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1

Bacterial drug resistance in meat animals: a review.  

PubMed

Prolonged oral or parenteral administration of antibiotics has led to the development of resistant strains of microorganisms. Bacteria acquire drug resistance by mutation, conjugation and transduction. Oral antibiotics by a process of selection pressure facilitate the proliferation of resistant population of bacteria. Drug resistant bacteria are capable of transferring their resistance to drugs to other bacteria by the process of transferable drug resistance (TDR). This can lead to multiple resistance to a vast number of therapeutically useful antibiotics which will, therefore, become ineffective for treatment. TDR can occur between pathogenic organism, between organism of different species, such as E. coli, Salmonella and Shigella; and also between pathogenic and non-pathogenic organisms. Faecal contamination of meat during slaughter may result in the transfer of antibiotic resistant E. coli to the meat. In the human gut this E. coli could transfer resistance to other gut flora, namely E. coli or Salmonella. Antibiotic-resistant coliforms have been isolated from carcases, fresh and cooked meat, raw meat handlers and livestock handlers. Handling of raw market meat by buyers in Nigeria could also lead to contamination of meat with resistant microorganisms. Veterinary drugs are sold and used without much control in Nigeria. This practice may have created a population of resistant bacteria in the meat animals. The presence of antibiotic residues in meat, milk and their products pose potential health hazards for man. Allergic skin conditions, nausea, vomiting, anaphylactic shock and even death have resulted from the ingestion of residues. Cooking and freezing have minimal effect on residues. Resistance to antibiotics have been detected in food poisoning bacteria, namely Salmonella typhimurium, Staphylococcus aureus and Clostridium perfringens. Some epidemiological link has been established between S. typhimurium of calves and food poisoning in man. Judicious use of antibiotics, public education on the health risks of the promiscuous use of drugs in livestock production; and hygienic slaughter at the slaughter houses, will help to reduce bacterial drug resistance in man and animals. PMID:3549599

Okolo, M I

1986-09-01

2

An approach to identifying drug resistance associated mutations in bacterial strains  

PubMed Central

Background Drug resistance in bacterial pathogens is an increasing problem, which stimulates research. However, our understanding of drug resistance mechanisms remains incomplete. Fortunately, the fast-growing number of fully sequenced bacterial strains now enables us to develop new methods to identify mutations associated with drug resistance. Results We present a new comparative approach to identify genes and mutations that are likely to be associated with drug resistance mechanisms. In order to test the approach, we collected genotype and phenotype data of 100 fully sequenced strains of S. aureus and 10 commonly used drugs. Then, applying the method, we re-discovered the most common genetic determinants of drug resistance and identified some novel putative associations. Conclusions Firstly, the collected data may help other researchers to develop and verify similar techniques. Secondly, the proposed method is successful in identifying drug resistance determinants. Thirdly, the in-silico identified genetic mutations, which are putatively involved in drug resistance mechanisms, may increase our understanding of the drug resistance mechanisms. PMID:23281931

2012-01-01

3

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

4

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 ...

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

2014-11-01

6

[Pneumonia in calves: characterization of the bacterial spectrum and the resistance patterns to antimicrobial drugs].  

PubMed

The population under study included young calves with pneumonia (group A, n = 13) and their controls (group B, n = 9), as well as older calves from which the lungs with (group C, n = 90) or without (group D, n = 10) lesions were collected after slaughter. Arcanobacterium pyogenes was the organism most commonly isolated from calves in group A (46%), followed by Haemophilus somnus (23%), Mannheimia haemolytica (15%), Streptococcus suis and Pasteurella multocida (7.7% each). Only S. suis (22%) and P. multocida (11%) were found in group B. P. multocida was isolated from 32% group C calves, H. somnus from 11%, A. pyogenes from 7.8%, M. haemolytica from 2.2% and S. suis from 1.1%. No specific pathogens were isolated in group D. Prevalence of Mycoplasma bovis infection was 69% in group A and 37% in group C. Ninety-eight strains were tested for resistAnce to antibiotics. Resistance to penicillin and ampicillin was present only in M. haemolytica (46%). High percentages of resistant strains were observed for streptomycin (48-100%), tetracycline (15-43%), sulfonamides alone (14-100%) or in combination with trimethoprim (0-100%). Therapeutic approaches to bacterial calf pneumonia in the area under study should be modified according to the isolated bacterial population, the observed antimicrobial resistances and the growing importance of Mycoplasma bovis. PMID:11476040

Vogel, G; Nicolet, J; Martig, J; Tschudi, P; Meylan, M

2001-07-01

7

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

8

Quantitative Drug Structure Complex Geometry Relationships in -Lactam Efflux by Bacterial Multidrug Resistance Pump AcrAB-TolC  

E-print Network

Quantitative Drug Structure ­ Complex Geometry Relationships in -Lactam Efflux by BacterialAB-TolC pump in E. coli. Two main drug efflux mechanism are shown, one starting in the periplasm, and other of 1-20. Most drugs expose positive, amphiphilic or hydrophobic heads (R or R1) toward predominantly

Ferreira, Márcia M. C.

9

Rationalization and prediction of drug resistant mutations in targets for clinical anti-tubercular drugs  

Microsoft Academic Search

Resistance to therapy limits the effectiveness of drug treatment in many diseases. Drug resistance can be considered as a successful outcome of the bacterial struggle to survive in the hostile environment of a drug-exposed cell. An important mechanism by which bacteria acquire drug resistance is through mutations in the drug target. Drug resistant strains (multi-drug resistant and extensively drug resistant)

Jyothi Padiadpu; Sumanta Mukherjee; Nagasuma Chandra

2012-01-01

10

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 Aj; Spigarelli, Michael G; Sherwin, Catherine Mt

2014-11-01

11

Drug resistance in leprosy.  

PubMed

Leprosy is caused by Mycobacterium leprae. Currently, leprosy control is mainly based on WHO-recommended multi-drug treatment; thus, emergence of drug resistance is a major concern. M. leprae isolates resistant to single and multiple drugs have been encountered. In this review, the history of chemotherapy and drug resistance in leprosy and molecular biological insights for drug resistance are described. New methodologies to test susceptibility to anti-leprosy drugs instead of the traditional mouse footpad method are introduced. Awareness of the need to monitor drug resistance to prevent the spread of resistant cases is emphasized. PMID:20093754

Matsuoka, Masanori

2010-01-01

12

Evolution and impact of bacterial drug resistance in the context of cystic fibrosis disease and nosocomial settings.  

PubMed

The use of antibiotics is unavoidable in trying to treat acute infections and in the prevention and control of chronic infections. Over the years, an ever increasing number of infections has escalated the use of antibiotics, which has necessitated action against an emerging bacterial resistance. There seems to be a continuous acquisition of new resistance mechanisms among bacteria that switch niches between human, animals, and the environment. An antibiotic resistant strain emerges when it acquires the DNA that confers the added capacity needed to survive in an unusual niche. Once acquired, a new resistance mechanism evolves according to the