-mediated drug resistance in breast cancer  

Microsoft Academic Search

Chemoresistance is one of the major hurdles to overcome for the successful treatment of breast cancer. At present, there are\\u000a several mechanisms proposed to explain drug resistance to chemotherapeutic agents, including decreased intracellular drug\\u000a concentrations, mediated by drug transporters and metabolic enzymes; impaired cellular responses that affect cell cycle arrest,\\u000a apoptosis, and DNA repair; the induction of signaling pathways that

Kristy R. Kutanzi; Olga V. Yurchenko; Frederick A. Beland; Vasyl’ F. Checkhun; Igor P. Pogribny

210

TRANSFORMATION OF ANTHURIUM WITH TRANSGENES FOR BACTERIAL BLIGHT AND NEMATODE RESISTANCE  

Technology Transfer Automated Retrieval System (TEKTRAN)

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

211

Discovery of Novel Materials with Broad Resistance to Bacterial Attachment Using Combinatorial Polymer Microarrays  

E-print Network

A new class of bacteria-attachment-resistant materials is discovered using a multi-generation polymer microarray methodology that reduces bacterial attachment by up to 99.3% compared with a leading commercially available ...

Hook, Andrew L.

212

CHARACTERIZATION OF ARSENIC RESISTANT BACTERIAL COMMUNITIES IN THE RHIZOSPHERE OF AN ARSENIC HYPERACCUMULATOR Pteris vittata L.  

E-print Network

CHARACTERIZATION OF ARSENIC RESISTANT BACTERIAL COMMUNITIES IN THE RHIZOSPHERE OF AN ARSENIC..................................................................................................................11 1.1 Environmental Sources of Arsenic..................................................................................11 1.1.1 Arsenic in the Environment

Ma, Lena

213

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

214

Dominant gene for common bean resistance to common bacterial blight caused by Xanthomonas axonopodis pv. phaseoli  

Technology Transfer Automated Retrieval System (TEKTRAN)

The common bacterial blight pathogen [Xanthomonas axonopodis pv. phaseoli (Xap)] is a limiting factor for common bean (Phaseolus vulgaris L.) production worldwide and resistance to the pathogen in most commercial cultivars is inadequate. Variability in virulence of the bacterial pathogen has been ob...

215

The interplay between drug resistance and fitness in malaria parasites  

PubMed Central

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

Rosenthal, Philip J.

2013-01-01

216

A Research-Inspired Laboratory Sequence Investigating Acquired Drug Resistance  

ERIC Educational Resources Information Center

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…

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

2010-01-01

217

Bacteremic Pneumonia Caused by Extensively Drug-Resistant Streptococcus pneumoniae  

PubMed Central

The emergence of antimicrobial resistance threatens the successful treatment of pneumococcal infections. Here we report a case of bacteremic pneumonia caused by an extremely drug-resistant strain of Streptococcus pneumoniae, nonsusceptible to at least one agent in all classes but vancomycin and linezolid, posing an important new public health threat in our region. PMID:23052301

Baek, Jin Yang; Jeon, Kyeongman; Kim, So Hyun; Chung, Doo Ryeon; Peck, Kyong Ran; Lee, Nam Yong; Song, Jae-Hoon

2012-01-01

218

Emergence of increased resistance and extensively drug-resistant tuberculosis despite treatment adherence, South Africa.  

PubMed

We investigated the emergence and evolution of drug-resistant tuberculosis (TB) in an HIV co-infected population at a South African gold mine with a well-functioning TB control program. Of 128 patients with drug-resistant TB diagnosed during January 2003-November 2005, a total of 77 had multidrug-resistant (MDR) TB, 26 had pre-extensively drug-resistant TB (XDR TB), and 5 had XDR TB. Genotyping suggested ongoing transmission of drug-resistant TB, and contact tracing among case-patients in the largest cluster demonstrated multiple possible points of contact. Phylogenetic analysis demonstrated stepwise evolution of drug resistance, despite stringent treatment adherence. These findings suggested that existing TB control measures were inadequate to control the spread of drug-resistant TB in this HIV co-infected population. Diagnosis delay and inappropriate therapy facilitated disease transmission and drug-resistance. These data call for improved infection control measures, implementation of rapid diagnostics, enhanced active screening strategies, and pharmacokinetic studies to determine optimal dosages and treatment regimens. PMID:20113557

Calver, Alistair D; Falmer, Alecia A; Murray, Megan; Strauss, Odelia J; Streicher, Elizabeth M; Hanekom, Madelene; Liversage, Thelma; Masibi, Mothusi; van Helden, Paul D; Warren, Robin M; Victor, Thomas C

2010-02-01

219

Molecular Biology of Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Tuberculosis (TB) has become a curable disease thanks to the discovery of antibiotics. However, it has remained one of the most difficult infections to treat. Most current TB regimens consist of six to nine months of daily doses of four drugs that are highly toxic to patients. The purpose of these lengthy treatments is to completely eradicate Mycobacterium tuberculosis, notorious for its ability to resist most antibacterial agents, thereby preventing the formation of drug resistant mutants. On the contrary, the prolonged therapies have led to poor patient adherence. This, together with a severe limit of drug choices, has resulted in the emergence of strains that are increasingly resistant to the few available antibiotics. Here we review our current understanding of molecular mechanisms underlying the profound drug resistance of M. tuberculosis. This knowledge is essential for the development of more effective antibiotics that not only are potent against drug resistant M. tuberculosis strains but also help shorten the current treatment courses required for drug susceptible TB. PMID:23179675

Smith, Tasha; Wolff, Kerstin A.; Nguyen, Liem

2014-01-01

220

Indoleamides are active against drug-resistant Mycobacterium tuberculosis  

PubMed Central

Responsible for nearly two million deaths each year, the infectious disease tuberculosis remains a serious global health challenge. The emergence of multidrug- and extensively drug-resistant strains of Mycobacterium tuberculosis confounds control efforts, and new drugs with novel molecular targets are desperately needed. Here we describe lead compounds, the indoleamides, with potent activity against both drug-susceptible and drug-resistant strains of M. tuberculosis by targeting the mycolic acid transporter MmpL3. We identify a single mutation in mmpL3 which confers high resistance to the indoleamide class while remaining susceptible to currently used first- and second-line tuberculosis drugs, indicating a lack of cross-resistance. Importantly, an indoleamide derivative exhibits dose-dependent anti-mycobacterial activity when orally administered to M. tuberculosis-infected mice. The bioavailability of the indoleamides, combined with their ability to kill tubercle bacilli, indicates great potential for translational developments of this structure class for the treatment of drug-resistant tuberculosis. PMID:24352433

Lun, Shichun; Guo, Haidan; Onajole, Oluseye K.; Pieroni, Marco; Gunosewoyo, Hendra; Chen, Gang; Tipparaju, Suresh K.; Ammerman, Nicole C.; Kozikowski, Alan P.; Bishai, William R.

2014-01-01

221

Interactions among Strategies Associated with Bacterial Infection: Pathogenicity, Epidemicity, and Antibiotic Resistance  

PubMed Central

Infections have been the major cause of disease throughout the history of human populations. With the introduction of antibiotics, it was thought that this problem should disappear. However, bacteria have been able to evolve to become antibiotic resistant. Nowadays, a proficient pathogen must be virulent, epidemic, and resistant to antibiotics. Analysis of the interplay among these features of bacterial populations is needed to predict the future of infectious diseases. In this regard, we have reviewed the genetic linkage of antibiotic resistance and bacterial virulence in the same genetic determinants as well as the cross talk between antibiotic resistance and virulence regulatory circuits with the aim of understanding the effect of acquisition of resistance on bacterial virulence. We also discuss the possibility that antibiotic resistance and bacterial virulence might prevail as linked phenotypes in the future. The novel situation brought about by the worldwide use of antibiotics is undoubtedly changing bacterial populations. These changes might alter the properties of not only bacterial pathogens, but also the normal host microbiota. The evolutionary consequences of the release of antibiotics into the environment are largely unknown, but most probably restoration of the microbiota from the preantibiotic era is beyond our current abilities. PMID:12364374

Martínez, José L.; Baquero, Fernando

2002-01-01

222

Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis  

PubMed Central

Background and objectives: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics. Methodology: We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively. Results: We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa. Conclusions and implications: Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB. PMID:24481187

Borrell, Sònia; Teo, Youjin; Giardina, Federica; Streicher, Elizabeth M.; Klopper, Marisa; Feldmann, Julia; Müller, Borna; Victor, Tommie C.; Gagneux, Sebastien

2013-01-01

223

Testing of herpes simplex virus for resistance to antiviral drugs.  

PubMed

Herpes simplex virus (HSV) infections can be treated efficiently by the application of antiviral compounds. Several drugs on the basis of acyclovir (ACV), penciclovir (PCV) and foscarnet (FOS) have been approved. Resistant viral isolates can be observed especially in immunocompromised patients, who are treated with antivirals for long time intervals. That is why methods for analysis of HSV resistance to antiviral drugs have to be available in virological laboratories. We analyzed HSV type 1 (HSV-1) and type 2 (HSV-2) isolates resistant to ACV for correlation between phenotypic and genotypic drug resistance using tetrazolium reduction assay as well as sequencing of thymidine kinase (TK) and DNA polymerase (pol) genes. All strains were characterized as cross-resistant to PCV, brivudin and susceptible to cidofovir. In addition, three sequential isolates were resistant to FOS. Genotypic analysis revealed high polymorphism of TK among HSV-1 isolates and high polymorphism of DNA pol among both HSV-1- and 2 isolates. In nearly half of ACV-resistant strains, nucleotide insertions and deletions, responsible for a frameshift and the synthesis of a non-functional TK could be related to resistance. In the remaining strains, there were non-synonymous nucleotide substitutions which were not known as part of gene polymorphism. In conclusion, for reliable interpretation of genotypic resistance, a database of non-synonymous mutations has to be established. PMID:21178503

Sauerbrei, Andreas; Deinhardt, Stefanie; Zell, Roland; Wutzler, Peter

2010-01-01

224

Update on antifungal drug resistance mechanisms of Aspergillus fumigatus.  

PubMed

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

Chamilos, G; Kontoyiannis, D P

2005-12-01

225

Surveillance for Antimicrobial Drug Resistance in Under-Resourced Countries  

PubMed Central

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

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

2014-01-01

226

Antimicrobial resistance: consideration as an adverse drug event.  

PubMed

Antimicrobial resistance has increased dramatically in the past 15 to 20 yrs and presents a patient safety concern unlike any other in the intensive care unit. Antimicrobial resistance in critically ill patients increases morbidity, mortality, length of hospital stay, and healthcare costs. Some organisms may have intrinsically high levels of resistance or may be spread between patients by poor infection control practices. However, a major driver of antimicrobial resistance is antibiotic use. As such, the development of antimicrobial resistance can often be thought of as an adverse drug event. This article explores the link between drug use, drug dosing, other selective pressures and resistance, and describes concepts to minimize the negative impact of antimicrobial therapy. Two broad themes of these concepts are minimizing the use of antibiotics whenever possible and optimizing antibiotic usage when they are needed. Strategies for minimizing the use of antimicrobials include using optimal diagnostic procedures to ensure the need for antimicrobials, streamlining or discontinuing therapy when possible based on culture results, and using the shortest duration of therapy needed for documented infections. Strategies for optimizing antimicrobial use include using optimal dosing based on the manufacturer's instructions and current pharmacodynamic data, guiding better prescribing based on local susceptibility patterns and formulary restriction, and avoiding drugs with more propensity to foster resistance. PMID:20502169

Martin, Steven J; Micek, Scott T; Wood, G Christopher

2010-06-01

227

C. elegans pgp-5 IS INVOLVED IN RESISTANCE TO BACTERIAL INFECTION AND HEAVY METAL AND ITS REGULATION  

E-print Network

C. elegans pgp-5 IS INVOLVED IN RESISTANCE TO BACTERIAL INFECTION AND HEAVY METAL AND ITS of a C. elegans ABC transporter, pgp-5 is induced by both bacterial infection and heavy metal stress contributes to resistance to bacterial infection and heavy metals. Using pgp-5 transcription as a read-out, we

Baillie, David

228

Establishing Drug Resistance in Microorganisms by Mass Spectrometry  

NASA Astrophysics Data System (ADS)

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

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

2013-08-01

229

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

PubMed

Antibiotic resistance represents a growing global health concern due to the overuse and misuse of antibiotics. There is, however, little information about how the selective pressure of clinical antibiotic usage can affect environmental communities in aquatic ecosystems and which bacterial groups might be responsible for dissemination of antibiotic resistance genes (ARGs) into the environment. In this study, chemical and biological characterization of water and sediments from three water supply reservoirs subjected to a wide pollution gradient allowed to draw an accurate picture of the concentration of antibiotics and prevalence of ARGs, in order to evaluate the potential role of ARGs in shaping bacterial communities, and to identify the bacterial groups most probably carrying and disseminating ARGs. Results showed significant correlation between the presence of ARG conferring resistance to macrolides and the composition of bacterial communities, suggesting that antibiotic pollution and the spreading of ARG might play a role in the conformation of bacterial communities in reservoirs. Results also pointed out the bacterial groups Actinobacteria and Firmicutes as the ones probably carrying and disseminating ARGs. The potential effect of antibiotic pollution and the presence of ARGs on the composition of bacterial communities in lacustrine ecosystems prompt the fundamental question about potential effects on bacterial-related ecosystem services supplied by lakes and reservoirs. PMID:23591067

Huerta, Belinda; Marti, Elisabet; Gros, Meritxell; López, Pilar; Pompêo, Marcelo; Armengol, Joan; Barceló, Damià; Balcázar, Jose Luis; Rodríguez-Mozaz, Sara; Marcé, Rafael

2013-07-01

230

Structure-based Methods for Predicting Target Mutation-induced Drug Resistance and Rational Drug Design to Overcome the Problem  

PubMed Central

Drug resistance has become one of the biggest challenges in drug discovery/development and attracted great research interests worldwide. During the last decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues, and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance. This is a brief review of recent advances in development of computational methods for target mutation-induced drug resistance prediction and strategies for rational design of novel inhibitors that could be effective also against the possible drug-resistant mutants of the target. PMID:22789991

Hao, Ge-Fei; Yang, Guang-Fu; Zhan, Chang-Guo

2012-01-01

231

Modeling the evolution of drug resistance in malaria  

PubMed Central

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

Fogel, Gary B.

2012-01-01

232

Drug Resistance Pattern of MTB Isolates from PTB Patients  

PubMed Central

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

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

2013-01-01

233

Drug Resistance Pattern of MTB Isolates from PTB Patients.  

PubMed

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

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

2013-01-01

234

Induction of anti-actin drug resistance in Tetrahymena.  

PubMed

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

Zackroff, Robert V; Hufnagel, Linda A

2002-01-01

235

Modelling the evolution of drug resistance in the presence of antiviral drugs  

PubMed Central

Background The emergence of drug resistance in treated populations and the transmission of drug resistant strains to newly infected individuals are important public health concerns in the prevention and control of infectious diseases such as HIV and influenza. Mathematical modelling may help guide the design of treatment programs and also may help us better understand the potential benefits and limitations of prevention strategies. Methods To explore further the potential synergies between modelling of drug resistance in HIV and in pandemic influenza, the Public Health Agency of Canada and the Mathematics for Information Technology and Complex Systems brought together selected scientists and public health experts for a workshop in Ottawa in January 2007, to discuss the emergence and transmission of HIV antiviral drug resistance, to report on progress in the use of mathematical models to study the emergence and spread of drug resistant influenza viral strains, and to recommend future research priorities. Results General lectures and round-table discussions were organized around the issues on HIV drug resistance at the population level, HIV drug resistance in Western Canada, HIV drug resistance at the host level (with focus on optimal treatment strategies), and drug resistance for pandemic influenza planning. Conclusion Some of the issues related to drug resistance in HIV and pandemic influenza can possibly be addressed using existing mathematical models, with a special focus on linking the existing models to the data obtained through the Canadian HIV Strain and DR Surveillance Program. Preliminary statistical analysis of these data carried out at PHAC, together with the general model framework developed by Dr. Blower and her collaborators, should provide further insights into the mechanisms behind the observed trends and thus could help with the prediction and analysis of future trends in the aforementioned items. Remarkable similarity between dynamic, compartmental models for the evolution of wild and drug resistance strains of both HIV and pandemic influenza may provide sufficient common ground to create synergies between modellers working in these two areas. One of the key contributions of mathematical modeling to the control of infectious diseases is the quantification and design of optimal strategies, combining techniques of operations research with dynamic modeling would enhance the contribution of mathematical modeling to the prevention and control of infectious diseases. PMID:17953775

Wu, Jianhong; Yan, Ping; Archibald, Chris

2007-01-01

236

Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies  

PubMed Central

Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria transmission through vector control measures. Conclusion This paper has demonstrated the use of a comprehensive mathematical model to describe malaria transmission and the spread of drug resistance. The model is strongly linked to the empirical evidence obtained from extensive data available from various sources. This model can be a useful tool to inform the design of treatment policies, particularly at a time when ACT has been endorsed by WHO as first-line treatment for falciparum malaria worldwide. PMID:18976503

Pongtavornpinyo, Wirichada; Yeung, Shunmay; Hastings, Ian M; Dondorp, Arjen M; Day, Nicholas PJ; White, Nicholas J

2008-01-01

237

Antifungal drug resistance evokedvia RNAi-dependent epimutations  

PubMed Central

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

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

238

Efficacy of OH-CATH30 and its analogs against drug-resistant bacteria in vitro and in mouse models.  

PubMed

Antimicrobial peptides (AMPs) have been considered alternatives to conventional antibiotics for drug-resistant bacterial infections. However, their comparatively high toxicity toward eukaryotic cells and poor efficacy in vivo hamper their clinical application. OH-CATH30, a novel cathelicidin peptide deduced from the king cobra, possesses potent antibacterial activity in vitro. The objective of this study is to evaluate the efficacy of OH-CATH30 and its analog OH-CM6 against drug-resistant bacteria in vitro and in vivo. The MICs of OH-CATH30 and OH-CM6 ranged from 1.56 to 12.5 ?g/ml against drug-resistant clinical isolates of several pathogenic species, including Escherichia coli, Pseudomonas aeruginosa, and methicillin-resistant Staphylococcus aureus. The MICs of OH-CATH30 and OH-CM6 were slightly altered in the presence of 25% human serum. OH-CATH30 and OH-CM6 killed E. coli quickly (within 60 min) by disrupting the bacterial cytoplasmic membrane. Importantly, the 50% lethal doses (LD(50)) of OH-CATH30 and OH-CM6 in mice following intraperitoneal (i.p.) injection were 120 mg/kg of body weight and 100 mg/kg, respectively, and no death was observed at any dose up to 160 mg/kg following subcutaneous (s.c.) injection. Moreover, 10 mg/kg OH-CATH30 or OH-CM6 significantly decreased the bacterial counts as well as the inflammatory response in a mouse thigh infection model and rescued infected mice in a bacteremia model induced by drug-resistant E. coli. Taken together, our findings demonstrate that the natural cathelicidin peptide OH-CATH30 and its analogs exhibit relatively low toxicity and potent efficacy in mouse models, indicating that they may have therapeutic potential against the systemic infections caused by drug-resistant bacteria. PMID:22491685

Li, Sheng-An; Lee, Wen-Hui; Zhang, Yun

2012-06-01

239

Potential risk for drug resistance globalization at the Hajj.  

PubMed

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

Al-Tawfiq, J A; Memish, Z A

2015-02-01

240

Drug resistance to targeted therapies: déjà vu all over again.  

PubMed

A major limitation of targeted anticancer therapies is intrinsic or acquired resistance. This review emphasizes similarities in the mechanisms of resistance to endocrine therapies in breast cancer and those seen with the new generation of targeted cancer therapeutics. Resistance to single-agent cancer therapeutics is frequently the result of reactivation of the signaling pathway, indicating that a major limitation of targeted agents lies in their inability to fully block the cancer-relevant signaling pathway. The development of mechanism-based combinations of targeted therapies together with non-invasive molecular disease monitoring is a logical way forward to delay and ultimately overcome drug resistance development. PMID:24910388

Groenendijk, Floris H; Bernards, René

2014-09-12

241

Effect of Vibration on Bacterial Growth and Antibiotic Resistance  

NASA Technical Reports Server (NTRS)

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

Juergensmeyer, Elizabeth A.; Juergensmeyer, Margaret A.

2004-01-01

242

Drug resistant tuberculosis can be controlled, says WHO.  

PubMed

Hard evidence on the prevention of drug resistant tuberculosis by using properly controlled treatment programs was gathered by the WHO. However, the WHO warned that a window of opportunity to prevent the spread of drug resistant strains will be missed if urgent action is not taken to persuade more health authorities to use its recommended treatment strategy. Reports from 58 countries have shown a disturbingly high prevalence of drug-resistant strains of Mycobacterium tuberculosis in Eastern Europe and Asia, while countries that have used the recommended treatment strategy tend to have low rates of resistance. The WHO has been arguing for directly observed treatment, short course for years on the basis of small-scale studies that show it helps to prevent the emergence of resistance. In countries like India, China, Indonesia, Bangladesh, and Pakistan, the scale of drug resistance is still unknown with high incidence of tuberculosis. Prevalence of tuberculosis is still high in Estonia, as well as in some provinces of India and China although the scale of the problem is small. PMID:10731157

Brown, P

2000-03-25

243

Drugs that target pathogen public goods are robust against evolved drug resistance  

PubMed Central

Pathogen drug resistance is a central problem in medicine and public health. It arises through somatic evolution, by mutation and selection among pathogen cells within a host. Here, we examine the hypothesis that evolution of drug resistance could be reduced by developing drugs that target the secreted metabolites produced by pathogen cells instead of directly targeting the cells themselves. Using an agent-based computational model of an evolving population of pathogen cells, we test this hypothesis and find support for it. We also use our model to explain this effect within the framework of standard evolutionary theory. We find that in our model, the drugs most robust against evolved drug resistance are those that target the most widely shared external products, or ‘public goods’, of pathogen cells. We also show that these drugs exert a weak selective pressure for resistance because they create only a weak correlation between drug resistance and cell fitness. The same principles apply to design of vaccines that are robust against vaccine escape. Because our theoretical results have crucial practical implications, they should be tested by empirical experiments. PMID:23144661

Pepper, John W

2012-01-01

244

Antibacterial effect of Allium sativum cloves and Zingiber officinale rhizomes against multiple-drug resistant clinical pathogens  

PubMed Central

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

Karuppiah, Ponmurugan; Rajaram, Shyamkumar

2012-01-01

245

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

246

Induction of Systemic Resistance Against Bacterial Wilt in Eucalyptus urophylla by Fluorescent Pseudomonas spp  

Microsoft Academic Search

The ability of selected strains of fluorescent Pseudomonas spp. to cause induced systemic resistance (ISR) in Eucalyptus urophylla against bacterial wilt caused by Ralstonia solanacearum was investigated. Four of the five strains used can produce salicylic acid (SA) in vitro and, therefore, chemical SA, that is known to induce resistance in many plant species, was used as a reference treatment.

L. X. Ran; Z. N. Li; G. J. Wu; L. C. van Loon; P. A. H. M. Bakker

2005-01-01

247

Antibiotic resistance of bacterial strains isolated from children in Child Health Center, Warsaw  

Microsoft Academic Search

This study examines the antibiotic susceptibility of 1792 bacterial strains isolated from hospitalized children between January and December 1993. A total of 1015 Gram-negative rods represented by members of Enterobacteriaceae family (770) and nonfermenters (245) were isolated. The most resistant strains were noticed among Klebsiella pneumoniae and Enterobacter cloacae. From 38% to 46% of K. pneumoniae strains were resistant to

D. Dzier?anowska; U. ?opaciuk; W. Kami?ska; J. Wieczy?ska; A. Pawi?ska; J. Patzer

1995-01-01

248

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

ERIC Educational Resources Information Center

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…

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

2009-01-01

249

Ecology and Evolution as Targets: the Need for Novel Eco-Evo Drugs and Strategies To Fight Antibiotic Resistance?†  

PubMed Central

In recent years, the explosive spread of antibiotic resistance determinants among pathogenic, commensal, and environmental bacteria has reached a global dimension. Classical measures trying to contain or slow locally the progress of antibiotic resistance in patients on the basis of better antibiotic prescribing policies have clearly become insufficient at the global level. Urgent measures are needed to directly confront the processes influencing antibiotic resistance pollution in the microbiosphere. Recent interdisciplinary research indicates that new eco-evo drugs and strategies, which take ecology and evolution into account, have a promising role in resistance prevention, decontamination, and the eventual restoration of antibiotic susceptibility. This minireview summarizes what is known and what should be further investigated to find drugs and strategies aiming to counteract the “four P's,” penetration, promiscuity, plasticity, and persistence of rapidly spreading bacterial clones, mobile genetic elements, or resistance genes. The term “drug” is used in this eco-evo perspective as a tool to fight resistance that is able to prevent, cure, or decrease potential damage caused by antibiotic resistance, not necessarily only at the individual level (the patient) but also at the ecological and evolutionary levels. This view offers a wealth of research opportunities for science and technology and also represents a large adaptive challenge for regulatory agencies and public health officers. Eco-evo drugs and interventions constitute a new avenue for research that might influence not only antibiotic resistance but the maintenance of a healthy interaction between humans and microbial systems in a rapidly changing biosphere. PMID:21576439

Baquero, Fernando; Coque, Teresa M.; de la Cruz, Fernando

2011-01-01

250

Treatment of drug-resistant Shigella infections.  

PubMed

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

Klontz, Karl C; Singh, Nalini

2015-01-01

251

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

NASA Astrophysics Data System (ADS)

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

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

2007-12-01

252

Polyacrylic acid-coated iron oxide nanoparticles for targeting drug resistance in mycobacteria.  

PubMed

The emergence of drug resistance is a major problem faced in current tuberculosis (TB) therapy, representing a global health concern. Mycobacterium is naturally resistant to most drugs due to export of the latter outside bacterial cells by active efflux pumps, resulting in a low intracellular drug concentration. Thus, development of agents that can enhance the effectiveness of drugs used in TB treatment and bypass the efflux mechanism is crucial. In this study, we present a new nanoparticle-based strategy for enhancing the efficacy of existing drugs. To that end, we have developed poly(acrylic acid) (PAA)-coated iron oxide (magnetite) nanoparticles (PAA-MNPs) as efflux inhibitors and used it together with rifampicin (a first line anti-TB drug) on Mycobacterium smegmatis. PAA-MNPs of mean diameter 9 nm interact with bacterial cells via surface attachment and are then internalized by cells. Although PAA-MNP alone does not inhibit cell growth, treatment of cells with a combination of PAA-MNP and rifampicin exhibits a synergistic 4-fold-higher growth inhibition compared to rifampicin alone. This is because the combination of PAA-MNP and rifampicin results in up to a 3-fold-increased accumulation of rifampicin inside the cells. This enhanced intracellular drug concentration has been explained by real-time transport studies on a common efflux pump substrate, ethidium bromide (EtBr). It is seen that PAA-MNP increases the accumulation of EtBr significantly and also minimizes the EtBr efflux in direct proportion to the PAA-MNP concentration. Our results thus illustrate that the addition of PAA-MNP with rifampicin may bypass the innate drug resistance mechanism of M. smegmatis. This generic strategy is also found to be successful for other anti-TB drugs, such as isoniazid and fluoroquinolones (e.g., norfloxacin), only when stabilized, coated nanoparticles (such as PAA-MNP) are used, not PAA or MNP alone. We hence establish coated nanoparticles as a new class of efflux inhibitors for potential therapeutic use. PMID:25375643

Padwal, Priyanka; Bandyopadhyaya, Rajdip; Mehra, Sarika

2014-12-23

253

Evolution of drug resistance in Salmonella panama isolates in Chile.  

PubMed Central

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

Cordano, A M; Virgilio, R

1996-01-01

254

Antiviral Drug- and Multidrug Resistance in Cytomegalovirus Infected SCT Patients  

PubMed Central

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.

Göhring, Katharina; Hamprecht, Klaus; Jahn, Gerhard

2015-01-01

255

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

PubMed Central

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 the mechanisms behind and the extent of multi-drug resistance among bacteria living under an extreme antibiotic selection pressure. PMID:24204801

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

2013-01-01

256

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

PubMed

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

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

257

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

PubMed Central

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

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

258

Sec and drugs and rock'n'roll: antibiotic targeting of bacterial protein translocation Anti-infectives  

E-print Network

Economou Sec and drugs and rock'n'roll: antibiotic targeting of bacterial protein translocation Anti-infectives Sec, drugs and rock'n'roll: antibiotic targeting of bacterial protein translocation of these secretory and membrane polypeptides is mediated by the Sec pathway. Protein secretion requires the co

Economou, Tassos

259

PERSPECTIVE Emergence of Drug-Resistant  

E-print Network

resist- ance, the efficacy of chemoprophylaxis is comparable to that of vaccines. The efficacy of an effective vaccine against influenza, antiviral agents will play an important role as a first-line defense of vaccines in preventing laboratory-confirmed illness is around 80% in children and adults

Bonhoeffer, Sebastian

260

Role of Integrin Alpha4 in Drug Resistance of Leukemia  

PubMed Central

Chemotherapeutic drug resistance in acute lymphoblastic leukemia (ALL) is a significant problem, resulting in poor responsiveness to first-line treatment or relapse after transient remission. Classical anti-leukemic drugs are non-specific cell cycle poisons; some more modern drugs target oncogenic pathways in leukemia cells, although in ALL these do not play a very significant role. By contrast, the molecular interactions between microenvironment and leukemia cells are often neglected in the design of novel therapies against drug resistant leukemia. It was shown however, that chemotherapy resistance is promoted in part through cell–cell contact of leukemia cells with bone marrow (BM) stromal cells, also called cell adhesion-mediated drug resistance (CAM-DR). Incomplete response to chemotherapy results in persistence of resistant clones with or without detectable minimal residual disease (MRD). Approaches for how to address CAM-DR and MRD remain elusive. Specifically, studies using anti-functional antibodies and genetic models have identified integrin alpha4 as a critical molecule regulating BM homing and active retention of normal and leukemic cells. Pre-clinical evidence has been provided that interference with alpha4-mediated adhesion of ALL cells can sensitize them to chemotherapy and thus facilitate eradication of ALL cells in an MRD setting. To this end, Andreeff and colleagues recently provided evidence of stroma-induced and alpha4-mediated nuclear factor-?B signaling in leukemia cells, disruption of which depletes leukemia cells of strong survival signals. We here review the available evidence supporting the targeting of alpha4 as a novel strategy for treatment of drug resistant leukemia. PMID:24904821

Shishido, Stephanie; Bönig, Halvard; Kim, Yong-Mi

2014-01-01

261

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

PubMed

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

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

2014-08-28

262

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

PubMed Central

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

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

2014-01-01

263

Plant ferredoxin-like protein (PFLP) outside chloroplast in Arabidopsis enhances disease resistance against bacterial pathogens.  

PubMed

Protection of crops against bacterial disease is an important issue in agricultural production. One of the strategies to lead plants become resistant against bacterial pathogens is employing a transgene, like plant ferredoxin-like protein (PFLP). PFLP is a photosynthetic type ferredoxin isolated from sweet pepper and contains a signal peptide for targeting towards chloroplasts. Our previous reports indicated that transgenic plants with this protein are more resistant against bacterial pathogens. However, this heterologous protein was visualized not only inside the chloroplasts, but also in the cytoplasm. In this article, we moved to study its heterologous expression in Arabidopsis by expressing the protein in chloroplast, apoplast and cytoplasm. This work was achieved by engineering a chloroplast target (CPF), an apoplast target (ESF), and cytoplasm target (DF) plants. The expression and subcellular localization of PFLP were analyzed by Western blot and immuno-staining by confocal microscopy, respectively. We tested the ability of the transgenic Arabidopsis for resistance to two Ralstonia solanacearum strains and their ability to increase the hypersensitive response (HR) triggered by harpin (HrpZ) from Pseudomonas syringae. The DF and ESF plants conferred resistance against bacterial wilt strains and increased HR by harpin, but no resistance found in the CPF plants. In addition, we determined the level of reduced ascorbate in all transgenic plants and further analyzed the expression of two NADPH-oxidase genes (AtrbohD and AtrbohF) in ESF plant. Among the transgenic Arabidopsis plants, ESF plants confer the highest resistance to bacterial pathogens and followed by DF plants. We concluded that PFLP enhances disease resistance in Arabidopsis when expressed in the apoplast or in cytoplasm but not when targeted into the chloroplast. This study provides a strategy for molecular breeding to improve resistance of crops against bacterial pathogens. PMID:21802603

Lin, Yi-Hsien; Huang, Hsiang-En; Wu, Fang-Sheng; Ger, Mang-Jye; Liao, Pei-Luan; Chen, Yen-Ru; Tzeng, Kuo-Ching; Feng, Teng-Yung

2010-11-01

264

Dynamic optical tweezers based assay for monitoring early drug resistance  

NASA Astrophysics Data System (ADS)

In this letter, a dynamic optical tweezers based assay is proposed and investigated for monitoring early drug resistance with Pemetrexed-resistant non-small cell lung cancer (NSCLC) cell lines. The validity and stability of the method are verified experimentally in terms of the physical parameters of the optical tweezers system. The results demonstrate that the proposed technique is more convenient and faster than traditional techniques when the capability of detecting small variations of the response of cells to a drug is maintained.

Wu, Xiaojing; Zhang, Yuquan; Min, Changjun; Zhu, Siwei; Feng, Jie; Yuan, X.-C.

2013-06-01

265

Microbial persistence and the road to drug resistance  

PubMed Central

Summary Microbial drug persistence is a widespread phenomenon in which a sub-population of microorganisms is able to survive antimicrobial treatment without acquiring resistance-conferring genetic changes. Microbial persisters can cause recurrent or intractable infections, and like resistant mutants, they carry an increasing clinical burden. In contrast to heritable drug resistance, however, the biology of persistence is only beginning to be unraveled. Persisters have traditionally been thought of as metabolically dormant, non-dividing cells. However, as discussed in this review, increasing evidence suggests that persistence is in fact an actively maintained state, triggered and enabled by a network of intracellular stress-responses that can accelerate processes of adaptive evolution. Beyond shedding light on the basis of persistence, these findings raise the possibility that persisters behave as an evolutionary reservoir from which resistant organisms can emerge. As persistence and its consequences come into clearer focus, clinically relevant eradication strategies are urgently needed. PMID:23768488

Cohen, Nadia R.; Lobritz, Michael A.; Collins, James J.

2013-01-01

266

The new concepts on overcoming drug resistance in lung cancer  

PubMed Central

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

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

2014-01-01

267

Genetic variation for bacterial wilt resistance in a population of tetraploid potato  

Microsoft Academic Search

Genetic variance components and heritability were estimated for resistance to bacterial wilt in a population of tetraploid potato with resistance derived from several specific sources. Both additive and non-additive variance components were significant. Their relative magnitudes indicated the importance of non-additive gene action in the genetic control of the resistance. Narrow-sense heritability was relatively low for both disease index and

Pham X. Tung

1992-01-01

268

Emerging novel and antimicrobial-resistant respiratory tract infections: new drug development and therapeutic options.  

PubMed

The emergence and spread of antimicrobial-resistant bacterial, viral, and fungal pathogens for which diminishing treatment options are available is of major global concern. New viral respiratory tract infections with epidemic potential, such as severe acute respiratory syndrome, swine-origin influenza A H1N1, and Middle East respiratory syndrome coronavirus infection, require development of new antiviral agents. The substantial rise in the global numbers of patients with respiratory tract infections caused by pan-antibiotic-resistant Gram-positive and Gram-negative bacteria, multidrug-resistant Mycobacterium tuberculosis, and multiazole-resistant fungi has focused attention on investments into development of new drugs and treatment regimens. Successful treatment outcomes for patients with respiratory tract infections across all health-care settings will necessitate rapid, precise diagnosis and more effective and pathogen-specific therapies. This Series paper describes the development and use of new antimicrobial agents and immune-based and host-directed therapies for a range of conventional and emerging viral, bacterial, and fungal causes of respiratory tract infections. PMID:25189352

Zumla, Alimuddin; Memish, Ziad A; Maeurer, Markus; Bates, Matthew; Mwaba, Peter; Al-Tawfiq, Jaffar A; Denning, David W; Hayden, Frederick G; Hui, David S

2014-11-01

269

Combinatorial discovery of polymers resistant to bacterial attachment  

PubMed Central

Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these ‘hit’ materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions. PMID:22885723

Luckett, Jeni; Cockayne, Alan; Atkinson, Steve; Mei, Ying; Bayston, Roger; Irvine, Derek J; Langer, Robert; Anderson, Daniel G; Williams, Paul; Davies, Martyn C; Alexander, Morgan R

2013-01-01

270

Combinatorial discovery of polymers resistant to bacterial attachment.  

PubMed

Bacterial attachment and subsequent biofilm formation pose key challenges to the optimal performance of medical devices. In this study, we determined the attachment of selected bacterial species to hundreds of polymeric materials in a high-throughput microarray format. Using this method, we identified a group of structurally related materials comprising ester and cyclic hydrocarbon moieties that substantially reduced the attachment of pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli). Coating silicone with these 'hit' materials achieved up to a 30-fold (96.7%) reduction in the surface area covered by bacteria compared with a commercial silver hydrogel coating in vitro, and the same material coatings were effective at reducing bacterial attachment in vivo in a mouse implant infection model. These polymers represent a class of materials that reduce the attachment of bacteria that could not have been predicted to have this property from the current understanding of bacteria-surface interactions. PMID:22885723

Hook, Andrew L; Chang, Chien-Yi; Yang, Jing; Luckett, Jeni; Cockayne, Alan; Atkinson, Steve; Mei, Ying; Bayston, Roger; Irvine, Derek J; Langer, Robert; Anderson, Daniel G; Williams, Paul; Davies, Martyn C; Alexander, Morgan R

2012-09-01

271

Getting personal perspectives on individualized treatment duration in multidrug-resistant and extensively drug-resistant tuberculosis.  

PubMed

Tuberculosis (TB) differs from most other bacterial infectious diseases by a very long duration of combination antibiotic therapy required to achieve relapse-free cure. Although the standard recommended "short-course" treatment length for TB is 6 months, the World Health Organization recommends a duration of 20 months for the treatment of patients with multidrug-resistant and extensively drug-resistant TB (M/XDR-TB). Apart from the long duration of anti-TB therapy, treatment of M/XDR-TB is very expensive and often associated with adverse drug events. The optimal duration for treatment of TB likely differs between individuals and depends on a variety of variables, such as the extent of the disease, the immune status of the host, and the virulence and the drug resistance of the causative strain of Mycobacterium tuberculosis. Some patients with M/XDR-TB may have to be treated with currently available antituberculosis drug regimens for more than 20 months, whereas much shorter treatment durations may be possible to achieve cure for the majority of patients with M/XDR-TB. Personalization of the duration of treatment for TB, especially for patients with M/XDR-TB, would be highly desired. Until recently there has been little interest in the identification of biosignatures that could eventually lead to individual recommendations for the duration of anti-TB therapy. This pulmonary perspective reviews the knowledge on clinical and radiological scores, host- and pathogen disease-related profiles, molecules, and signatures that are currently explored as biomarkers to personalize the duration of therapy in TB. PMID:24941306

Heyckendorf, Jan; Olaru, Ioana D; Ruhwald, Morten; Lange, Christoph

2014-08-15

272

Abies koreana Essential Oil Inhibits Drug-Resistant Skin Pathogen Growth and LPS-Induced Inflammatory Effects of Murine Macrophage  

Microsoft Academic Search

Since acne vulgaris is the combined result of a bacterial infection and the inflammatory response to that infection, we examined\\u000a whether Abies koreana essential oil (AKE) possessed anti-inflammatory and antibacterial activities against skin pathogens. In this study, AKE showed\\u000a excellent antibacterial activities against drug-susceptible and -resistant Propionibacterium acnes and Staphylococcus epidermidis, which are acne-causing bacteria. In addition, AKE reduced the

Weon-Jong Yoon; Sang-Suk Kim; Tae-Heon Oh; Nam Ho Lee; Chang-Gu Hyun

2009-01-01

273

O1.2Drugging the cancer genome to overcome drug resistance.  

PubMed

We are facing a major transformational inflection point in the history of cancer drug discovery. We have successfully transitioned from the first golden age of cytotoxic chemotherapy into the second golden age of molecularly targeted drugs that exploit the molecular addictions and vulnerabilities of cancer cells. But despite the successes, we have encountered the same therapeutic roadblock: the inexorable and enduring problem of drug resistance. On the more optimistic side, we now understand the fundamental processes that underpin drug resistance. These involve genetic instability; genetic and phenotypic heterogeneity; and evolution under the selective pressure of the tumour microenvironment and therapeutic challenge. This understanding arms us with knowledge upon which to mount an attack on cancer evolution that will lead us into the third golden age of cancer drug discovery with the expectation of achieving long term control and eventual cure for many patients. I propose a 3-pronged attack involving: Extending the druggable genome (beyond the current 5% coverage of targeted cancer genes) to provide drugs that cover all elements of the network of oncogenic mechanisms Use of our expanded armamentarium of drugs in intelligent combinations to reduce the opportunity for bypass mechanisms Design of drugs that target key fundamental drivers of cancer evolution and drug resistance which may be different from targets that exploit addictions and synthetic lethalities. In addition to exploring these concepts I will present recent work from my laboratory that demonstrates the potential of PI3 kinase and HSP90 inhibitors to contribute to overcoming and preventing cancer evolution and drug resistance. PMID:25795796

Workman, P

2015-03-01

274

Role of the Mmr Efflux Pump in Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Efflux pumps are membrane proteins capable of actively transporting a broad range of substrates from the cytoplasm to the exterior of the cell. Increased efflux activity in response to drug treatment may be the first step in the development of bacterial drug resistance. Previous studies showed that the efflux pump Mmr was significantly overexpressed in strains exposed to isoniazid. In the work to be described, we constructed mutants lacking or overexpressing Mmr in order to clarify the role of this efflux pump in the development of resistance to isoniazid and other drugs in M. tuberculosis. The mmr knockout mutant showed an increased susceptibility to ethidium bromide, tetraphenylphosphonium, and cetyltrimethylammonium bromide (CTAB). Overexpression of mmr caused a decreased susceptibility to ethidium bromide, acriflavine, and safranin O that was obliterated in the presence of the efflux inhibitors verapamil and carbonyl cyanide m-chlorophenylhydrazone. Isoniazid susceptibility was not affected by the absence or overexpression of mmr. The fluorometric method allowed the detection of a decreased efflux of ethidium bromide in the knockout mutant, whereas the overexpressed strain showed increased efflux of this dye. This increased efflux activity was inhibited in the presence of efflux inhibitors. Under our experimental conditions, we have found that efflux pump Mmr is mainly involved in the susceptibility to quaternary compounds such as ethidium bromide and disinfectants such as CTAB. The contribution of this efflux pump to isoniazid resistance in Mycobacterium tuberculosis still needs to be further elucidated. PMID:23165464

Rodrigues, Liliana; Villellas, Cristina; Bailo, Rebeca; Viveiros, Miguel

2013-01-01

275

Dominant gene for common bean resistance to common bacterial blight caused by Xanthomonas axonopodis pv. phaseoli  

Microsoft Academic Search

The common bacterial blight pathogen [Xanthomonas axonopodis pv. phaseoli (Xap)] is a limiting factor for common bean (Phaseolus vulgaris L.) production worldwide and resistance to the pathogen in most commercial cultivars is inadequate. Variability in virulence\\u000a of the bacterial pathogen has been observed in strains isolated from Puerto Rico and Central America. A few common bean lines\\u000a show a differential

Mildred Zapata; James S. Beaver; Timothy G. Porch

2011-01-01

276

Broad-spectrum in vitro antibacterial activities of clay minerals against antibiotic-susceptible and antibiotic-resistant bacterial pathogens  

PubMed Central

SYNOPSIS Objectives The capacity to properly address the worldwide incidence of infectious diseases lies in the ability to detect, prevent, and effectively treat these infections. Therefore, identifying and analyzing inhibitory agents are worthwhile endeavors in an era when few new classes of effective antimicrobials have been developed. The use of geological nanomaterials to heal skin infections has been evident since the earliest recorded history, and specific clay minerals may prove valuable in the treatment of bacterial diseases, including infections for which there are no effective antibiotics, such as Buruli ulcer and multi-drug resistant infections. Methods We have subjected two iron-rich clay minerals, which have previously been used to treat Buruli ulcer patients, to broth culture testing of antibiotic-susceptible and -resistant pathogenic bacteria to assess the feasibility of using clay minerals as therapeutic agents. Results One specific mineral, CsAg02, demonstrated bactericidal activity against pathogenic Escherichia coli, extended-spectrum ?-lactamase (ESBL) E. coli, S. enterica serovar Typhimurium, Pseudomonas aeruginosa, and Mycobacterium marinum and a combined bacteriostatic/bactericidal effect against Staphylococcus aureus, penicillin-resistant S. aureus (PRSA), methicillin-resistant S. aureus (MRSA), and Mycobacterium smegmatis, while another mineral with similar structure and bulk crystal chemistry, CsAr02, had no effect on or enhanced bacterial growth. The <0.2 ?m fraction of CsAg02 and CsAg02 heated to 200°C or 550°C retained bactericidal activity, while cation-exchanged CsAg02 and CsAg02 heated to 900°C no longer killed E. coli. Conclusions Our results indicate that specific mineral products have intrinsic, heat-stable antibacterial properties, which could provide an inexpensive treatment against numerous human bacterial infections. PMID:18070832

HAYDEL, SHELLEY E.; REMENIH, CHRISTINE M.; WILLIAMS, LYNDA B.

2008-01-01

277

Epigenetics as a mechanism driving polygenic clinical drug resistance  

Microsoft Academic Search

Aberrant methylation of CpG islands located at or near gene promoters is associated with inactivation of gene expression during tumour development. It is increasingly recognised that such epimutations may occur at a much higher frequency than gene mutation and therefore have a greater impact on selection of subpopulations of cells during tumour progression or acquisition of resistance to anticancer drugs.

R M Glasspool; J M Teodoridis; R Brown

2006-01-01

278

Knowledgebased Avoidance of DrugResistant HIV Mutants  

E-print Network

knowledge base encode knowledge about sequence mutations in the HIV genome that have been found to result sequence mutations in the HIV genome have been described in the scientific literature and associatedKnowledge­based Avoidance of Drug­Resistant HIV Mutants Richard H. Lathrop, Nicholas R. Steffen

Pazzani, Michael J.

279

METHOD FOR MEASURING BACTERIAL RESISTANCE TO METALS EMPLOYING EPIFLUORESCENT MICROSCOPY  

EPA Science Inventory

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

280

Enterococcus faecalis Constitutes an Unusual Bacterial Model in Lysozyme Resistance  

Microsoft Academic Search

Lysozyme is an important and widespread compound of the host constitutive defense system, and it is assumed that Enterococcus faecalis is one of the few bacteria that are almost completely lysozyme resistant. On the basis of the sequence analysis of the whole genome of E. faecalis V583 strain, we identified two genes that are potentially involved in lysozyme resistance, EF_0783

Laurent Hebert; Pascal Courtin; Riccardo Torelli; Maurizio Sanguinetti; Marie-Pierre Chapot-Chartier; Yanick Auffray; Abdellah Benachour

2007-01-01

281

Resistance to fluoroquinolones and second-line injectable drugs: impact on multidrug-resistant TB outcomes.  

PubMed

A meta-analysis for response to treatment was undertaken using individual data of multidrug-resistant tuberculosis (MDR-TB) (resistance to isoniazid and rifampicin) patients from 26 centres. The analysis assessed the impact of additional resistance to fluoroquinolones and/or second-line injectable drugs on treatment outcome. Compared with treatment failure, relapse and death, treatment success was higher in MDR-TB patients infected with strains without additional resistance (n=4763; 64%, 95% CI 57-72%) or with resistance to second-line injectable drugs only (n=1130; 56%, 95% CI 45-66%), than in those having resistance to fluoroquinolones alone (n=426; 48%, 95% CI 36-60%) or to fluoroquinolones plus second-line injectable drugs (extensively drug resistant (XDR)-TB) (n=405; 40%, 95% CI 27-53%). In XDR-TB patients, treatment success was highest if at least six drugs were used in the intensive phase (adjusted OR 4.9, 95% CI 1.4-16.6; reference fewer than three drugs) and four in the continuation phase (OR 6.1, 95% CI 1.4-26.3). The odds of success in XDR-TB patients was maximised when the intensive phase reached 6.6-9.0 months duration and the total duration of treatment 20.1-25.0 months. In XDR-TB patients, regimens containing more drugs than those recommended in MDR-TB but given for a similar duration were associated with the highest odds of success. All data were from observational studies and methodologies varied between centres, therefore, the bias may be substantial. Better quality evidence is needed to optimise regimens. PMID:23100499

Falzon, Dennis; Gandhi, Neel; Migliori, Giovanni B; Sotgiu, Giovanni; Cox, Helen S; Holtz, Timothy H; Hollm-Delgado, Maria-Graciela; Keshavjee, Salmaan; DeRiemer, Kathryn; Centis, Rosella; D'Ambrosio, Lia; Lange, Christoph G; Bauer, Melissa; Menzies, Dick

2013-07-01

282

Modeling mass drug treatment and resistant filaria disease transmission  

NASA Astrophysics Data System (ADS)

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.

Fuady, A. M.; Nuraini, N.; Soewono, E.; Tasman, H.; Supriatna, A. K.

2014-03-01

283

Correlation Models between Environmental Factors and Bacterial Resistance to Antimony and Copper  

PubMed Central

Antimony (Sb) and copper (Cu) are toxic heavy metals that are associated with a wide variety of minerals. Sb(III)-oxidizing bacteria that convert the toxic Sb(III) to the less toxic Sb(V) are potentially useful for environmental Sb bioremediation. A total of 125 culturable Sb(III)/Cu(II)-resistant bacteria from 11 different types of mining soils were isolated. Four strains identified as Arthrobacter, Acinetobacter and Janibacter exhibited notably high minimum inhibitory concentrations (MICs) for Sb(III) (>10 mM),making them the most highly Sb(III)-resistant bacteria to date. Thirty-six strains were able to oxidize Sb(III), including Pseudomonas-, Comamonas-, Acinetobacter-, Sphingopyxis-, Paracoccus- Aminobacter-, Arthrobacter-, Bacillus-, Janibacter- and Variovorax-like isolates. Canonical correspondence analysis (CCA) revealed that the soil concentrations of Sb and Cu were the most obvious environmental factors affecting the culturable bacterial population structures. Stepwise linear regression was used to create two predictive models for the correlation between soil characteristics and the bacterial Sb(III) or Cu(II) resistance. The concentrations of Sb and Cu in the soil was the significant factors affecting the bacterial Sb(III) resistance, whereas the concentrations of S and P in the soil greatly affected the bacterial Cu(II) resistance. The two stepwise linear regression models that we derived are as follows: and [where the MICSb(III) and MICCu(II) represent the average bacterial MIC for the metal of each soil (µM), and the CSb, CCu, CS and CP represent concentrations for Sb, Cu, S and P (mg/kg) in soil, respectively, p<0.01]. The stepwise linear regression models we developed suggest that metals as well as other soil physicochemical parameters can contribute to bacterial resistance to metals. PMID:24205252

Shi, Zunji; Cao, Zhan; Qin, Dong; Zhu, Wentao; Wang, Qian; Li, Mingshun; Wang, Gejiao

2013-01-01

284

Analysis of some common pathogens and their drug resistance to antibiotics  

PubMed Central

Objective: To investigate the common bacterial resistance of clinical isolates in our hospital in the second half of 2011. Methodology: Pathogens isolated from clinical samples in the second half of 2011 were analyzed and categorized to perform susceptibility tests. Results: In the gram-negative bacteria, Enterobacteriaceae and non-fermenting gram-negative bacilli accounted for 55.89% and 34.51%. In the gram-positive bacteria, Staphylococcus aureus, Coagulase-negative staphylococci, Enterococcus, Strptococcus pneumonia accounted for 32.85%, 40.39%, 12.41% and 10.22%, respectively. Other species accounted for 4.14%. Klebsiella pneumonia and Pseudomonas aeruginosa were sensitive to cepoperazon, cefepime and imipenem. However,Acinetobacter baumannii was more sensitive to carbapenems antibiotics, which was followed by fourth generation cephalosporins. Klebsiella pneumoniae was extremely sensitive to amikacin, cefepime and imipenem, but was resistant to ampicillin. The detection rates of the broad-spectrum Escherichia coli, Pseudomonasaeruginosa and Klebsiella pneumoniae were 54.51%, 52.08% and 38.65%. The gram negative bacilli were the prevalent clinical pathogens in our hospital in the second half of 2011. Conclusion: The drug resistance of pathogenic bacteria has increased significantly recently, thus the surveillance of antibacterial agents is necessary, and rational use of antibiotic will be urgently needed to reduce the production and dissemination of drug resistant strains. PMID:24353525

Bao, Lidao; Peng, Rui; Ren, Xianhua; Ma, Ruilian; Li, Junping; Wang, Yi

2013-01-01

285

Wear and corrosion resistance of anti-bacterial Ti-Cu-N coatings on titanium implants  

NASA Astrophysics Data System (ADS)

Anti-bacterial coatings with excellent wear and corrosion resistance play a vital role in ensuring the durability of implant materials in constant use. To this end, a novel anti-bacterial surface modification by combining magnetron sputtering with plasma nitriding was adopted in this paper to fabricate Cu-bearing Ti-based nitrides coatings (Ti-Cu-N) on titanium surface. The anti-bacterial properties of Ti-Cu-N coatings were evaluated. The microstructures and composition of the coatings were investigated by using FESEM, EDS, GDOES, XRD. The wear and corrosion resistance of the coatings were investigated. The results confirmed that an anti-bacterial Ti-Cu-N coating with a thickness of 6 ?m and good adhesive strength to substrate was successfully achieved on titanium surface. As implied by XRD, the coatings were consisted of TiN, Ti2N, TiN0.3 phases. The surface micro-hardness and wear resistance of Ti-Cu-N coatings were significantly enhanced after plasma nitriding treatment. The analysis of potentiodynamic polarization curves and Nyquist plots obtained in 0.9 wt.% NaCl solution suggested that the Ti-Cu-N coatings also exhibited an excellent corrosion resistance. As mentioned above, it can be concluded that the duplex-treatment reported here was a versatile approach to develop anti-bacterial Ti-Cu-N coatings with excellent comprehensive properties on titanium implants.

Wu, Haibo; Zhang, Xiangyu; He, Xiaojing; Li, Meng; Huang, Xiaobo; Hang, Ruiqiang; Tang, Bin

2014-10-01

286

Using experimental evolution to explore natural patterns between bacterial motility and resistance to bacteriophages  

PubMed Central

Resistance of bacteria to phages may be gained by alteration of surface proteins to which phages bind, a mechanism that is likely to be costly as these molecules typically have critical functions such as movement or nutrient uptake. To address this potential trade-off, we combine a systematic study of natural bacteria and phage populations with an experimental evolution approach. We compare motility, growth rate and susceptibility to local phages for 80 bacteria isolated from horse chestnut leaves and, contrary to expectation, find no negative association between resistance to phages and bacterial motility or growth rate. However, because correlational patterns (and their absence) are open to numerous interpretations, we test for any causal association between resistance to phages and bacterial motility using experimental evolution of a subset of bacteria in both the presence and absence of naturally associated phages. Again, we find no clear link between the acquisition of resistance and bacterial motility, suggesting that for these natural bacterial populations, phage-mediated selection is unlikely to shape bacterial motility, a key fitness trait for many bacteria in the phyllosphere. The agreement between the observed natural pattern and the experimental evolution results presented here demonstrates the power of this combined approach for testing evolutionary trade-offs. PMID:21509046

Koskella, Britt; Taylor, Tiffany B; Bates, Jennifer; Buckling, Angus

2011-01-01

287

The “Connection” Between HIV Drug Resistance and RNase H  

PubMed Central

Currently, nucleoside reverse transcriptase inhibitors (NRTIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) are two classes of antiretroviral agents that are approved for treatment of HIV-1 infection. Since both NRTIs and NNRTIs target the polymerase (pol) domain of reverse transcriptase (RT), most genotypic analysis for drug resistance is limited to the first ?300 amino acids of RT. However, recent studies have demonstrated that mutations in the C-terminal domain of RT, specifically the connection subdomain and RNase H domain, can also increase resistance to both NRTIs and NNRTIs. In this review we will present the potential mechanisms by which mutations in the C-terminal domain of RT influence NRTI and NNRTI susceptibility, summarize the prevalence of the mutations in these regions of RT identified to date, and discuss their importance to clinical drug resistance. PMID:21088701

Delviks-Frankenberry, Krista A.; Nikolenko, Galina N.; Pathak, Vinay K.

2010-01-01

288

75 FR 52755 - Draft Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing...  

Federal Register 2010, 2011, 2012, 2013, 2014

...development of new drugs to treat drug-resistant bacterial pathogens implicated in ABSSSI, such as methicillin-resistant Staphylococcus aureus. The definitions of ABSSSI and the designs of ABSSSI clinical trials were discussed at a meeting of the...

2010-08-27

289

Compassionate use of and expanded access to new drugs for drug-resistant tuberculosis.  

PubMed

Several new classes of anti-tuberculosis agents are likely to become available in the coming decade. Ensuring prompt access to these drugs for patients without other treatment options is an important medical and public health issue. This article reviews the current state of 'compassionate use' and 'expanded access' programs for these new drugs, and identifies several shortcomings that will limit patient access to the drugs. A series of five steps is outlined that will need to be taken by national health bodies, international agencies and non-governmental organizations to prevent undue delays in access to new tuberculosis drugs for patients who could benefit from them. Following these steps can ensure that patients will be able to benefit from access to these drugs, while minimizing the risk of emergence of resistance to the drug. PMID:23211610

Horsburgh, C R; Haxaire-Theeuwes, M; Lienhardt, C; Wingfield, C; McNeeley, D; Pyne-Mercier, L; Keshavjee, S; Varaine, F

2013-02-01

290

Clinically Relevant Transmitted Drug Resistance to First Line Antiretroviral Drugs and Implications for Recommendations  

PubMed Central

Background The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR) defined by the 2009 update of the WHO SDRM list. Methods We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain) between 2007–2011. Using the Stanford algorithm “Low-level resistance”, “Intermediate resistance” and “High-level resistance” categories were considered as “Resistant”. Results 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8–7.7)], and 221 harbored TDR using the WHO list [7.9% (6.9–9.0)]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8–2.9) vs. 3.6% (2.9–4.3) by the WHO list] and PIs [0.8% (0.4–1.1) vs. 1.7% (1.2–2.2)], while it was higher for NNRTIs [4.6% (3.8–5.3) vs. 3.7% (3.0–4.7)]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p?=?0.02). Conclusions Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations. PMID:24637804

Monge, Susana; Guillot, Vicente; Alvarez, Marta; Chueca, Natalia; Stella, Natalia; Peña, Alejandro; Delgado, Rafael; Córdoba, Juan; Aguilera, Antonio; Vidal, Carmen; García, Federico; CoRIS

2014-01-01

291

Antimicrobial drug resistance in Salmonella: problems and perspectives in food- and water-borne infections.  

PubMed

Strains of Salmonella spp. with resistance to antimicrobial drugs are now widespread in both developed and developing countries. In developed countries it is now increasingly accepted that for the most part such strains are zoonotic in origin and acquire their resistance in the food-animal host before onward transmission to humans through the food chain. Of particular importance since the early 1990s has been a multiresistant strain of Salmonella typhimurium definitive phage type (DT) 104, displaying resistance to up to six commonly used antimicrobials, with about 15% of isolates also exhibiting decreased susceptibility to ciprofloxacin. Mutations in the gyrA gene in such isolates have been characterised by a PCR LightCycler-based gyrA mutation assay, and at least four different mutations have been identified. Multiple resistance (to four or more antimicrobials) is also common in the poultry-associated pathogens Salmonella virchow and Salmonella hadar, with an increasing number of strains of these serotypes exhibiting decreased susceptibility to ciprofloxacin. Multiple resistance is also being found in other serotypes in several other European countries, and has been associated with treatment failures. For Salmonella typhi, multiple drug resistance is now the norm in strains originating in the Indian subcontinent and south-east Asia. Such multiresistant strains have been responsible for several epidemics and some of these have been associated with contaminated water supplies. Furthermore, an increasing number of multiresistant strains of S. typhi are now exhibiting decreased susceptibility to ciprofloxacin, with concomitant treatment failures. In developed countries antimicrobial resistance in zoonotic salmonellas has been attributed to the injudicious use of antimicrobials in food-producing animals. It is hoped that the application of Codes of Practice for the use of such agents, which have been prepared by the pharmaceutical industry in response to widespread international concern about the development of drug resistance in bacterial pathogens, will now result in a widespread reduction in the incidence of drug-resistant salmonellas in food production animals and humans on an international scale. PMID:12069879

Threlfall, E John

2002-06-01

292

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

NASA Astrophysics Data System (ADS)

Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance.Considering the obvious advantages in efficacy and price, doxorubicin (DOX) has been widely used for a range of cancers, which is usually encapsulated in various nanocarriers for drug delivery. Although effective, in most nanocarrier-based delivery systems, the drug loading capacity of DOX is rather low; this can lead to undesired systemic toxicity and excretion concern. Herein, we report for the first time the usage of pure doxorubicin nanoparticles (DOX NPs) without addition of any carriers for enhanced chemotherapy against drug-resistance. The drug payload reaches as high as 90.47%, which largely surpassed those in previous reports. These PEG stabilized DOX NPs exhibit good biocompatibility and stability, long blood circulation time, fast release in an acidic environment and high accumulation in tumors. Compared with free DOX, DOX NPs display a dramatically enhanced anticancer therapeutic efficacy in the inhibition of cell and tumor growth. Moreover, they can also be readily incorporated with other anticancer drugs for synergistic chemotherapy to overcome the drug resistance of cancers. The fluorescence properties of DOX also endow these NPs with imaging capabilities, thus making it a multifunctional system for diagnosis and treatment. This work demonstrates great potential of DOX NPs for cancer diagnosis, therapy and overcoming drug tolerance. Electronic supplementary information (ESI) available. See DOI: 10.1039/c5nr00290g

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

2015-03-01

293

Drug resistance following irradiation of RIF-1 tumors: Influence of the interval between irradiation and drug treatment  

SciTech Connect

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.

Hopwood, L.E.; Davies, B.M.; Moulder, J.E. (Medical College of Wisconsin, Milwaukee (USA))

1990-09-01

294

Antibiotic-resistant gram-negative bacterial infections in patients with cancer.  

PubMed

Patients with cancer are at high risk for infections caused by antibiotic resistant gram-negative bacteria. In this review, we summarize trends among the major pathogens and clinical syndromes associated with antibiotic resistant gram-negative bacterial infection in patients with malignancy, with special attention to carbapenem and expanded-spectrum ?-lactam resistance in Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia--all major threats to our cancer patients. Optimal therapy for these antibiotic-resistant pathogens still remains to be determined. PMID:25352627

Perez, Federico; Adachi, Javier; Bonomo, Robert A

2014-11-15

295

Antimicrobial Resistance and Virulence: a Successful or Deleterious Association in the Bacterial World?  

PubMed Central

SUMMARY Hosts and bacteria have coevolved over millions of years, during which pathogenic bacteria have modified their virulence mechanisms to adapt to host defense systems. Although the spread of pathogens has been hindered by the discovery and widespread use of antimicrobial agents, antimicrobial resistance has increased globally. The emergence of resistant bacteria has accelerated in recent years, mainly as a result of increased selective pressure. However, although antimicrobial resistance and bacterial virulence have developed on different timescales, they share some common characteristics. This review considers how bacterial virulence and fitness are affected by antibiotic resistance and also how the relationship between virulence and resistance is affected by different genetic mechanisms (e.g., coselection and compensatory mutations) and by the most prevalent global responses. The interplay between these factors and the associated biological costs depend on four main factors: the bacterial species involved, virulence and resistance mechanisms, the ecological niche, and the host. The development of new strategies involving new antimicrobials or nonantimicrobial compounds and of novel diagnostic methods that focus on high-risk clones and rapid tests to detect virulence markers may help to resolve the increasing problem of the association between virulence and resistance, which is becoming more beneficial for pathogenic bacteria. PMID:23554414

Beceiro, Alejandro; Tomás, María

2013-01-01

296

Pyramiding B genes in cotton achieves broader but not always higher resistance to bacterial blight.  

PubMed

ABSTRACT Near-isogenic lines of upland cotton (Gossypium hirsutum) carrying single, race-specific genes B4, BIn, and b7 for resistance to bacterial blight were used to develop a pyramid of lines with all possible combinations of two and three genes to learn whether the pyramid could achieve broad and high resistance approaching that of L. A. Brinkerhoff's exceptional line Im216. Isogenic strains of Xanthomonas axonopodis pv. malvacearum carrying single avirulence (avr) genes were used to identify plants carrying specific resistance (B) genes. Under field conditions in north-central Oklahoma, pyramid lines exhibited broader resistance to individual races and, consequently, higher resistance to a race mixture. It was predicted that lines carrying two or three B genes would also exhibit higher resistance to race 1, which possesses many avr genes. Although some enhancements were observed, they did not approach the level of resistance of Im216. In a growth chamber, bacterial populations attained by race 1 in and on leaves of the pyramid lines decreased significantly with increasing number of B genes in only one of four experiments. The older lines, Im216 and AcHR, exhibited considerably lower bacterial populations than any of the one-, two-, or three-B-gene lines. A spreading collapse of spray-inoculated AcBIn and AcBInb7 leaves appears to be a defense response (conditioned by BIn) that is out of control. PMID:24655289

Essenberg, Margaret; Bayles, Melanie B; Pierce, Margaret L; Verhalen, Laval M

2014-10-01

297

Role of wild birds as carriers of multi-drug resistant Escherichia coli and Escherichia vulneris  

PubMed Central

Emergence and distribution of multi-drug resistant (MDR) bacteria in environments pose a risk to human and animal health. A total of 82 isolates of Escherichia spp. were recovered from cloacal swabs of migrating and non-migrating wild birds. All bacterial isolates were identified and characterized morphologically and biochemically. 72% and 50% of isolates recovered from non-migrating and migrating birds, respectively, showed positive congo red dye binding (a virulence factor). Also, hemolysin production (a virulence factor) was showed in 8% of isolates recovered from non-migrating birds and 75% of isolates recovered from migrating birds. All isolates recovered from non-migrating birds were found resistant to Oxacillin while all isolates recovered from migrating birds demonstrated resistance to Oxacillin, Chloramphenicol, Oxytetracycline and Lincomycin. Some bacterial isolates recovered from non-migrating birds and migrating birds exhibited MDR phenotype. The MDR isolates were further characterized by API 20E and 16S rRNA as E. coli and E. vulneris. MDR Escherichia isolates contain ~1–5 plasmids of high-molecular weights. Accordingly, wild birds could create a potential threat to human and animal health by transmitting MDR bacteria to water streams and other environmental sources through their faecal residues, and to remote regions by migration. PMID:25763023

Shobrak, Mohammed Y.; Abo-Amer, Aly E.

2014-01-01

298

Bacterial antibiotic resistance in soils irrigated with reclaimed municipal wastewater  

Technology Transfer Automated Retrieval System (TEKTRAN)

Wastewater reclamation for municipal irrigation and groundwater recharge is an increasingly attractive option for extending water supplies. However, public health concerns include the potential for development of antibiotic resistance (AR) in soil bacteria after exposure to residual chemicals in rec...

299

Prevalence of Extensively Drug Resistant Tuberculosis among Archived Multidrug Resistant Tuberculosis Isolates in Zimbabwe  

PubMed Central

We conducted a cross-sectional study of second line drug resistance patterns and genetic diversity of MDR-TB isolates archived at the BRTI-TB Laboratory, Harare, between January 2007 and December 2011. DSTs were performed for second line antituberculosis drugs. XDR-TB strains were defined as MDR-TB strains with resistance to either kanamycin and ofloxacin or capreomycin and ofloxacin. Strain types were identified by spoligotyping. No resistance to any second line drugs was shown in 73% of the isolates, with 23% resistant to one or two drugs but not meeting the definition of XDR-TB. A total of 26 shared types were identified, and 18 (69%) matched preexisting shared types in the current published spoligotype databases. Of the 11 out of 18 clustered SITs, 4 predominant (>6 isolates per shared type) were identified. The most and least abundant types were SIT 1468 (LAM 11-ZWE) with 12 (18%) isolates and SIT 53 (T1) with 6 (9%) isolates, respectively. XDR-TB strains are rare in Zimbabwe, but the high proportion of “pre-XDR-TB” strains and treatment failure cases is of concern. The genetic diversity of the MDR-TB strains showed no significant association between SITs and drug resistance. PMID:24967101

Sagonda, Tichaona; Mupfumi, Lucy; Manzou, Rumbidzai; Makamure, Beauty; Tshabalala, Mqondisi; Gwanzura, Lovemore; Mason, Peter; Mutetwa, Reggie

2014-01-01

300

Bacterial disease resistance in Arabidopsis through flagellin perception  

Microsoft Academic Search

Plants and animals recognize microbial invaders by detecting pathogen-associated molecular patterns (PAMPs) such as flagellin. However, the importance of flagellin perception for disease resistance has, until now, not been demonstrated. Here we show that treatment of plants with flg22, a peptide representing the elicitor-active epitope of flagellin, induces the expression of numerous defence-related genes and triggers resistance to pathogenic bacteria

Cyril Zipfel; Silke Robatzek; Lionel Navarro; Edward J. Oakeley; Jonathan D. G. Jones; Georg Felix; Thomas Boller

2004-01-01

301

Absence of bacterial resistance to medical-grade manuka honey  

Microsoft Academic Search

Clinical use of honey in the topical treatment of wounds has increased in Europe and North America since licensed wound care\\u000a products became available in 2004 and 2007, respectively. Honey-resistant bacteria have not been isolated from wounds, but\\u000a there is a need to investigate whether honey has the potential to select for honey resistance. Two cultures of bacteria from\\u000a reference

R. A. Cooper; L. Jenkins; A. F. M. Henriques; R. S. Duggan; N. F. Burton

2010-01-01

302

Development of a protocol for predicting bacterial resistance to microbicides.  

PubMed

Regulations dealing with microbicides in Europe and the United States are evolving and now require data on the risk of the development of resistance in organisms targeted by microbicidal products. There is no standard protocol to assess the risk of the development of resistance to microbicidal formulations. This study aimed to validate the use of changes in microbicide and antibiotic susceptibility as initial markers for predicting microbicide resistance and cross-resistance to antibiotics. Three industrial isolates (Pseudomonas aeruginosa, Burkholderia cepacia, and Klebsiella pneumoniae) and two Salmonella enterica serovar Typhimurium strains (SL1344 and 14028S) were exposed to a shampoo, a mouthwash, eye makeup remover, and the microbicides contained within these formulations (chlorhexidine digluconate [CHG] and benzalkonium chloride [BZC]) under realistic, in-use conditions. Baseline and postexposure data were compared. No significant increases in the MIC or the minimum bactericidal concentration (MBC) were observed for any strain after exposure to the three formulations. Increases as high as 100-fold in the MICs and MBCs of CHG and BZC for SL1344 and 14028S were observed but were unstable. Changes in antibiotic susceptibility were not clinically significant. The use of MICs and MBCs combined with antibiotic susceptibility profiling and stability testing generated reproducible data that allowed for an initial prediction of the development of resistance to microbicides. These approaches measure characteristics that are directly relevant to the concern over resistance and cross-resistance development following the use of microbicides. These are low-cost, high-throughput techniques, allowing manufacturers to provide to regulatory bodies, promptly and efficiently, data supporting an early assessment of the risk of resistance development. PMID:25636848

Knapp, Laura; Amézquita, Alejandro; McClure, Peter; Stewart, Sara; Maillard, Jean-Yves

2015-04-15

303

Differential protein expressions in breast cancer between drug sensitive tissues and drug resistant tissues  

PubMed Central

Objective To investigate the differential expression of the sensitive and resistant relative proteins in human breast cancer tissue. Methods A drug sensitive group and a drug resistant group for chemotherapy in patients with breast cancer were selected through neoadjuvant therapy. The differential protein expression in 2 groups was detected by proteomic techniques, and parts of differential proteins were identified by Western blotting. Results There were 13 differential proteins in the 2 groups, in which the expression of 3 proteins was up-regulated and 10 down-regulated. Seven proteins were identified by Western blotting. The expressions of keratin type I cytoskeletal 19 (KIC19) and thymidine phosphorylase (TYPH) were up-regulated, and the expressions of heat shock protein 27 (HSP27), keratin type I cytoskeletal 9 (KIC9), collagen alpha-2(VI) (CO6A2), vimentin (VIME), and actin cytoplasmic 1 (ACTB) were down-regulated in the drug resistant group. There were significant differences between these 2 groups (P<0.01). Conclusions The expressions of KIC19 and TYPH may be correlated with drug resistance in patients with breast cancer, and HSP27, KIC9, CO6A2, VIME, and ACTB may be correlated with drug sensitivity. PMID:25083461

Peng, Jing; Zhang, Yajie; Fu, Fenfen; Zou, Qiongyan; Tang, Yuanyuan

2013-01-01

304

Rapid detection of bacterial resistance to antibiotics using AFM cantilevers as nanomechanical sensors  

NASA Astrophysics Data System (ADS)

The widespread misuse of drugs has increased the number of multiresistant bacteria, and this means that tools that can rapidly detect and characterize bacterial response to antibiotics are much needed in the management of infections. Various techniques, such as the resazurin-reduction assays, the mycobacterial growth indicator tube or polymerase chain reaction-based methods, have been used to investigate bacterial metabolism and its response to drugs. However, many are relatively expensive or unable to distinguish between living and dead bacteria. Here we show that the fluctuations of highly sensitive atomic force microscope cantilevers can be used to detect low concentrations of bacteria, characterize their metabolism and quantitatively screen (within minutes) their response to antibiotics. We applied this methodology to Escherichia coli and Staphylococcus aureus, showing that live bacteria produced larger cantilever fluctuations than bacteria exposed to antibiotics. Our preliminary experiments suggest that the fluctuation is associated with bacterial metabolism.

Longo, G.; Alonso-Sarduy, L.; Rio, L. Marques; Bizzini, A.; Trampuz, A.; Notz, J.; Dietler, G.; Kasas, S.

2013-07-01

305

Global Phenotypic Characterization of Effects of Fluoroquinolone Resistance Selection on the Metabolic Activities and Drug Susceptibilities of Clostridium perfringens Strains.  

PubMed

Fluoroquinolone resistance affects toxin production of Clostridium perfringens strains differently. To investigate the effect of fluoroquinolone resistance selection on global changes in metabolic activities and drug susceptibilities, four C. perfringens strains and their norfloxacin-, ciprofloxacin-, and gatifloxacin-resistant mutants were compared in nearly 2000 assays, using phenotype microarray plates. Variations among mutant strains resulting from resistance selection were observed in all aspects of metabolism. Carbon utilization, pH range, osmotic tolerance, and chemical sensitivity of resistant strains were affected differently in the resistant mutants depending on both the bacterial genotype and the fluoroquinolone to which the bacterium was resistant. The susceptibilities to gentamicin and erythromycin of all resistant mutants except one increased, but some resistant strains were less susceptible to amoxicillin, cefoxitin, ceftriaxone, chloramphenicol, and metronidazole than their wild types. Sensitivity to ethidium bromide decreased in some resistant mutants and increased in others. Microarray analysis of two gatifloxacin-resistant mutants showed changes in metabolic activities that were correlated with altered expression of various genes. Both the chemical structures of fluoroquinolones and the genomic makeup of the wild types influenced the changes found in resistant mutants, which may explain some inconsistent reports of the effects of therapeutic use of fluoroquinolones on clinical isolates of bacteria. PMID:25587280

Park, Miseon; Rafii, Fatemeh

2014-01-01

306

Global Phenotypic Characterization of Effects of Fluoroquinolone Resistance Selection on the Metabolic Activities and Drug Susceptibilities of Clostridium perfringens Strains  

PubMed Central

Fluoroquinolone resistance affects toxin production of Clostridium perfringens strains differently. To investigate the effect of fluoroquinolone resistance selection on global changes in metabolic activities and drug susceptibilities, four C. perfringens strains and their norfloxacin-, ciprofloxacin-, and gatifloxacin-resistant mutants were compared in nearly 2000 assays, using phenotype microarray plates. Variations among mutant strains resulting from resistance selection were observed in all aspects of metabolism. Carbon utilization, pH range, osmotic tolerance, and chemical sensitivity of resistant strains were affected differently in the resistant mutants depending on both the bacterial genotype and the fluoroquinolone to which the bacterium was resistant. The susceptibilities to gentamicin and erythromycin of all resistant mutants except one increased, but some resistant strains were less susceptible to amoxicillin, cefoxitin, ceftriaxone, chloramphenicol, and metronidazole than their wild types. Sensitivity to ethidium bromide decreased in some resistant mutants and increased in others. Microarray analysis of two gatifloxacin-resistant mutants showed changes in metabolic activities that were correlated with altered expression of various genes. Both the chemical structures of fluoroquinolones and the genomic makeup of the wild types influenced the changes found in resistant mutants, which may explain some inconsistent reports of the effects of therapeutic use of fluoroquinolones on clinical isolates of bacteria. PMID:25587280

Park, Miseon

2014-01-01

307

Modeling HIV-1 Drug Resistance as Episodic Directional Selection  

PubMed Central

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

Murrell, Ben; de Oliveira, Tulio; Seebregts, Chris; Kosakovsky Pond, Sergei L.; Scheffler, Konrad

2012-01-01

308

Drug-resistant herpes simplex virus in HIV infected patients.  

PubMed

Herpes simplex virus type 2 (HSV2) infection is a major source of morbidity in human immunodeficiency virus (HIV)-infected patients, since reactivations - whether symptomatic or asymptomatic - are associated with increased HIV viral load and viral shedding. Acyclovir, valacyclovir and famcyclovir are indicated for the treatment of HSV2 in HIV patients. This class of drugs has been shown to enhance survival in HIV-infected individuals. However, with the emergence of drug-resistant strains of HSV2, the rates of resistance among HIV patients are almost ten-fold those in immunocompetent individuals, comparing 0.6% to 6%. These HSV2 infections tend to be more severe and to recur. More ominously, disease progression of HIV is promoted by concurrent infection with HSV2. Intravenous foscarnet and cidofovir may be used for acyclovir-resistant HSV; however, resistance to these drugs has been documented. Newer therapies such as the toll-like receptor agonist imiquimod and immunomodulating dipeptides offer promise for the treatment of HSV2 in HIV-infected individuals. PMID:19111144

Lolis, Margarita S; González, Lenis; Cohen, Philip J; Schwartz, Robert A

2008-01-01

309

HIV Drug-Resistant Patient Information Management, Analysis, and Interpretation  

PubMed Central

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, arti?cial 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

Mars, Maurice

2012-01-01

310

Metabolic adaptations of Leishmania donovani in relation to differentiation, drug resistance, and drug pressure.  

PubMed

Antimonial (sodium stibogluconate, SSG) resistance and differentiation have been shown to be closely linked in Leishmania donovani, with SSG-resistant strains showing an increased capacity to generate infectious (metacyclic) forms. This is the first untargeted LC-MS metabolomics study which integrated both phenomena in one experimental design and provided insights into metabolic differences between three clinical L.?donovani strains with a similar genetic background but different SSG-susceptibilities. We performed this analysis at different stages during promastigote growth and in the absence or presence of drug pressure. When comparing SSG-resistant and SSG-sensitive strains, a number of metabolic changes appeared to be constitutively present in all growth stages, pointing towards a clear link with SSG-resistance, whereas most metabolic changes were only detected in the stationary stage. These changes reflect the close intertwinement between SSG-resistance and an increased metacyclogenesis in resistant parasites. The metabolic changes suggest that SSG-resistant parasites have (i) an increased capacity for protection against oxidative stress; (ii) a higher fluidity of the plasma membrane; and (iii) a metabolic survival kit to better endure infection. These changes were even more pronounced in a resistant strain kept under Sb(III) drug pressure. PMID:24020363

Berg, Maya; Vanaerschot, Manu; Jankevics, Andris; Cuypers, Bart; Maes, Ilse; Mukherjee, Sandip; Khanal, Basudha; Rijal, Suman; Roy, Syamal; Opperdoes, Fred; Breitling, Rainer; Dujardin, Jean-Claude

2013-10-01

311

Efflux Pump-Mediated Intrinsic Drug Resistance in Mycobacterium smegmatis  

PubMed Central

The Mycobacterium smegmatis genome contains many genes encoding putative drug efflux pumps. Yet with the exception of lfrA, it is not clear whether these genes contribute to the intrinsic drug resistance of this organism. We showed first by reverse transcription (RT)-PCR that several of these genes, including lfrA as well as the homologues of Mycobacterium tuberculosis Rv1145, Rv1146, Rv1877, Rv2846c (efpA), and Rv3065 (mmr and emrE), were expressed at detectable levels in the strain mc2155. Null mutants each carrying an in-frame deletion of these genes were then constructed in M. smegmatis. The deletions of the lfrA gene or mmr homologue rendered the mutant more susceptible to multiple drugs such as fluoroquinolones, ethidium bromide, and acriflavine (two- to eightfold decrease in MICs). The deletion of the efpA homologue also produced increased susceptibility to these agents but unexpectedly also resulted in decreased susceptibility to rifamycins, isoniazid, and chloramphenicol (two- to fourfold increase in MICs). Deletion of the Rv1877 homologue produced some increased susceptibility to ethidium bromide, acriflavine, and erythromycin. The upstream region of lfrA contained a gene encoding a putative TetR family transcriptional repressor, dubbed LfrR. The deletion of lfrR elevated the expression of lfrA and produced higher resistance to multiple drugs. Multidrug-resistant single-step mutants, independent of LfrA and attributed to a yet-unidentified drug efflux pump (here called LfrX), were selected in vitro and showed decreased accumulation of norfloxacin, ethidium bromide, and acriflavine in intact cells. Finally, use of isogenic ?-lactamase-deficient strains showed the contribution of LfrA and LfrX to resistance to certain ?-lactams in M. smegmatis. PMID:15215089

Li, Xian-Zhi; Zhang, Li; Nikaido, Hiroshi

2004-01-01

312

Screening and identification of resistance to bacterial soft rot in Brassica rapa  

Microsoft Academic Search

Mist-chamber, field, and detached leaf inoculation procedures identified plants resistant to bacterial soft rot [Erwinia carotovora subsp. carotovora, (Ecc)] in Brassica rapa and related species. The mist-chamber seedling inoculation provided the best correlation of mean disease severity ratings\\u000a with the field plant inoculation (r = 0.67**) and was used to identify resistant materials. The optimum mist-chamber incubation conditions to distinguish

Jianping Ren; Rixana Petzoldt; Michael H. Dickson

2001-01-01

313

Bacterial silver resistance: molecular biology and uses and misuses of silver compounds  

Microsoft Academic Search

Resistance to silver compounds as determined by bacterial plasmids and genes has been defined by molecular genetics. Silver resistance conferred by the Salmonella plasmid pMGH100 involves nine genes in three transcription units. A sensor\\/responder (SilRS) two-component transcriptional regulatory system governs synthesis of a periplasmic Ag(I)-binding protein (SilE) and two efflux pumps (a P-type ATPase (SilP) plus a three-protein chemiosmotic RND

Simon Silver

2003-01-01

314

Effect of crop rotation and cultivar resistance on bacterial wilt of tomato in Nepal  

Microsoft Academic Search

The effect of crop rotation and cultivar resistance on bacterial wilt of tomato (Lycopersicon esculentum), caused by Ralstonia solanacearum (biovar 3 and race I), were studied from 1994 to 1996 in a field experiment in Chitwan, Nepal. Corn (Zea mays), lady's finger (Ahelomoschus esculentum), cowpea (Vigna unguiculata), and the partially resistant tomato line CL1131-0-0-43-4 (CL1131) were rotated with susceptible tomato

Tika B. Adhikari; Ram Chandra Basnyat

1998-01-01

315

Quantitative trait Loci mapping for bacterial blight resistance in rice using bulked segregant analysis.  

PubMed

Oryza meyeriana is highly resistant to rice bacterial blight (BB) and this resistance trait has been transferred to cultivated rice (O. sativa) using asymmetric somatic hybridization. However, no resistance genes have yet been cloned. In the present study, a progeny of the somatic hybridization with high BB resistance was crossed with a rice cultivar with high BB susceptibility to develop an F2 population. Using bulked segregant analysis (BSA), 17 polymorphic markers that were linked to rice BB resistance were obtained through scanning a total of 186 simple sequence repeats (SSR) and sequence-tagged site (STS) markers, evenly distributed on 12 chromosomes. A genetic linkage map was then constructed based on the 17 linkage markers and the F2 segregating population, which was followed by mapping for quantitative trait loci (QTLs) for BB resistance. Three QTLs were identified on chromosomes 1, 3 and 5, respectively, and the alleles of the resistant parent at any of the QTLs increased BB resistance. All of the three QTLs had a strong effect on resistance, explaining about 21.5%, 12.3% and 39.2% of the resistance variance, respectively. These QTLs were different from the loci of the BB resistance genes that have been identified in previous studies. The QTLs mapped in this work will facilitate the isolation of novel BB resistance genes and their utilization in rice resistance breeding. PMID:24995697

Han, Xueying; Yang, Yong; Wang, Xuming; Zhou, Jie; Zhang, Wenhao; Yu, Chulang; Cheng, Chen; Cheng, Ye; Yan, Chengqi; Chen, Jianping

2014-01-01

316

A RAPD-derived STS marker is linked to a bacterial wilt ( Burkholderia caryophylli ) resistance gene in carnation  

Microsoft Academic Search

Bacterial wilt caused by Burkholderia caryophylli is one of the most important and damaging diseases of carnations (Dianthus caryophyllus) in Japan. We aimed to identify random amplified polymorphic DNA (RAPD) markers associated with the genes controlling bacterial wilt resistance in a resistance-segregating population of 134 progeny plants derived from a cross between ‘Carnation Nou No. 1’ (a carnation breeding line

Takashi Onozaki; Natsu Tanikawa; Mitsuyasu Taneya; Kiyofumi Kudo; Takuya Funayama; Hiroshi Ikeda; Michio Shibata

2004-01-01

317

Interferon in resistance to bacterial and protozoan infections  

NASA Technical Reports Server (NTRS)

The effects of genetic differences in mouse strains on the modulation of protozoan infections by interferon (IFN) were investigated. In one set of experiments, three different strains of mice were injected with T. cruzi, and their sera were assayed at five time intervals for IFN titer. A greater quantity of IFN was produced by mouse strains that were susceptible to T. cruzi infection than by the more resistant strain. In another set of experiments, spleen cell cultures from inbred strains of mice were challenged with an antigen made from T.b. rhodesiense. The cells from mice resistant to infection, produced greater amounts of IFN-gamma than did cells from the susceptible mice. In a third set of experiments, it was found that mice injected with T.b. rhodesiense before being infected with a diabetogenic virus (EMC-D) were resistant to the effects of the virus and did not produce virus-specific antibody.

Sonnenfeld, Gerald; Gould, Cheryl L.; Kierszenbaum, Felipe; Degee, Antonie L. W.; Mansfield, John M.

1986-01-01

318

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

PubMed

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

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

2015-03-19

319

Breeding Strains of Cotton Resistant to Bacterial Blight.  

E-print Network

of breaking down the resistance of Stoneville 20. Methods developed for artifically inoculating cotton plants with the blight causal organism have proved effective to the extent - that selections for resistance can be made with a high degree of certainty... were obtained by growing the causal organism in petri ,tes and diluting the growth of one plate with 2y2 gallons of ter. Their inoculation was most effective when the spray was ected toward the lower surface of the leaves and when the loculation...

Blank, Lester M. (Lester Marion); Bird, L. S. (Luther Smith)

1951-01-01

320

[Bacterial efflux pumps - their role in antibiotic resistance and potential inhibitors].  

PubMed

Efflux pumps capable of actively draining antibiotic agents from bacterial cells may be considered one of potential mechanisms of the development of antimicrobial resistance. The most important group of efflux pumps capable of removing several types of antibiotics include RND (resistance - nodulation - division) pumps. These are three proteins that cross the bacterial cell wall, allowing direct expulsion of the agent out from the bacterial cell. The most investigated efflux pumps are the AcrAB-TolC system in Escherichia coli and the MexAB-OprM system in Pseudomonas aeruginosa. Moreover, efflux pumps are able to export other than antibacterial agents such as disinfectants, thus decreasing their effectiveness. One potential approach to inactivation of an efflux pump is to use the so-called efflux pump inhibitors (EPIs). Potential inhibitors tested in vitro involve, for example, phenylalanyl-arginyl-b-naphthylamide (PAbN), carbonyl cyanide m-chlorophenylhydrazone (CCCP) or agents of the phenothiazine class. PMID:25702054

Hricová, Kristýna; Kolá?, Milan

2014-12-01

321

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

Technology Transfer Automated Retrieval System (TEKTRAN)

A family-based selection program was initiated at the National Center for Cool and Cold Water Aquaculture in 2005 to improve resistance to bacterial cold water disease (BCWD) in rainbow trout. The objective of this study was to estimate response to 2 generations of selection. A total of 14,841 juven...

322

RELEASE OF COMMON BACTERIAL BLIGHT RESISTANT WHITE KIDNEY BEAN GERMPLASM LINE USWK-CBB-17  

Technology Transfer Automated Retrieval System (TEKTRAN)

The Agricultural Research Service, U.S. Department of Agriculture, and the Idaho Agricultural Experiment Station announce the release of USWK-CBB-17 white kidney (Phaseolus vulgaris L.) germplasm line with a high level of resistance to common bacterial blight caused by Xanthomonas axonopodis pv. ph...

323

Inducible Resistance of Fish Bacterial Pathogens to the Antimicrobial Peptide Cecropin B  

Microsoft Academic Search

Cecropin B is a cationic antimicrobial peptide originally isolated from the diapausing pupae of the giant silk moth, Hylphora cecropia. Cecropin B elicits its antimicrobial effects through disruption of the anionic cell membranes of gram-negative bacteria. Previous work by our laboratory demonstrated that a constitutively expressed cecropin B transgene conferred enhanced resistance to bacterial infection in medaka. The develop- ment

Ulysses W. Sallum; Thomas T. Chen

2008-01-01

324

Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents  

PubMed Central

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

Pettigrew, Jonathan; Miller-Day, Michelle; Krieger, Janice; Hecht, Michael L.

2011-01-01

325

Coherent feedforward transcriptional regulatory motifs enhance drug resistance  

NASA Astrophysics Data System (ADS)

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.

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

2014-05-01

326

Enteric dysbiosis promotes antibiotic-resistant bacterial infection: systemic dissemination of resistant and commensal bacteria through epithelial transcytosis.  

PubMed

Antibiotic usage promotes intestinal colonization of antibiotic-resistant bacteria. However, whether resistant bacteria gain dominance in enteric microflora or disseminate to extraintestinal viscera remains unclear. Our aim was to investigate temporal diversity changes in microbiota and transepithelial routes of bacterial translocation after antibiotic-resistant enterobacterial colonization. Mice drinking water with or without antibiotics were intragastrically gavaged with ampicillin-resistant (Amp-r) nonpathogenic Escherichia coli (E. coli) and given normal water afterward. The composition and spatial distribution of intestinal bacteria were evaluated using 16S rDNA sequencing and fluorescence in situ hybridization. Bacterial endocytosis in epithelial cells was examined using gentamicin resistance assay and transmission electromicroscopy. Paracellular permeability was assessed by tight junctional immunostaining and measured by tissue conductance and luminal-to-serosal dextran fluxes. Our results showed that antibiotic treatment enabled intestinal colonization and transient dominance of orally acquired Amp-r E. coli in mice. The colonized Amp-r E. coli peaked on day 3 postinoculation and was competed out after 1 wk, as evidenced by the recovery of commensals, such as Escherichia, Bacteroides, Lachnospiraceae, Clostridium, and Lactobacillus. Mucosal penetration and extraintestinal dissemination of exogenous and endogenous enterobacteria were correlated with abnormal epithelial transcytosis but uncoupled with paracellular tight junctional damage. In conclusion, antibiotic-induced enteric dysbiosis predisposes to exogenous infection and causes systemic dissemination of both antibiotic-resistant and commensal enterobacteria through transcytotic routes across epithelial layers. These results may help explain the susceptibility to sepsis in antibiotic-resistant enteric bacterial infection. PMID:25059827

Yu, Linda Chia-Hui; Shih, Yi-An; Wu, Li-Ling; Lin, Yang-Ding; Kuo, Wei-Ting; Peng, Wei-Hao; Lu, Kuo-Shyan; Wei, Shu-Chen; Turner, Jerrold R; Ni, Yen-Hsuan

2014-10-15

327

Differential Expression of Drug Resistance-Related Genes between Sensitive and Resistant Blasts in Acute Myeloid Leukemia  

Microsoft Academic Search

Drug resistance constitutes a considerable problem in the therapy of acute myeloid leukemia (AML). In order to identify genes which might be related to drug resistance, we retrospectively studied gene expression patterns in blast populations of 14 patients with de novo AML, focusing on known or potential resistance mechanisms against cytosine arabinoside and anthracyclines. Following induction and postremission chemotherapy, 7

L. Eisele; L. Klein-Hitpass; N. Chatzimanolis; B. Opalka; T. Boes; S. Seeber; T. Moritz; M. Flasshove

2007-01-01

328

Studies Show Microenvironment Plays Key Role in Anticancer Drug Resistance | Physical Sciences in Oncology  

Cancer.gov

As mounting evidence continues to show that evolutionary selective pressure will ultimately drive cancer cells to develop resistance to drug therapies, cancer researchers are looking for new treatment paradigms that might avoid or surmount drug resistance. One promising approach aims to better understand how the microenvironment surrounding a tumor impacts drug resistance and use that knowledge to create novel strategies for attacking tumors.

329

Consensus drug resistance mutations for epidemiological surveillance: basic principles and potential controversies  

Microsoft Academic Search

Programmes that monitor local, national and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programmes. The World Health Organization (WHO) has established a global programme for genotypic surveillance of HIV-1 drug resistance and has recom- mended the adoption of a consensus definition of genotypic drug resistance. Such

Robert W Shafer; Soo-Yon Rhee; Diane E Bennett

2008-01-01

330

Evolution of Drug-resistant Viral Populations during Interruption of Antiretroviral Therapy  

E-print Network

therapy (ART), some HIV-2 infected patients still fail treatment due to drug resistance, poor adherence1 Evolution of Drug-resistant Viral Populations during Interruption of Antiretroviral Therapy antiretroviral treatment (ART) interruption allows determination of the evolution of3 drug-resistant viruses

Ahlers, Guenter

331

Association of house spraying with suppressed levels of drug resistance in Zimbabwe  

Microsoft Academic Search

BACKGROUND: Public health strategies are needed to curb antimalarial drug resistance. Theoretical argument points to an association between malaria transmission and drug resistance although field evidence remains limited. Field observations, made in Zimbabwe, on the relationship between transmission and multigenic drug resistance, typified by chloroquine, are reported here. METHODS: Periodic assessments of the therapeutic response of uncomplicated falciparum malaria to

Sungano Mharakurwa; Susan L Mutambu; Robert Mudyiradima; Tawanda Chimbadzwa; Steven K Chandiwana; Karen P Day

2004-01-01

332

Diversity and complexity of HIV1 drug resistance: A bioinformatics approach to predicting phenotype from genotype  

Microsoft Academic Search

Drug resistance testing has been shown to be beneficial for clinical management of HIV type 1 infected patients. Whereas phenotypic assays directly measure drug resistance, the commonly used genotypic assays provide only indirect evidence of drug resistance, the major challenge being the interpretation of the sequence information. We analyzed the significance of sequence variations in the protease and reverse transcriptase

Niko Beerenwinkel; Barbara Schmidt; Hauke Walter; Rolf Kaiser; Thomas Lengauer; Daniel Hoffmann; Klaus Korn; Joachim Selbig

2002-01-01

333

Antibiotic resistant bacterial profiles of anaerobic swine lagoon effluent  

Technology Transfer Automated Retrieval System (TEKTRAN)

Although land application of swine manure lagoon effluent is a common and effective method of disposal, the presence of antibiotic-resistant bacteria, both pathogenic and commensal can complicate already understood issues associated with its safe disposal. To better understand this, more data is ne...

334

Antibiotic Resistant Bacterial Profiles of Anaerobic Swine Lagoon Effluent  

Technology Transfer Automated Retrieval System (TEKTRAN)

Although land application of swine manure lagoon effluent is a common and effective method of disposal, the presence of antibiotic-resistant bacteria, both pathogenic and commensal can complicate already understood issues associated with its safe disposal. The aim of this study was to assess antibi...

335

Polyacylated neohesperidosides from Geranium caespitosum: bacterial multidrug resistance pump inhibitors.  

PubMed

Bioassay-directed fractionation for Staphylococcus aureus multidrug resistance efflux pump inhibitors resulted in isolation of novel acylated neohesperidosides from Geranium caespitosum. The more highly acylated compounds had no direct activity against S. aureus, but potentiated activity of the antibiotics berberine, rhein, ciprofloxacin and norfloxacin. Cellular concentrations of berberine were greatly increased in the presence of active esters. PMID:12749897

Stermitz, Frank R; Cashman, Kevin K; Halligan, Kathleen M; Morel, Cécile; Tegos, George P; Lewis, Kim

2003-06-01

336

Polyacylated neohesperidosides From Geranium caespitosum: bacterial multidrug resistance pump inhibitors  

Microsoft Academic Search

Bioassay-directed fractionation for Staphylococcus aureus multidrug resistance efflux pump inhibitors resulted in isolation of novel acylated neohesperidosides from Geranium caespitosum. The more highly acylated compounds had no direct activity against S. aureus, but potentiated activity of the antibiotics berberine, rhein, ciprofloxacin and norfloxacin. Cellular concentrations of berberine were greatly increased in the presence of active esters.

Frank R Stermitz; Kevin K Cashman; Kathleen M Halligan; Cécile Morel; George P Tegos; Kim Lewis

2003-01-01

337

Oxazolidinone Resistance Mutations in 23S rRNA of Escherichia coli Reveal the Central Region of Domain V as the Primary Site of Drug Action  

Microsoft Academic Search

Oxazolidinone antibiotics inhibit bacterial protein synthesis by interacting with the large ribosomal subunit. The structure and exact location of the oxazolidinone binding site remain obscure, as does the manner in which these drugs inhibit translation. To investigate the drug-ribosome interaction, we selected Escherichia coli oxazolidinone-resistant mutants, which contained a randomly mutagenized plasmid-borne rRNA operon. The same mutation, G2032 to A,

LIQUN XIONG; PATRICIA KLOSS; STEPHEN DOUTHWAITE; NIELS MØLLER ANDERSEN; STEVEN SWANEY; DEAN L. SHINABARGER; ALEXANDER S. MANKIN

2000-01-01

338

The biopolymer bacterial nanocellulose as drug delivery system: investigation of drug loading and release using the model protein albumin.  

PubMed

Although bacterial nanocellulose (BNC) has reached enormous interest for biomedical applications because of its outstanding material properties, investigations about its potential as drug delivery system are very rare. In the present study, for the first time, the applicability of BNC as drug delivery system for proteins using serum albumin as model drug was systematically investigated. Additionally, never-dried BNC was compared with freeze-dried BNC. For both types of BNC, a dependency of concentration, temperature, time, and preswelling for albumin loading and release could be demonstrated. These findings indicated an overlay of diffusion- and swelling-controlled processes, which could be confirmed by Ritger-Peppas equation. Freeze-dried samples showed a lower uptake capacity for albumin than native BNC, which was found to be related to changes of the fiber network during the freeze drying process as demonstrated by electron microscopy and protein staining experiments. The integrity and biological activity of proteins could be retained during the loading and release processes, which was demonstrated by gel electrophoresis and the use of luciferase as biologically active molecule. In conclusion, hydrophilicity, high biocompatibility, and controllable drug loading and release render BNC an innovative and attractive biopolymer for controlled drug delivery. PMID:23192666

Müller, Astrid; Ni, Zhixu; Hessler, Nadine; Wesarg, Falko; Müller, Frank A; Kralisch, Dana; Fischer, Dagmar

2013-02-01

339

Recombination favors the evolution of drug resistance in HIV-1 during antiretroviral therapy  

E-print Network

Recombination favors the evolution of drug resistance in HIV-1 during antiretroviral therapy the relationship between recombination and the fixation time of multiple drug resistance mutations after HIV-1 drug et al. [Bretscher, Althaus, Muller, Bonhoeffer, 2004. Recombination in HIV and the evolution of drug

Posada, David

340

Transmitted drug resistance in nonsubtype B HIV-1 infection  

PubMed Central

HIV-1 nonsubtype B variants account for the majority of HIV infections worldwide. Drug resistance in individuals who have never undergone antiretroviral therapy can lead to early failure and limited treatment options and, therefore, is an important concern. Evaluation of reported transmitted drug resistance (TDR) is challenging owing to varying definitions and study designs, and is further complicated by HIV-1 subtype diversity. In this article, we discuss the importance of various mutation lists for TDR definition, summarize TDR in nonsubtype B HIV-1 and highlight TDR reporting and interpreting challenges in the context of HIV-1 diversity. When examined carefully, TDR in HIV-1 non-B protease and reverse transcriptase is still relatively low in most regions. Whether it will increase with time and therapy access, as observed in subtype-B-predominant regions, remains to be determined. PMID:20161523

Chan, Philip A; Kantor, Rami

2009-01-01

341

In Vitro Pharmacodynamics of Various Antibiotics in Combination against Extensively Drug-Resistant Klebsiella pneumoniae.  

PubMed

Extensively drug-resistant (XDR) Klebsiella pneumoniae is an emerging pathogen in Singapore. With limited therapeutic options available, combination antibiotics may be the only viable option. In this study, we aimed to elucidate effective antibiotic combinations against XDR K. pneumoniae isolates. Six NDM-1-producing and two OXA-181-producing K. pneumoniae strains were exposed to 12 antibiotics alone and in combination via time-kill studies. A hollow-fiber infection model (HFIM) with pharmacokinetic validation was used to simulate clinically relevant tigecycline-plus-meropenem dosing regimens against 2 XDR K. pneumoniae isolates over 240 h. The emergence of resistance against tigecycline was quantified using drug-free and selective (tigecycline at 3× the MIC) media. The in vitro growth rates were determined and serial passages on drug-free and selective media were carried out on resistant isolates obtained at 240 h. Both the polymyxin B and tigecycline MICs ranged from 1 to 4 mg/liter. In single time-kill studies, all antibiotics alone demonstrated regrowth at 24 h, except for polymyxin B against 2 isolates. Tigecycline plus meropenem was found to be bactericidal in 50% of the isolates. For the isolates that produced OXA-181-like carbapenemases, none of the 55 tested antibiotic combinations was bactericidal. Against 2 isolates in the HFIM, tigecycline plus meropenem achieved a >90% reduction in bacterial burden for 96 h before regrowth was observed until 10(9) CFU/ml at 240 h. Phenotypically stable and resistant isolates, which were recovered from tigecycline-supplemented plates post-HFIM studies, had lower growth rates than those of their respective parent isolates, possibly implying a substantial biofitness deficit in this population. We found that tigecycline plus meropenem may be a potential antibiotic combination for XDR K. pneumoniae infections, but its efficacy was strain specific. PMID:25691628

Lim, Tze-Peng; Cai, Yiying; Hong, Yanjun; Chan, Eric Chun Yong; Suranthran, Sasikala; Teo, Jocelyn Qi-Min; Lee, Winnie Huiling; Tan, Thean-Yen; Hsu, Li-Yang; Koh, Tse-Hsien; Tan, Thuan-Tong; Kwa, Andrea Lay-Hoon

2015-05-01

342

Antibacterial activity of natural spices on multiple drug resistant Escherichia coli isolated from drinking water, Bangladesh  

PubMed Central

Background Spices traditionally have been used as coloring agents, flavoring agents, preservatives, food additives and medicine in Bangladesh. The present work aimed to find out the antimicrobial activity of natural spices on multi-drug resistant Escherichia coli isolates. Methods Anti-bacterial potentials of six crude plant extracts (Allium sativum, Zingiber officinale, Allium cepa, Coriandrum sativum, Piper nigrum and Citrus aurantifolia) were tested against five Escherichia coli isolated from potable water sources at kushtia, Bangladesh. Results All the bacterial isolates were susceptible to undiluted lime-juice. None of them were found to be susceptible against the aqueous extracts of garlic, onion, coriander, pepper and ginger alone. However, all the isolates were susceptible when subjected to 1:1:1 aqueous extract of lime, garlic and ginger. The highest inhibition zone was observed with lime (11 mm). Conclusion Natural spices might have anti-bacterial activity against enteric pathogens and could be used for prevention of diarrheal diseases. Further evaluation is necessary. PMID:21406097

2011-01-01

343

Hepatitis B virus drug resistance tools: one sequence, two predictions.  

PubMed

Drug resistance testing, genotype analysis, and the determination of immune and vaccine escape variants support personalized antiviral treatment for hepatitis B patients. As phenotypic drug resistance testing for hepatitis B virus (HBV) is especially labor-intensive, due to the lack of simple cell culture systems, genotypic methods play a very pronounced role. The genetic structure of HBV allows the simultaneous analysis of two different genes by examination of a single region in the genome of HBV. Nevertheless, the overlapping open reading frames of the hepatitis B surface antigen (HBsAg) and the reverse transcriptase (RT) have to be interpreted separately. In diagnostic procedures, standard Sanger type sequencing (mostly performed as a dye-dideoxynucleotide terminator system) is still the most commonly used method. This allows using established techniques for interpreting those types of genetic information. Besides reviewing the foundation of drug resistance interpretation for HBV, different interpretation systems, either commercially available (TRUGENE, Abbott, ViroScore) or free to use (geno2pheno[HBV], HIV-GRADE HBV tool), are compared in this article. PMID:25034493

Neumann-Fraune, Maria; Beggel, Bastian; Kaiser, Rolf; Obermeier, Martin

2014-01-01

344

Bacterial metal resistance genes and metal bioavailability in contaminated sediments.  

PubMed

In bacteria a metal may be defined as bioavailable if it crosses the cytoplasmic membrane to reach the cytoplasm. Once inside the cell, specific metal resistance systems may be triggered. In this research, specific metal resistance genes were used to estimate metal bioavailability in sediment microbial communities. Gene levels were measured by quantitative PCR and correlated to metals in sediments using five different protocols to estimate dissolved, particle-adsorbed and occluded metals. The best correlations were obtained with czcA (a Cd/Zn/Co efflux pump) and Cd/Zn adsorbed or occluded in particles. Only adsorbed Co was correlated to czcA levels. We concluded that the measurement of czcA gene levels by quantitative PCR is a promising tool which may complement the classical approaches used to estimate Cd/Zn/Co bioavailability in sediment compartments. PMID:24662000

Roosa, Stéphanie; Wattiez, Ruddy; Prygiel, Emilie; Lesven, Ludovic; Billon, Gabriel; Gillan, David C

2014-06-01

345

Overcoming Drug Resistance and Treating Advanced Prostate Cancer  

PubMed Central

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

Semenas, Julius; Allegrucci, Cinzia; Boorjian, Stephen A; Mongan, Nigel P; Persson, Jenny Liao

2012-01-01

346

Fluoroquinolone-metal complexes: a route to counteract bacterial resistance?  

PubMed

Microbial resistance to antibiotics is one of the biggest public health threats of the modern world. Antibiotic resistance is an area of much clinical relevance and therefore research that has the potential to identify agents that may circumvent it or treat resistant infections is paramount. Solution behavior of various fluoroquinolone (FQ) complexes with copper(II) in the presence and absence of 1,10-phenanthroline (phen) was studied in aqueous solution, by potentiometry and/or spectrophotometry, and are herein described. The results obtained showed that under physiological conditions (micromolar concentration range and pH7.4) only copper(II):FQ:phen ternary complexes are stable. Hence, these complexes were synthesised and characterised by means of UV-visible and IR spectroscopy, elemental analysis and single-crystal X-ray diffraction. In these complexes, the FQ acts as a bidentate ligand that coordinates the metal cation through the carbonyl and carboxyl oxygen atoms and phen coordinates through two N-atoms forming the equatorial plane of a distorted square-pyramidal geometry. The fifth position of the penta-coordinated Cu(II) centre is generally occupied axially by an oxygen atom from a water molecule or from a nitrate ion. Minimum inhibitory concentration (MIC) determinations of the complexes and comparison with free FQ in various E. coli strains indicate that the Cu-complexes are as efficient antimicrobials as the free antibiotic. Moreover, results strongly suggest that the cell intake route of both species is different supporting, therefore, the complexes' suitability as candidates for further biological testing in FQ-resistant microorganisms. PMID:24952152

Feio, Maria J; Sousa, Isabel; Ferreira, Mariana; Cunha-Silva, Luís; Saraiva, Raúl G; Queirós, Carla; Alexandre, José G; Claro, Vasco; Mendes, Adélia; Ortiz, Rosa; Lopes, Sandra; Amaral, Ana Luísa; Lino, João; Fernandes, Patrícia; Silva, Ana João; Moutinho, Lisete; de Castro, Baltazar; Pereira, Eulália; Perelló, Lourdes; Gameiro, Paula

2014-09-01

347

Clock and ATF4 transcription system regulates drug resistance in human cancer cell lines  

Microsoft Academic Search

The mechanisms underlying cellular drug resistance have been extensively studied, but little is known about its regulation. We have previously reported that activating transcription factor 4 (ATF4) is upregulated in cisplatin-resistant cells and plays a role in cisplatin resistance. Here, we find out a novel relationship between the circadian transcription factor Clock and drug resistance. Clock drives the periodical expression

T Igarashi; H Izumi; T Uchiumi; K Nishio; T Arao; M Tanabe; H Uramoto; K Sugio; K Yasumoto; Y Sasaguri; K Y Wang; Y Otsuji; K Kohno

2007-01-01

348

Resazurin Microtiter Assay Plate: Simple and Inexpensive Method for Detection of Drug Resistance in Mycobacterium tuberculosis  

Microsoft Academic Search

Multidrug-resistant (MDR) tuberculosis (TB), defined as resistance to isoniazid (INH) and rifampin (RIF), is a severe problem for TB control. Recent reports document the global emergence of highly resistant Mycobacterium tuberculosis strains, particularly in countries of Eastern Europe (7, 36). The emergence of MDR TB highlights the need for drug suscepti- bility testing (DST), patient management, and drug resistance surveillance.

Juan-Carlos Palomino; Anandi Martin; Mirtha Camacho; Humberto Guerra; Jean Swings; Francoise Portaels

2002-01-01

349

Drug Resistance and the Kinetics of Metastatic Cancer  

NASA Astrophysics Data System (ADS)

Most metastatic cancers after initial response to current drug therapies develop resistance to the treatment. We present cancer data and a theory that explains the observed kinetics of tumor growth in cancer patients and using a stochastic model based on this theory we relate the kinetics of tumor growth to Kaplan-Meyer survival curves. The theory points to the tumor growth rate as the most important parameter determining the outcome of a drug treatment. The overall tumor growth or decay rate is a reflection of the balance between cell division, senescence and apoptosis and we propose that the deviation of the decay rate from exponential is a measure of the emergence of drug resistance. In clinical trials the progression free survival, the overall survival, and the shape of the Kaplan-Meyer plots are determined by the tumor growth rate probability distribution among the patients in the trial. How drug treatments modify this distribution will also be described. At the end of the talk we will discuss the connection between the theory described here and the age related cancer mortality rates in the United States.

Blagoev, Krastan B.

2012-02-01

350

High-throughput decoding of drug targets and drug resistance mechanisms in African trypanosomes.  

PubMed

The availability of genome sequence data has facilitated the development of high-throughput genetic screening approaches in microbial pathogens. In the African trypanosome, Trypanosoma brucei, genome-scale RNA interference screens have proven particularly effective in this regard. These genetic screens allow for identification of the genes that contribute to a particular pathway or mechanisms of interest. The approach has been used to assess loss-of-fitness, revealing the genes and proteins required for parasite viability and growth. The outputs from these screens predict essential and dispensable genes and facilitate drug target prioritization efforts. The approach has also been used to assess resistance to anti-trypanosomal drugs, revealing the genes and proteins that facilitate drug uptake and action. These outputs also highlight likely mechanisms underlying clinically relevant drug resistance. I first review these findings in the context of what we know about current drugs. I then describe potential contributions that these high-throughput approaches could make to the development and implementation of new drugs. PMID:23561654

Horn, David

2014-01-01

351

Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease  

PubMed Central

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

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

2011-01-01

352

Complete DNA Sequence and Analysis of the Transferable Multiple-Drug Resistance Plasmids (R Plasmids) from Photobacterium damselae subsp. piscicida Isolates Collected in Japan and the United States? †  

PubMed Central

Photobacterium damselae subsp. piscicida is a bacterial fish pathogen that causes a disease known as pasteurellosis. Two transferable multiple-drug resistance (R) plasmids, pP99-018 (carrying resistance to kanamycin, chloramphenicol, tetracycline, and sulfonamide) and pP91278 (carrying resistance to tetracycline, trimethoprim, and sulfonamide), isolated from P. damselae subsp. piscicida strains from Japan (P99-018) and the United States (P91278), respectively, were completely sequenced and analyzed, along with the multiple-drug resistance regions of three other R plasmids also from P. damselae subsp. piscicida strains from Japan. The sequence structures of pP99-018 (150,057 bp) and pP91278 (131,520 bp) were highly conserved, with differences due to variation in the drug resistance and conjugative transfer regions. These plasmids, shown to be closely related to the IncJ element R391 (a conjugative, self-transmitting, integrating element, or constin), were divided into the conjugative transfer, replication, partition, and multiple-drug resistance regions. Each of the five multiple-drug resistance regions sequenced exhibited unique drug resistance marker composition and arrangement. PMID:18070959

Kim, Mi-Jung; Hirono, Ikuo; Kurokawa, Ken; Maki, Takeshi; Hawke, John; Kondo, Hidehiro; Santos, Mudjekeewis D.; Aoki, Takashi

2008-01-01

353

Resistance mutations against HCV protease inhibitors and antiviral drug design.  

PubMed

The treatment for hepatitis C virus (HCV) infection has been significantly improved with the approval of the first two HCV NS3/4A protease inhibitors, telaprevir (Incivek) and boceprevir (Victrelis). These two direct acting antivirals (DAAs) are used clinically in combination with pegylated interferon-alpha (PEG-IFN?) and ribavirin (RBV). The sustained virologic response (SVR) rates are increased to ~70% and the duration of the treatment is ~50% shorter among treatment-naïve patients with genotype 1 HCV. Variants (quasi species) are almost constantly introduced during HCV replication due to its rapid replication rate and the low fidelity of its polymerase. Drug resistant variants carrying mutations that affect the binding of DAAs have the growth advantage over wild-type virus and could become the dominant viral quasi species during treatment with DAAs. Mutations at a number of key positions of the NS3/4A protease have been reported to be associated with drug resistance. This review summarizes the mutations that are responsible for resistance against the two approved protease inhibitors and several compounds in advanced clinical trials. The impacts of the resistance mutations on the binding of the inhibitors as well as the design of next-generation protease inhibitors are discussed from the perspective of medicinal chemistry. PMID:23688081

Shang, Luqing; Lin, Kai; Yin, Zheng

2014-01-01

354

Triclosan exposure increases triclosan resistance and influences taxonomic composition of benthic bacterial communities.  

PubMed

Triclosan (TCS) is a broad-spectrum antimicrobial compound that is incorporated into numerous consumer products. TCS has been detected in aquatic ecosystems across the U.S., raising concern about its potential ecological effects. We conducted a field survey and an artificial stream experiment to assess effects of TCS on benthic bacterial communities. Field sampling indicated that TCS concentrations in stream sediments increased with degree of urbanization. There was significant correlation between sediment TCS concentration and the proportion of cultivable benthic bacteria that were resistant to TCS, demonstrating that the levels of TCS present in these streams was affecting the native communities. An artificial stream experiment confirmed that TCS exposure could trigger increases in TCS resistance within cultivable benthic bacteria, and pyrosequencing analysis indicated that TCS resulted in decreased benthic bacterial diversity and shifts in bacterial community composition. One notable change was a 6-fold increase in the relative abundance of cyanobacterial sequences and a dramatic die-off of algae within the artificial streams. Selection of cyanobacteria over algae could have significant implications for higher trophic levels within streams. Finally, there were no observed effects of TCS on bacterial abundance or respiration rates, suggesting that bacterial density and function were highly resilient to TCS exposure. PMID:23865377

Drury, Bradley; Scott, John; Rosi-Marshall, Emma J; Kelly, John J

2013-08-01

355

Recognition of the Hyaloperonospora parasitica effector ATR13 triggers resistance against oomycete, bacterial, and viral pathogens.  

PubMed

Phytopathogenic oomycetes cause some of the most devastating diseases affecting agricultural crops. Hyaloperonospora parasitica is a native oomycete pathogen of Arabidopsis and is related to other oomycete phytopathogens that include several species of Phytophthora, including the causal agent of potato late blight. Recently, four oomycete effector genes have been isolated, and several oomycete genomes have been sequenced. We have developed an efficient and genetically amenable system to test putative effector genes using the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. The H. parasitica effector protein ATR13 was delivered via P. syringae by fusing the ATR13 gene with the avrRpm1 type three secretion signal peptide, a bacterial sequence that allows transfer of proteins into the host cell through the bacterial type III secretion system. We also inserted ATR13 into the genome of the turnip mosaic virus, a single-stranded RNA virus. Our results show that delivery of ATR13 via the bacterial or viral pathogen triggers defense responses in plants containing the cognate resistance protein RPP13(Nd), which restricts proliferation of both pathogens. Hence, recognition of ATR13 by RPP13 initiates defense responses that are effective against oomycete, bacterial and viral pathogens, pointing to a common defense mechanism. We have characterized regions of the RPP13(Nd) resistance protein that are essential for effector recognition and/or downstream signaling, using transient coexpression in Nicotiana benthamiana. PMID:18198274

Rentel, Maike C; Leonelli, Lauriebeth; Dahlbeck, Douglas; Zhao, Bingyu; Staskawicz, Brian J

2008-01-22

356

Recognition of the Hyaloperonospora parasitica effector ATR13 triggers resistance against oomycete, bacterial, and viral pathogens  

PubMed Central

Phytopathogenic oomycetes cause some of the most devastating diseases affecting agricultural crops. Hyaloperonospora parasitica is a native oomycete pathogen of Arabidopsis and is related to other oomycete phytopathogens that include several species of Phytophthora, including the causal agent of potato late blight. Recently, four oomycete effector genes have been isolated, and several oomycete genomes have been sequenced. We have developed an efficient and genetically amenable system to test putative effector genes using the bacterial pathogen Pseudomonas syringae pv. tomato DC3000. The H. parasitica effector protein ATR13 was delivered via P. syringae by fusing the ATR13 gene with the avrRpm1 type three secretion signal peptide, a bacterial sequence that allows transfer of proteins into the host cell through the bacterial type III secretion system. We also inserted ATR13 into the genome of the turnip mosaic virus, a single-stranded RNA virus. Our results show that delivery of ATR13 via the bacterial or viral pathogen triggers defense responses in plants containing the cognate resistance protein RPP13Nd, which restricts proliferation of both pathogens. Hence, recognition of ATR13 by RPP13 initiates defense responses that are effective against oomycete, bacterial and viral pathogens, pointing to a common defense mechanism. We have characterized regions of the RPP13Nd resistance protein that are essential for effector recognition and/or downstream signaling, using transient coexpression in Nicotiana benthamiana. PMID:18198274

Rentel, Maike C.; Leonelli, Lauriebeth; Dahlbeck, Douglas; Zhao, Bingyu; Staskawicz, Brian J.

2008-01-01

357

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

PubMed

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 Toru?. 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

Miko?ajczyk, Dorota; Budzy?ska, Anna; Kaczmarek, Agnieszka; Gospodarek, Eugenia

2007-01-01

358

MICROBIOLOGY: Weapons of Microbial Drug Resistance Abound in Soil Flora  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required. D'Costa et al. provides a fascinating view of the flip side of this story. The authors isolated 480 morphologically diverse spore-forming microbes from the soil and tested these not as producers of antimicrobial agents but rather as microbes that are resistant to existing antibiotics. Astonishingly, they found that every isolate was resistant to at least six to eight different antimicrobial agents and some to as many as 20! The antibiotics tested included both well-established and recently developed agents, natural products, semisynthetic derivatives, and fully synthetic antimicrobial agents. Bacteria found in soils show robust resistance to many antibiotics. These protective mechanisms may offer clues for generating a new arsenal of therapeutic drugs.

Alexander Tomasz (Rockefeller University; Laboratory of Microbiology)

2006-01-20

359

Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase  

SciTech Connect

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.

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

2013-04-08

360

Antibiotic resistance differentiates Echinacea purpurea endophytic bacterial communities with respect to plant organs.  

PubMed

Recent findings have shown that antibiotic resistance is widespread in multiple environments and multicellular organisms, as plants, harboring rich and complex bacterial communities, could be hot spot for emergence of antibiotic resistances as a response to bioactive molecules production by members of the same community. Here, we investigated a panel of 137 bacterial isolates present in different organs of the medicinal plant Echinacea purpurea, aiming to evaluate if different plant organs harbor strains with different antibiotic resistance profiles, implying then the presence of different biological interactions in the communities inhabiting different plant organs. Data obtained showed a large antibiotic resistance variability among strains, which was strongly related to the different plant organs (26% of total variance, P < 0.0001). Interestingly this uneven antibiotic resistance pattern was present also when a single genus (Pseudomonas), ubiquitous in all organs, was analyzed and no correlation of antibiotic resistance pattern with genomic relatedness among strains was found. In conclusion, we speculate that antibiotic resistance patterns are tightly linked to the type of plant organ under investigation, suggesting the presence of differential forms of biological interaction in stem/leaves, roots and rhizosphere. PMID:25283726

Mengoni, Alessio; Maida, Isabel; Chiellini, Carolina; Emiliani, Giovanni; Mocali, Stefano; Fabiani, Arturo; Fondi, Marco; Firenzuoli, Fabio; Fani, Renato

2014-10-01

361

Stacking of antimicrobial genes in potato transgenic plants confers increased resistance to bacterial and fungal pathogens.  

PubMed

Solanum tuberosum plants were transformed with three genetic constructions expressing the Nicotiana tabacum AP24 osmotine, Phyllomedusa sauvagii dermaseptin and Gallus gallus lysozyme, and with a double-transgene construction expressing the AP24 and lysozyme sequences. Re-transformation of dermaseptin-transformed plants with the AP24/lysozyme construction allowed selection of plants simultaneously expressing the three transgenes. Potato lines expressing individual transgenes or double- and triple-transgene combinations were assayed for resistance to Erwinia carotovora using whole-plant and tuber infection assays. Resistance levels for both infection tests compared consistently for most potato lines and allowed selection of highly resistant phenotypes. Higher resistance levels were found in lines carrying the dermaseptin and lysozyme sequences, indicating that theses proteins are the major contributors to antibacterial activity. Similar results were obtained in tuber infection tests conducted with Streptomyces scabies. Plant lines showing the higher resistance to bacterial infections were challenged with Phytophthora infestans, Rhizoctonia solani and Fusarium solani. Considerable levels of resistance to each of these pathogens were evidenced employing semi-quantitative tests based in detached-leaf inoculation, fungal growth inhibition and in vitro plant inoculation. On the basis of these results, we propose that stacking of these transgenes is a promising approach to achieve resistance to both bacterial and fungal pathogens. PMID:22115953

Rivero, Mercedes; Furman, Nicolás; Mencacci, Nicolás; Picca, Pablo; Toum, Laila; Lentz, Ezequiel; Bravo-Almonacid, Fernando; Mentaberry, Alejandro

2012-01-20

362

Occurrence of multiple metal-resistance in bacterial isolates associated with transgenic white poplars ( Populus alba L.)  

Microsoft Academic Search

The occurrence of multiple metal-resistance was assessed in two bacterial collections, named Herbicide Resistant Bacteria\\u000a (HRB) and Nuclease-Producing Bacteria (NPB) respectively, consisting of 15 and 11 isolates obtained from a loamy sand cultivated\\u000a with transgenic white poplars (Populus alba L., cv ‘Vilafranca’) engineered for herbicide resistance. A third collection of 11 bacterial isolates, named Leaf-Associated\\u000a Bacteria (LAB), obtained from the

Alma Balestrazzi; Martina Bonadei; Emanuele Quattrini; Daniela Carbonera

2009-01-01

363

Possible Role of Curcumin as an Efflux Pump Inhibitor in Multi Drug Resistant Clinical Isolates of Pseudomonas aeruginosa  

PubMed Central

Introduction: Multidrug resistant non-fermenters are continuously increasing in hospital and ICU settings. One of the mechanisms of developing drug resistance is possession of efflux pump through which bacteria extrude antimicrobial agents and other toxic substances. If these efflux channels are blocked or inhibited, increased drug concentration can be achieved in a bacterial cell with optimal drug dose. Present study was aimed to investigate role of curcumin as efflux pump inhibitor (EPI) and to compare its activity with a known EPI like phe-arg-beta-naphthylamide (PA?N). Materials and Methods: A total of 170 clinical isolates of Pseudomonas aeruginosa were taken, antimicrobial susceptibility was performed by disc diffusion test and minimum inhibitory concentration (MIC) against selected drugs before and after adding known synthetic EPI, PA?N (20mg/L). Out of these, 30 multidrug resistant strains were taken and MIC was performed with curcumin (50mg/L) with and without selected drugs. Results : Significant reduction in MIC was observed after adding curcumin (50mg/L) with selected antimicrobial agents in 9/30 (30%) of multi drug resistant (MDR) isolates of Pseudomonas aeruginosa, while no change in MIC was observed when curcumin (50mg/L) was used alone, indicating its efflux pump inhibitor activity. Conclusion: This study suggests role of efflux pump in development of drug resistance which can be overcome by use of an efflux pump inhibitor, with more emphasis on compound like curcumin which will have less or no adverse effects if used in vivo. PMID:25478340

Prakash, Pradyot; Gupta, Mohan Lal; Mohapatra, Tribhuban Mohan

2014-01-01

364

Mathematical Modeling of Bacterial Kinetics to Predict the Impact of Antibiotic Colonic Exposure and Treatment Duration on the Amount of Resistant Enterobacteria Excreted  

PubMed Central

Fecal excretion of antibiotics and resistant bacteria in the environment are major public health threats associated with extensive farming and modern medical care. Innovative strategies that can reduce the intestinal antibiotic concentrations during treatments are in development. However, the effect of lower exposure on the amount of resistant enterobacteria excreted has not been quantified, making it difficult to anticipate the impact of these strategies. Here, we introduce a bacterial kinetic model to capture the complex relationships between drug exposure, loss of susceptible enterobacteria and growth of resistant strains in the feces of piglets receiving placebo, 1.5 or 15 mg/kg/day ciprofloxacin, a fluoroquinolone, for 5 days. The model could well describe the kinetics of drug susceptible and resistant enterobacteria observed during treatment, and up to 22 days after treatment cessation. Next, the model was used to predict the expected amount of resistant enterobacteria excreted over an average piglet's lifetime (150 days) when varying drug exposure and treatment duration. For the clinically relevant dose of 15 mg/kg/day for 5 days, the total amount of resistant enterobacteria excreted was predicted to be reduced by 75% and 98% when reducing treatment duration to 3 and 1 day treatment, respectively. Alternatively, for a fixed 5-days treatment, the level of resistance excreted could be reduced by 18%, 33%, 57.5% and 97% if 3, 5, 10 and 30 times lower levels of colonic drug concentrations were achieved, respectively. This characterization on in vivo data of the dynamics of resistance to antibiotics in the colonic flora could provide new insights into the mechanism of dissemination of resistance and can be used to design strategies aiming to reduce it. PMID:25210849

Nguyen, Thu Thuy; Guedj, Jeremie; Chachaty, Elisabeth; de Gunzburg, Jean; Andremont, Antoine; Mentré, France

2014-01-01

365

Genetics of drug resistance in malaria : identification of genes conferring chloroquine and artemisinin resistance in rodent malaria parasite Plasmodium chabaudi   

E-print Network

Resistance to antimalarial drugs continues to be a major obstacle in controlling and eradicating malaria. The identification of genetic markers of resistance is vital for disease management but they can be difficult to ...

Modrzynska, Katarzyna Kinga

2011-01-01

366

Overcoming platinum drug resistance with copper-lowering agents.  

PubMed

Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, up-regulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Cu-lowering agents through enhanced hCtr1 expression by up-regulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy. PMID:24122978

Chen, Helen H W; Kuo, Macus Tien

2013-10-01

367

Overcoming Platinum Drug Resistance with Copper-lowering Agents  

PubMed Central

Platinum (Pt)-based antitumor agents have been the mainstay of cancer chemotherapy for the last three decades. While multiple mechanisms are responsible for treatment failure, deficiency in drug transport is an important contributor. The human high-affinity copper (Cu) transporter-1 (hCtr1) can also transport Pt-based drugs including cisplatin (cDDP) and carboplatin. Reduced hCtr1 expression frequently occurs in cDDP-resistant cell lines and in cancer in patients who failed chemotherapy with these drugs. We previously demonstrated that Cu chelation induces the expression of transcription factor Sp1 which binds the promoters of Sp1 and hCtr1, thereby, up-regulating their expression, whereas Cu overload shuts down hCtr1 and Sp1 expression by dissociating Sp1 from their promoter promoters. Thus, mammalian Cu homeostasis is transcriptionally regulated within a loop consisting of Sp1, hCtr1, and Cu in a three-way mutually regulated manner. These findings suggest that it is feasible to module cDDP transport capacity through intervention of mammalian Cu homeostasis. Indeed, we found that cDDP resistance can be overcome by Cu-lowering agents through enhanced hCtr1 expression by up-regulation of Sp1 in cultured cells. This discovery provided a mechanistic basis for the ongoing clinical study using Cu chelator to overcome cDDP resistance in ovarian cancer chemotherapy. Preliminary study using copper chelator (trientine) for enhancing the treatment efficacy of carboplatin in 5 ovarian cancer patients showed encouraging results. This short review describes the perspectives of using Cu-lowering agents in overcoming Pt resistance in cancer chemotherapy. PMID:24122978

CHEN, HELEN H.W.; KUO, MACUS TIEN

2014-01-01

368

Life in cellulose houses: Symbiotic bacterial biosynthesis of ascidian drugs and drug leads  

PubMed Central

Ascidians (tunicates; sea squirts) are sources of diverse, bioactive natural products, one of which is an approved drug and many of which are potent drug leads. It has been shown that symbiotic bacteria living with ascidians produce some of the bioactive compounds isolated from whole animals, and indirect evidence strongly implicates symbiotic bacteria in the synthesis of many others. However, for the majority the producing organism has not been identified. In cases where a symbiotic origin has been definitively assigned, the resulting data lead to improved paths to drug discovery and development from marine animals. This review traces evidence for symbiotic production where such evidence exists and describes the strengths and limitations of that evidence. PMID:21050742

Schmidt, Eric W.; Donia, Mohamed S.

2010-01-01

369

The Impact of Resource Availability on Bacterial Resistance to Phages in Soil  

PubMed Central

Resource availability can affect the coevolutionary dynamics between host and parasites, shaping communities and hence ecosystem function. A key finding from theoretical and in vitro studies is that host resistance evolves to greater levels with increased resources, but the relevance to natural communities is less clear. We took two complementary approaches to investigate the effect of resource availability on the evolution of bacterial resistance to phages in soil. First, we measured the resistance and infectivity of natural communities of soil bacteria and phage in the presence and absence of nutrient-providing plants. Second, we followed the real-time coevolution between defined bacteria and phage populations with resource availability manipulated by the addition or not of an artificial plant root exudate. Increased resource availability resulted in increases in bacterial resistance to phages, but without a concomitant increase in phage infectivity. These results suggest that phages may have a reduced impact on the control of bacterial densities and community composition in stable, high resource environments. PMID:25856079

Gómez, Pedro; Bennie, Jonathan; Gaston, Kevin J.; Buckling, Angus

2015-01-01

370

Capillary Electrophoresis – Single Strand Conformation Polymorphism for the Detection of Multiple Mutations Leading to Tuberculosis Drug Resistance  

PubMed Central

Drug resistant tuberculosis (TB) is a major health problem in both developed and developing countries. Mutations in the Mycobacterium (M.) tuberculosis bacterial genome, such as those to the rpoB gene and mabA-inhA promoter region, have been linked to TB drug resistance in against rifampicin and isoniazid, respectively. The rapid, accurate, and inexpensive identification of these and other mutations leading to TB drug resistance is an essential tool for improving human health. Capillary electrophoresis (CE) single strand conformation polymorphism (SSCP) can be a highly sensitive technique for the detection of genetic mutation that has not been previously explored for drug resistance mutations in M. tuberculosis. This work explores the potential of CE-SSCP through the optimization of variables such as polymer separation matrix concentration, capillary wall coating, electric field strength, and temperature on resolution of mutation detection. The successful detection of an rpoB gene mutation and two mabA-inhA promoter region mutations while simultaneously differentiating a TB-causing mycobacteria from a non-TB bacteria was accomplished using the optimum conditions of 4.5% (w/v) PDMA in a PDMA coated capillary at 20°C using a separation voltage of 278 V/cm. This multiplexed analysis that can be completed in a few hours demonstrates the potential of CE-SSCP to be an inexpensive and rapid analysis method. PMID:22884688

Krothapalli, Sowmya; May, Michael K.; Hestekin, Christa N.

2013-01-01

371

[Pulmonary tuberculosis with resistance to 4 antitubercular drugs].  

PubMed

A 32-year-old immigrant from Pakistan was admitted to our hospital with cavernous pulmonary tuberculosis. He gave a history of several 1 to 2-months courses of antimycobacterial treatment administered earlier in Pakistan. We initiated combined therapy including isoniazid, rifampin, pyrazinamide, and ethambutol. Subsequently, results of susceptibility testing from M. tuberculosis-complex strains isolated before the onset of treatment documented the presence of resistance against both isoniazid and rifampin which may have been primary or acquired drug resistances. During the course of treatment, two additional resistances to pyrazinamide and ethambutol developed which were probably due to the initial therapy with only two active antimycobacterial agents. The emergence of multidrug-resistant strains of M. tuberculosis complex is a world-wide problem. Our case indicates that multiresistance must be considered in every patient presenting with tuberculosis. If there is a strong suspicion of multidrug-resistant tuberculosis, initial treatment with a combination of 5-6 antimycobacterial agents seems advisable until the results of susceptibility testing become available. PMID:9540152

Reichlin, S; Frei, R; Reusser, P

1998-02-14

372

Development of in vitro Antimicrobial Resistance in Bacteria Exposed to Residue Level Exposures of Antimicrobial Drugs, Pesticides and Veterinary Drugs  

Microsoft Academic Search

Ten ppb or less of antibacterial drugs, pesticides and veterinary drugs could increase antibacterial resistance in bacteria. The minimum inhibitory concentration (MIC) was the indicator of resistance and Staphylococcus aureus ATCC 9144 the indicator organism. Seventeen compounds used in human, veterinary medicine, crop production, and found in the environment, were studied singly, and as combinations. Single compounds decreased MIC values

David K. Kleiner; Stanley E. Katz; Paula-Marie L. Ward

2007-01-01

373

Structure of supported bilayers composed of lipopolysaccharides and bacterial phospholipids: raft formation and implications for bacterial resistance.  

PubMed

Lipopolysaccharide (LPS), the major lipid on the surface of Gram-negative bacteria, plays a key role in bacterial resistance to hydrophobic antibiotics and antimicrobial peptides. Using atomic force microscopy (AFM) we characterized supported bilayers composed of LPSs from two bacterial chemotypes with different sensitivities to such antibiotics and peptides. Rd LPS, from more sensitive "deep rough" mutants, contains only an inner saccharide core, whereas Ra LPS, from "rough" mutants, contains a longer polysaccharide region. A vesicle fusion technique was used to deposit LPS onto either freshly cleaved mica or polyethylenimine-coated mica substrates. The thickness of the supported bilayers measured with contact-mode AFM was 7 nm for Rd LPS and 9 nm for Ra LPS, consistent with previous x-ray diffraction measurements. In water the Ra LPS bilayer surface was more disordered than Rd LPS bilayers, likely due to the greater volume occupied by the longer Ra LPS polysaccharide region. Since deep rough mutants contain bacterial phospholipid (BPL) as well as LPS on their surfaces, we also investigated the organization of Rd LPS/BPL bilayers. Differential scanning calorimetry and x-ray diffraction indicated that incorporation of BPL reduced the phase transition temperature, enthalpy, and average bilayer thickness of Rd LPS. For Rd LPS/BPL mixtures, AFM showed irregularly shaped regions thinner than Rd LPS bilayers by 2 nm (the difference in thickness between Rd LPS and BPL bilayers), whose area increased with increasing BPL concentration. We argue that the increased permeability of deep rough mutants is due to structural modifications caused by BPL to the LPS membrane, in LPS hydrocarbon chain packing and in the formation of BPL-enriched microdomains. PMID:15189872

Tong, Jihong; McIntosh, Thomas J

2004-06-01

374

Rifampin drug resistance tests for tuberculosis: challenging the gold standard.  

PubMed

The rapid diagnosis of rifampin resistance is hampered by a reported insufficient specificity of molecular techniques for detection of rpoB mutations. Our objective for this study was to document the prevalence and prognostic value of rpoB mutations with unclear phenotypic resistance. The study design entailed sequencing directly from sputum of first failure or relapse patients without phenotypic selection and comparison of the standard retreatment regimen outcome, according to the mutation present. We found that among all rpoB mutations, the best-documented "disputed" rifampin resistance mutations (511Pro, 516Tyr, 526Asn, 526Leu, 533Pro, and 572Phe) made up 13.1% and 10.6% of all mutations in strains from Bangladesh and Kinshasa, respectively. Except for the 511Pro and 526Asn mutations, most of these strains with disputed mutations tested rifampin resistant in routine Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified. PMID:23761144

Van Deun, Armand; Aung, Kya J M; Bola, Valentin; Lebeke, Rossin; Hossain, Mohamed Anwar; de Rijk, Willem Bram; Rigouts, Leen; Gumusboga, Aysel; Torrea, Gabriela; de Jong, Bouke C

2013-08-01

375

Infectious prosthetic hip joint loosening: bacterial species involved in its aetiology and their antibiotic resistance profiles against antibiotics recommended for the therapy of implant-associated infections.  

PubMed

Reliable microbiological diagnosis along with surgery and prolonged antibiotic therapy are key elements in the management of prosthetic-joint infections (PJIs). The purpose of this study was to characterize antibiotic resistance profiles of bacteria involved in the aetiology of PJIs. A total of 33 bacterial isolates cultured from 31 patients undergoing exchange of total hip prostheses were analyzed. The diagnostic approach toward isolation of prosthesis- associated microorganisms included sonication of retrieved implants and conventional cultures of periprosthetic tissues and synovial fluid. The in vitro resistance profiles of bacterial isolates were determined in relation to antibiotics recommended for the therapy of PJIs using the disc diffusion method, E-tests(®) and broth microdilution system. Coagulase-negative staphylococci (CNS) were predominant microorganisms followed by Staphylococcus aureus, Enterobacter cloacae, Streptococcus mitis, and Propionibacterium acnes. Twenty out of 30 and 12 out of 30 staphylococcal isolates were methicillin- and multi-drug resistant, respectively. Only two isolates were rifampicinresistant. All staphylococci were susceptible to glycopeptides and linezolid. This paper stresses the pathogenic role of staphylococci in patients suffering from implant loosening and reports high methicillin- and multidrug-resistance rates in these bacteria. Hence, antimicrobial susceptibility tests of individual bacterial isolates must always be performed to guide selection of the optimal therapeutic option. PMID:24858648

Bogut, Agnieszka; Nied?wiadek, Justyna; Strzelec-Nowak, Dagmara; Blacha, Jan; Mazurkiewicz, Tomasz; Marczy?ski, Wojciech; Kozio?-Montewka, Maria

2014-04-01

376

Accelerating resistance, inadequate antibacterial drug pipelines and international responses.  

PubMed

The pandemic of multidrug-resistant (MDR) pathogens and their continuing spread is beyond dispute. In contrast to the past, today's antibacterial research and development (R&D) pipelines are nearly dry, failing to provide the flow of novel antibiotics required to match the clinical challenges of the multidrug resistance (MDR) crisis. Concerned over the rapidly worsening potential global healthcare crisis caused by MDR bacteria and the lack of robust drug pipelines, several multinational campaigns have issued policy recommendations and have initiated broad discussion with a goal of stimulating the development of novel antibacterial drugs and technologies. These activities have resulted in intensified co-operation between the USA and the EU. The recently announced extensive 'Action plan against the rising threats from antimicrobial resistance' substantially ramps up action within the EU. In recognising the potential crisis caused by MDR and the limited treatment options, the European Commission decided on an unprecedented approach to drive the search for novel antibiotics by integrating the pharmaceutical industry, the research capacities of universities and small companies supported by public funding along with pricing/reimbursement and regulatory bodies. The European Commission has shown leadership and put action plans in place. Only the future will tell whether these initiatives will help curb the impact of the MDR pandemic. PMID:22341298

Theuretzbacher, Ursula

2012-04-01

377

Evaluation of radiation resistance of the bacterial contaminants from femoral heads processed for allogeneic transplantation  

NASA Astrophysics Data System (ADS)

Femoral heads excised during surgery were obtained from patients who had a fractured neck of the femur and were processed as bone allograft. The bacterial contaminants were isolated from femoral heads at different stages of processing and identified based on morphological characteristics and biochemical tests. Bacterial contaminants on bone were mainly Gram-positive bacilli and cocci (58.3%). Twenty-four isolates from bone samples were screened for resistance to radiation. The D10 values for Gram-negative bacteria isolated from femoral heads ranged from 0.17 to 0.65 kGy. Higher D10 values 0.56-1.04 kGy were observed for Gram-positive bacterial isolates.

Singh, Rita; Singh, Durgeshwer

2009-09-01

378

Trastuzumab emtansine: mechanisms of action and drug resistance  

PubMed Central

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that is effective and generally well tolerated when administered as a single agent to treat advanced breast cancer. Efficacy has now been demonstrated in randomized trials as first line, second line, and later than the second line treatment of advanced breast cancer. T-DM1 is currently being evaluated as adjuvant treatment for early breast cancer. It has several mechanisms of action consisting of the anti-tumor effects of trastuzumab and those of DM1, a cytotoxic anti-microtubule agent released within the target cells upon degradation of the human epidermal growth factor receptor-2 (HER2)-T-DM1 complex in lysosomes. The cytotoxic effect of T-DM1 likely varies depending on the intracellular concentration of DM1 accumulated in cancer cells, high intracellular levels resulting in rapid apoptosis, somewhat lower levels in impaired cellular trafficking and mitotic catastrophe, while the lowest levels lead to poor response to T-DM1. Primary resistance of HER2-positive metastatic breast cancer to T-DM1 appears to be relatively infrequent, but most patients treated with T-DM1 develop acquired drug resistance. The mechanisms of resistance are incompletely understood, but mechanisms limiting the binding of trastuzumab to cancer cells may be involved. The cytotoxic effect of T-DM1 may be impaired by inefficient internalization or enhanced recycling of the HER2-T-DM1 complex in cancer cells, or impaired lysosomal degradation of trastuzumab or intracellular trafficking of HER2. The effect of T-DM1 may also be compromised by multidrug resistance proteins that pump DM1 out of cancer cells. In this review we discuss the mechanism of action of T-DM1 and the key clinical results obtained with it, the combinations of T-DM1 with other cytotoxic agents and anti-HER drugs, and the potential resistance mechanisms and the strategies to overcome resistance to T-DM1. PMID:24887180

2014-01-01

379

Monitoring bacterial processes by Fourier transform infrared spectroscopy: Helicobacter pylori drug inactivation and plasmid bioproduction in recombinant Escherichia coli cultures  

Microsoft Academic Search

Fourier transform infrared (FTIR) spectroscopy is evaluated as a tool to monitor two bacterial processes: strain discrimination and drug inactivation studies with the gastric pathogen Helicobacter pylori and the plasmid production process based on high-density cultures of recombinant Escherichia coli. Results show, that after evaluation of different incubation condi- tions of H.pylori with the drug model, the application of principal

Teresa Scholz; Vitor V. Lopes; Cecilia R. C. Calado

2011-01-01

380

Resistance of bacterial isolates from poultry products to therapeutic veterinary antibiotics.  

PubMed

Bacterial isolates from poultry products were tested for their susceptibility to 10 antibiotics commonly used in the therapeutic treatment of poultry. Bacteria were isolated from fresh whole broiler carcasses or from cut-up meat samples (breast with or without skin, wings, and thighs) that were either fresh or stored at 4 or 13 degrees C (temperatures relevant to poultry-processing facilities). The Biolog system was used to identify isolates, and a broth dilution method was used to determine the antibiotic resistance properties of both these isolates and complementary cultures from the American Type Culture Collection. The antibiotics to which the most resistance was noted were penicillin G, sulfadimethoxine, and erythromycin; the antibiotic to which the least resistance was noted was enrofloxacin. Individual isolates exhibited resistances to as many as six antibiotics, with the most common resistance pattern involving the resistance of gram-negative bacteria to penicillin G, sulfadimethoxine, and erythromycin. Differences in resistance patterns were noted among 18 gram-positive and 7 gram-negative bacteria, and comparisons were made between species within the same genus. The data obtained in this study provide a useful reference for the species and resistance properties of bacteria found on various raw poultry products, either fresh or stored at temperatures and for times relevant to commercial processing, storage, and distribution. The results of this study show that resistance to antibiotics used for the therapeutic treatment of poultry occurs in bacteria in the processing environment. PMID:12540187

Boothe, D H; Arnold, J W

2003-01-01

381

Drug efflux by a small multidrug resistance protein is inhibited by a transmembrane peptide.  

PubMed

Drug-resistant bacteria use several families of membrane-embedded transporters to remove antibiotics from the cell. One such family is the small multidrug resistance proteins (SMRs) that, because of their relatively small size (ca. 110 residues with four transmembrane [TM] helices), must form (at least) dimers to efflux drugs. Here, we use a Lys-tagged synthetic peptide with exactly the same sequence as TM4 of the full-length SMR Hsmr from Halobacterium salinarum [TM4 sequence: AcA(Sar)(3)-VAGVVGLALIVAGVVVLNVAS-KKK (Sar = N-methylglycine)] to compete with and disrupt the native TM4-TM4 interactions believed to constitute the locus of Hsmr dimerization. Using a cellular efflux assay of the fluorescent SMR substrate ethidium bromide, we determined that bacterial cells containing Hsmr are able to remove cellular ethidium via first-order exponential decay with a rate constant (k) of 10.1 × 10(-3) ± 0.7 × 10(-3) s(-1). Upon treatment of the cells with the TM4 peptide, we observed a saturable ~60% decrease in the efflux rate constant to 3.7 × 10(-3) ± 0.2 × 10(-3) s(-1). In corresponding experiments with control peptides, including scrambled sequences and a sequence with d-chirality, a decrease in ethidium efflux either was not observed or was marginal, likely from nonspecific effects. The designed peptides did not evoke bacterial lysis, indicating that they act via the ?-helicity and membrane insertion propensities of the native TM4 helix. Our overall results suggest that this approach could conceivably be used to design hydrophobic peptides for disruption of key TM-TM interactions of membrane proteins and represent a valuable route to the discovery of new therapeutics. PMID:22526304

Poulsen, Bradley E; Deber, Charles M

2012-07-01

382

A MAJOR QTL FOR COMMON BACTERIAL BLIGHT RESISTANCE DERIVES FROM THE COMMON BEAN GREAT NORTHERN LANDRACE CULTIVAR MONTANA NO. 5  

Technology Transfer Automated Retrieval System (TEKTRAN)

Knowledge of the evolutionary origin and sources of pest resistance genes will facilitate gene deployment and development of crop cultivars with durable resistance. Our objective was to determine the source of common bacterial blight (CBB) resistance in great northern dry bean cultivars. Several cul...

383

Role of integrated cancer nanomedicine in overcoming drug resistance.  

PubMed

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

Iyer, Arun K; Singh, Amit; Ganta, Srinivas; Amiji, Mansoor M

2013-11-01

384

Dodecyltriphenylphosphonium inhibits multiple drug resistance in the yeast Saccharomyces cerevisiae.  

PubMed

Multiple drug resistance pumps are potential drug targets. Here we asked whether the lipophilic cation dodecyltriphenylphosphonium (C12TPP) can interfere with their functioning. First, we found that suppression of ABC transporter gene PDR5 increases the toxicity of C12TPP in yeast. Second, C12TPP appeared to prevent the efflux of rhodamine 6G - a fluorescent substrate of Pdr5p. Moreover, C12TPP increased the cytostatic effects of some other known Pdr5p substrates. The chemical nature of C12TPP suggests that after Pdr5p-driven extrusion the molecules return to the plasma membrane and then into the cytosol, thus effectively competing with other substrates of the pump. PMID:25019981

Knorre, Dmitry A; Markova, Olga V; Smirnova, Ekaterina A; Karavaeva, Iuliia E; Sokolov, Svyatoslav S; Severin, Fedor F

2014-08-01

385

Drug resistance in trypanosomes; selective interference with trypanocidal action  

PubMed Central

Selective reversal of the trypanocidal action of carboxylated arsenicals by p-aminobenzoic acid and of melaminyl arsenicals and diamidines by melamine has been demonstrated in vivo and in vitro. The structural specificity of these reversal phenomena is high, and suggests preferential adsorption of the antagonist during a reversible primary drug fixation stage. Thiols antagonized neutral, carboxylated and melaminyl aromatic arsenicals equally, but not diamidines; p-aminobenzoic acid antagonism is specific for carboxylated arsenicals, and melamine antagonizes only the melaminyl arsenicals and the diamidines. These reversals reflect the pattern of crossresistance behaviour and suggest that cellular structures associated with a reversible stereospecific drug adsorption phase are modified during the development of resistance. PMID:13844960

Williamson, J.

1959-01-01

386

MinION nanopore sequencing identifies the position and structure of a bacterial antibiotic resistance island.  

PubMed

Short-read, high-throughput sequencing technology cannot identify the chromosomal position of repetitive insertion sequences that typically flank horizontally acquired genes such as bacterial virulence genes and antibiotic resistance genes. The MinION nanopore sequencer can produce long sequencing reads on a device similar in size to a USB memory stick. Here we apply a MinION sequencer to resolve the structure and chromosomal insertion site of a composite antibiotic resistance island in Salmonella Typhi Haplotype 58. Nanopore sequencing data from a single 18-h run was used to create a scaffold for an assembly generated from short-read Illumina data. Our results demonstrate the potential of the MinION device in clinical laboratories to fully characterize the epidemic spread of bacterial pathogens. PMID:25485618

Ashton, Philip M; Nair, Satheesh; Dallman, Tim; Rubino, Salvatore; Rabsch, Wolfgang; Mwaigwisya, Solomon; Wain, John; O'Grady, Justin

2015-03-01

387

Bacterial mechanisms for Cr(VI) resistance and reduction: an overview and recent advances.  

PubMed

Chromium pollution is increasing incessantly due to continuing industrialization. Of various oxidation states, Cr(6+) is very toxic due to its carcinogenic and mutagenic nature. It also has deleterious effects on different microorganisms as well as on plants. Many species of bacteria thriving in the Cr(6+)-contaminated environments have evolved novel strategies to cope with Cr(6+) toxicity. Generally, decreased uptake or exclusion of Cr(6+) compounds through the membranes, biosorption, and the upregulation of genes associated with oxidative stress response are some of the resistance mechanisms in bacterial cells to overcome the Cr(6+) stress. In addition, bacterial Cr(6+) reduction into Cr(3+) is also a mechanism of specific significance as it transforms toxic and mobile chromium derivatives into reduced species which are innocuous and immobile. Ecologically, the bacterial trait of reductive immobilization of Cr(6+) derivatives is of great advantage in bioremediation. The present review is an effort to underline the bacterial resistance and reducing mechanisms to Cr(6+) compounds with recent development in order to garner a broad perspective. PMID:24470188

Ahemad, Munees

2014-07-01

388

Feline urinary tract pathogens: prevalence of bacterial species and antimicrobial resistance over a 10-year period.  

PubMed

The purpose of this retrospective study was to identify bacterial species in cats with bacterial urinary tract infections (UTIs) and to investigate their antimicrobial susceptibilities over a 10-year period. Three hundred and thirty cultures from 280 cats were included in the study. The mean age of affected cats was 9.9?years; female cats with bacterial UTIs were significantly older than male cats with UTIs. The most common pathogen identified was Escherichia coli (42.3 per cent), followed by Streptococcus species (19.3 per cent), Staphylococcus species (15.6 per cent), Enterococcus species (6.6 per cent) and Micrococcaceae (5.8 per cent). Forty specimens (12.1 per cent) yielded growth of more than one isolate. Streptococcus and Enterococcus isolates were resistant to a significantly higher number of antimicrobial agents than E coli and Staphylococcus species isolates. Applying the formula to select rational antimicrobial therapy, bacterial isolates were most likely to be susceptible to nitrofurantoin, amoxicillin clavulanic acid, enrofloxacin and gentamicin. The antimicrobial impact factor for nitrofurantoin increased significantly over the 10-year period, whereas there was no significant change in antimicrobial impact factors for doxycycline, trimethoprim-sulfamethoxazole, gentamicin, enrofloxacin, cephalothin and amoxicillin clavulanic acid. The detected changes in in vitro antimicrobial efficacy could help to develop hospital-specific guidelines for antimicrobial use to prevent the further development of resistance in feline uropathogens. PMID:25351232

Dorsch, Roswitha; von Vopelius-Feldt, Clara; Wolf, Georg; Straubinger, Reinhard K; Hartmann, Katrin

2015-02-21

389

Drug resistance. K13-propeller mutations confer artemisinin resistance in Plasmodium falciparum clinical isolates.  

PubMed

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

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

390

In vivo resistance to bacterial biofilm formation on tympanostomy tubes as a function of tube material  

Microsoft Academic Search

Adherent bacterial biofilms have been implicated in the irreversible contamination of implanted medical devices. We evaluated the resistance of various tympanostomy (pressure equalization [PE]) tube materials to biofilm formation using an in vivo model. PE tubes of silicone, silver oxide–impregnated silicone, fluoroplastic, silver oxide–impregnated fluoroplastic, and ion-bombarded silicone were inserted into the tympanic membranes of 18 Hartley guinea pigs. Staphylococcus

IYAD S SAIDI; JOHN F BIEDLINGMAIER; PHILIP WHELAN

1999-01-01

391

Breeding Rice Cultivars Resistant to Bacterial Leaf Blight (Xanthomonas campestris pv. oryzae) in Vietnam  

Microsoft Academic Search

\\u000a Bacterial leaf blight (BLB) represents one of the most destructive rice diseases in Vietnam. Yield losses in severely infested\\u000a fields range from 20 to 65%. Various kinds of chemicals have been tested to control BLB but no effective chemical control\\u000a can yet be recommended for practical use. Varietal resistance, however, is found effective. Much effort has been devoted to\\u000a the

Ta Minh Son

392

Enhanced resistance against bacterial wilt in transgenic tomato ( Lycopersicon esculentum ) lines expressing the Xa21 gene  

Microsoft Academic Search

To enhance bacterial wilt resistance in tomato plants and simplify the protocol of Agrobacterium tumefaciens mediated gene transfer, parameters affecting transformation efficiency in tomato have been optimized. A. tumefaciens strain EHA101, harboring a recombinant binary expression vector pTCL5 containing the Xa21 gene under the control of the CaMV 35S promoter was used for transformation. Five cultivars of tomato (Rio Grande,

Amber Afroz; Zubeda Chaudhry; Umer Rashid; Ghulam Muhammad Ali; Farhat Nazir; Javaid Iqbal; Muhammad Rashid Khan

2011-01-01

393

Structural model of ATP-binding proteing associated with cystic fibrosis, multidrug resistance and bacterial transport  

Microsoft Academic Search

THE ATP-binding cassette (ABC) superfamily of transport systems now includes over thirty proteins that share extensive sequence similarity and domain organization (reviewed in refs 1-3). This superfamily includes the well characterized periplasmic binding protein-dependent uptake systems of prokaryotes, bacterial exporters, and eukaryotic proteins including the P-glycoprotein associated with multidrug resistance in tumours (MDR), the STE6 gene product that mediates export

Stephen C. Hyde; Paul Emsley; Michael J. Hartshorn; Michael M. Mimmack; Uzi Gileadi; Stephen R. Pearce; Maurice P. Gallagher; Deborah R. Gill; Roderick E. Hubbard; Christopher F. Higgins

1990-01-01

394

Phenotypic and molecular characterization of conjugative antibiotic resistance plasmids isolated from bacterial communities of activated sludge  

Microsoft Academic Search

In order to isolate antibiotic resistance plasmids from bacterial communities found in activated sludge, derivatives of the\\u000a 3-chlorobenzoate-degrading strain Pseudomonas sp. B13, tagged with the green fluorescent protein as an identification marker, were used as recipients in filter crosses.\\u000a Transconjugants were selected on agar plates containing 3-chlorobenzoate as the sole carbon source and the antibiotic tetracycline,\\u000a streptomycin or spectinomycin, and

M. Dröge; A. Pühler; W. Selbitschka

2000-01-01

395

Exploring Culturally Specific Drug Resistance Strategies of Hawaiian Youth in Rural Communities  

ERIC Educational Resources Information Center

This qualitative study examined the drug resistance strategies of Hawaiian youth residing in rural communities in Hawai'i. Forty seven youth participated in 14 focus groups which focused on the social and environmental context of drug use for these youth. The findings indicated that there were 47 references to resistance strategies used in drug

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

2010-01-01

396

Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance  

E-print Network

Modeling of the human rhinovirus C capsid suggests possible causes for antiviral drug resistance: Rhinovirus Capsid structure Model Rhinovirus C Pleconaril Antiviral therapy Drug-binding pocket Pore Drug resistance a b s t r a c t Human rhinoviruses of the RV-C species are recently discovered pathogens

397

Drug Resistance in Breast Cancer Cells: Biophysical Characterization of and Doxorubicin Interactions with Membrane Lipids  

PubMed Central

Understanding the role of lipids in drug transport is critical in cancer chemotherapy to overcome drug resistance. In this study, we isolated lipids from doxorubicin-sensitive (MCF-7) and -resistant (MCF-7/ADR) breast cancer cells to characterize the biophysical properties of membrane lipids (particularly lipid packing and membrane fluidity) and to understand the role of the interaction of cell membrane lipids with drug/nanocarrier on drug uptake and efficacy. Resistant cell membrane lipids showed significantly different composition and formed more condensed, less fluid monolayers than did lipids from sensitive cells. Doxorubicin, used as a model anticancer agent, showed a strong hydrophobic interaction with resistant cell membrane lipids but significantly less interaction, as well as a different pattern of interaction (i.e., ionic), with sensitive ones. The threshold intracellular doxorubicin concentration required to produce an antiproliferative effect was similar for both sensitive and resistant cell lines, suggesting that drug transport is a major barrier in determining drug efficacy in resistant cells. In addition to the biophysical characteristics of resistant cell membrane lipids, lipid-doxorubicin interactions appear to decrease intracellular drug transport via diffusion as the drug is trapped in the lipid bilayer. The rigid nature of resistant cell membranes also seems to influence endosomal functions that inhibit drug uptake when a liposomal formulation of doxorubicin is used. In conclusion, biophysical properties of resistant cell membrane lipids significantly influence drug transport, and hence drug efficacy. A better understanding of the mechanisms of cancer drug resistance is vital to developing more effective therapeutic interventions. In this regard, biophysical interaction studies with cell membrane lipids might be helpful to improve drug transport and efficacy through drug discovery and/or drug delivery approaches by overcoming the lipid barrier in resistant cells. PMID:20958074

Peetla, Chiranjeevi; Bhave, Radhika; Vijayaraghavalu, Sivakumar; Stine, Andrew; Kooijman, Edgar; Labhasetwar, Vinod

2010-01-01

398

Multi Drug and Other Forms of Drug Resistant Tuberculosis Are Uncommon among Treatment Naïve Tuberculosis Patients in Tanzania  

PubMed Central

Background Surveillance and effective management of drug resistance is important to sustaining tuberculosis (TB) control efforts. We aimed to determine resistance rates to first line anti tuberculosis drugs and to describe factors associated with the resistance to any of the first line anti tuberculosis drugs in Dar es Salaam Tanzania. Materials Newly diagnosed, TB patients with neither history of tuberculosis treatment nor isoniazid prophylaxis were included into the study. Sputum specimens were cultured on either mycobacteria growth indicator tube 960 (MGIT 960) or Lowenstein Jenstein (LJ) medium supplemented with either glycerol (GLJ) or pyruvate (PLJ). Drug susceptibility for isoniazid, rifampicin, streptomycin and ethambutol was determined by either Lowenstein–Jensen (LJ) medium or mycobacteria growth indicator tube 960 (MGIT 960). Results A total of 933 newly diagnosed TB patients, were included into the study. Multi drug resistance (MDR) tuberculosis was detected among 2 (0.2%) patients. Resistance to any of the four tested drugs was detected among 54 (5.8%) patients. Mono-resistance to isoniazid, rifampicin, streptomycin and ethambutol were 21(2.3%), 3 (0.3%), 13 (1.4%), 9 (1.0%) respectively. Conclusion Primary resistance to first line anti tuberculosis drugs is still low in this setting. Continued vigilance including periodic national surveillance of anti-tuberculosis resistance is recommended. PMID:25849784

Nagu, Tumaini J.; Aboud, Said; Mwiru, Ramadhani; Matee, Mecky; Fawzi, Wafaie; Mugusi, Ferdinand

2015-01-01

399

High prevalence of antimicrobial resistance among common bacterial isolates in a tertiary healthcare facility in rwanda.  

PubMed

Antimicrobial resistance (AMR) is a serious public health threat in both developed and developing countries. Many developing countries, including Rwanda, lack adequate surveillance systems, and therefore, the prevalence of AMR is not well-known. We conducted a prospective observational study to assess the prevalence of AMR among common bacterial isolates from clinical specimens obtained from patients on the medical wards of Kigali University Teaching Hospital (KUTH). We evaluated the antibiotic sensitivity patterns of bacterial pathogens cultured from urine, blood, sputum, and wound swab specimens obtained over a 6-month period (July 1 to December 30, 2013). There were 154 positive cultures from specimens obtained from 141 unique patients over the study period. Urine, blood, wound swab, and sputum cultures comprised 55.2%, 25.3%, 16.2%, and 3.3% of the total specimens evaluated; 31.4% and 58.7% of Escherichia coli and Klebsiella isolates, respectively, were resistant to at least one of the third generation cephalosporins. Eight percent of E. coli isolates were resistant to imipenem; 82% and 6% of Staphylococcus aureus strains were oxacillin- and vancomycin-resistant respectively. Antimicrobial resistance rates are high in Rwanda and pose a serious therapeutic challenge to the management of common infections. PMID:25646259

Ntirenganya, Cyprien; Manzi, Olivier; Muvunyi, Claude Mambo; Ogbuagu, Onyema

2015-04-01

400

Impact of treatment heterogeneity on drug resistance and supply chain costs?  

PubMed Central

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.

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

2013-01-01

401

Multi-drug-resistant Staphylococcus aureus and future chemotherapy.  

PubMed

Staphylococcus (S.) aureus silently stays as our natural flora, and yet sometimes threatens our life as a tenacious pathogen. In addition to its ability to outwit our immune system, its multi-drug resistance phenotype makes it one of the most intractable pathogenic bacteria in the history of antibiotic chemotherapy. It conquered practically all the antibiotics that have been developed since 1940s. In 1961, the first MRSA was found among S. aureus clinical isolates. Then MRSA prevailed throughout the world as a multi-resistant hospital pathogen. In 1997, MRSA strain Mu50 with reduced susceptibility to vancomycin was isolated. Vancomycin-intermediate S. aureus (VISA), so named according to the CLSI criteria, was the product of adaptive mutation of S. aureus against vancomycin that had long been the last resort to MRSA infection. Here, we describe the genetic basis for the remarkable ability of S. aureus to acquire multi-antibiotic resistance, and propose a novel paradigm for future chemotherapy against the multi-resistant pathogens. PMID:25172776

Hiramatsu, K; Katayama, Y; Matsuo, M; Sasaki, T; Morimoto, Y; Sekiguchi, A; Baba, T

2014-10-01

402

Microfilament depletion and circumvention of multiple drug resistance by sphinxolides.  

PubMed

Sphinxolides, a newly described family of cytotoxins from the New Caledonian sponge Neosiphonia superstes, bear structural resemblance to scytophycins. We now demonstrate that the cytotoxicity of sphinxolides is associated with cell cycle arrest in G2-M and induction of apoptosis. Like scytophycins and cytochalasins, sphinxolides caused rapid loss of microfilaments in cultured cells, without affecting microtubule organization. Microfilament reassembly was very slow after removal of the sphinxolide, consistent with the slow recovery of cellular proliferation. Sphinxolides potently inhibited actin polymerization in vitro and the microfilament-dependent ATPase activity of purified actomyosin, indicating a direct effect on actin. Importantly, sphinxolides were equally cytotoxic toward MCF-7 human breast carcinoma cells and a subline which overexpresses P-glycoprotein (MCF-7/ADR). Similarly, overexpression of the multidrug resistance-associated protein MRP by HL-60 cells did not confer resistance to the sphinxolides. These studies demonstrate that sphinxolides are potent new antimicrofilament compounds that circumvent multidrug resistance mediated by overexpression of either P-glycoprotein or MRP. Therefore, these agents may be useful in the treatment of drug-resistant tumors. PMID:9288783

Zhang, X; Minale, L; Zampella, A; Smith, C D

1997-09-01

403

The Landscape of Host Transcriptional Response Programs Commonly Perturbed by Bacterial Pathogens: Towards Host-Oriented Broad-Spectrum Drug Targets  

PubMed Central

Background The emergence of drug-resistant pathogen strains and new infectious agents pose major challenges to public health. A promising approach to combat these problems is to target the host’s genes or proteins, especially to discover targets that are effective against multiple pathogens, i.e., host-oriented broad-spectrum (HOBS) drug targets. An important first step in the discovery of such drug targets is the identification of host responses that are commonly perturbed by multiple pathogens. Results In this paper, we present a methodology to identify common host responses elicited by multiple pathogens. First, we identified host responses perturbed by each pathogen using a gene set enrichment analysis of publicly available genome-wide transcriptional datasets. Then, we used biclustering to identify groups of host pathways and biological processes that were perturbed only by a subset of the analyzed pathogens. Finally, we tested the enrichment of each bicluster in human genes that are known drug targets, on the basis of which we elicited putative HOBS targets for specific groups of bacterial pathogens. We identified 84 up-regulated and three down-regulated statistically significant biclusters. Each bicluster contained a group of pathogens that commonly dysregulated a group of biological processes. We validated our approach by checking whether these biclusters correspond to known hallmarks of bacterial infection. Indeed, these biclusters contained biological process such as inflammation, activation of dendritic cells, pro- and anti- apoptotic responses and other innate immune responses. Next, we identified biclusters containing pathogens that infected the same tissue. After a literature-based analysis of the drug targets contained in these biclusters, we suggested new uses of the drugs Anakinra, Etanercept, and Infliximab for gastrointestinal pathogens Yersinia enterocolitica, Helicobacter pylori kx2 strain, and enterohemorrhagic Escherichia coli and the drug Simvastatin for hematopoietic pathogen Ehrlichia chaffeensis. Conclusions Using a combination of automated analysis of host-response gene expression data and manual study of the literature, we have been able to suggest host-oriented treatments for specific bacterial infections. The analyses and suggestions made in this study may be utilized to generate concrete hypothesis on which gene sets to probe further in the quest for HOBS drug targets for bacterial infections. All our results are available at the following supplementary website: http://bioinformatics.cs.vt.edu/ murali/supplements/2013-kidane-plos-one PMID:23516507

Kidane, Yared H.; Lawrence, Christopher; Murali, T. M.

2013-01-01

404

Resistance to common bacterial blight in Phaseolus vulgaris L. recombinant inbred lines under natural infection of Xanthomonas axonopodis pv. phaseoli  

Microsoft Academic Search

Among the main causes of poor yield in common beans are fungal, viral and bacterial diseases. Common bacterial blight, caused\\u000a by Xanthomonas axonopodis pv. phaseoli (Xap), is one of the major bacterial diseases leading to significant losses in Brazil. Chemical control is ineffective, therefore,\\u000a the use of resistant varieties becomes an interesting alternative. The objective of the present work was

Claudia Fortes Ferreira; Messias Gonzaga Pereira; Amaury da Silva dos Santos; Rosana Rodrigues; Ricardo Enrique Bressan-Smith; Alexandre PioViana; R. Figueiredo Daher

2003-01-01

405

BMP7 Expression Correlates with Secondary Drug Resistance in Mantle Cell Lymphoma  

E-print Network

of cell line. Incubation of BMP7 with MCL cell lines increased their resistance to bortezomibBMP7 Expression Correlates with Secondary Drug Resistance in Mantle Cell Lymphoma Valérie Camara to identify genes involved in secondary drug resistance in mantle cell lymphomas (MCL). Experimental Design

Boyer, Edmond

406

Combating Drug-Resistant Bacteria: Small Molecule Mimics of Plasmid Incompatibility as Antiplasmid Compounds  

E-print Network

Combating Drug-Resistant Bacteria: Small Molecule Mimics of Plasmid Incompatibility as Antiplasmid, 2004; E-mail: hergenro@uiuc.edu Multidrug resistant bacteria are now ubiquitous in both hospital to vancomycin.2 Due to this prevalence of drug-resistant bacteria, there is a pressing need for novel classes

Hergenrother, Paul J.

407

The Role of Compensatory Mutations in the Emergence of Drug Resistance  

E-print Network

mutations affect population-wide resistance emergence as a function of drug treatment. Using a model, such as malaria [16], HIV [17,18], HSV [19,20], multidrug-resistant tuber- culosis [21,22], and influenza [23, the resistant pathogen strain is less fit than the sensitive strain. Drug treatment reduces the fitness

Handel, Andreas

408

Novel aspects of resistance to drugs targeted to dihydrofolate reductase and thymidylate synthase  

Microsoft Academic Search

Drug resistance is often a limiting factor in successful chemotherapy. Our laboratory has been interested in studying mechanisms of resistance to drugs that are targeted to the thymidylate biosynthesis pathway especially those that target thymidylate synthase (TS) and dihydrofolate reductase (DHFR). We have used leukemia as a model system to study resistance to methotrexate (MTX) and colorectal cancer as the

Debabrata Banerjee; Philipp Mayer-Kuckuk; Gina Capiaux; Tulin Budak-Alpdogan; Richard Gorlick; Joseph R Bertino

2002-01-01

409

Environmental monitoring of bacterial contamination and antibiotic resistance patterns of the fecal coliforms isolated from Cauvery River, a major drinking water source in Karnataka, India.  

PubMed

The present study focuses prudent elucidation of microbial pollution and antibiotic sensitivity profiling of the fecal coliforms isolated from River Cauvery, a major drinking water source in Karnataka, India. Water samples were collected from ten hotspots during the year 2011-2012. The physiochemical characteristics and microbial count of water samples collected from most of the hotspots exhibited greater biological oxygen demand and bacterial count especially coliforms in comparison with control samples (p???0.01). The antibiotic sensitivity testing was performed using 48 antibiotics against the bacterial isolates by disk-diffusion assay. The current study showed that out of 848 bacterial isolates, 93.51 % (n?=?793) of the isolates were found to be multidrug-resistant to most of the current generation antibiotics. Among the major isolates, 96.46 % (n?=?273) of the isolates were found to be multidrug-resistant to 30 antibiotics and they were identified to be Escherichia coli by 16S rDNA gene sequencing. Similarly, 93.85 % (n?=?107), 94.49 % (n?=?103), and 90.22 % (n?=?157) of the isolates exhibited multiple drug resistance to 32, 40, and 37 antibiotics, and they were identified to be Enterobacter cloacae, Pseudomonas trivialis, and Shigella sonnei, respectively. The molecular studies suggested the prevalence of bla TEM genes in all the four isolates and dhfr gene in Escherichia coli and Sh. sonnei. Analogously, most of the other Gram-negative bacteria were found to be multidrug-resistant and the Gram-positive bacteria, Staphylococcus spp. isolated from the water samples were found to be methicillin and vancomycin-resistant Staphylococcus aureus. This is probably the first study elucidating the bacterial pollution and antibiotic sensitivity profiling of fecal coliforms isolated from River Cauvery, Karnataka, India. PMID:25896199

Skariyachan, Sinosh; Mahajanakatti, Arpitha Badarinath; Grandhi, Nisha Jayaprakash; Prasanna, Akshatha; Sen, Ballari; Sharma, Narasimha; Vasist, Kiran S; Narayanappa, Rajeswari

2015-05-01

410

Multidrug-resistant and extensively drug-resistant tuberculosis: a review of current concepts and future challenges.  

PubMed

Multidrug-resistant and extensively drug-resistant tuberculosis are recent global health issues, which makes tuberculosis - after the success of short course treatment during the second half of the last century - a major health challenge. Globalisation, health inequalities, competing economic interests and political instability contribute substantially to the spread of drug-resistant strains, which are associated with high rates of morbidity and mortality. Issues such as increasing transmission of drug-resistant strains, poor diagnostic coverage and a lengthy, toxic treatment need to be overcome by innovative approaches to tuberculosis control, prevention, diagnostics and treatment. This review addresses recent developments and future concepts. PMID:24889573

Günther, Gunar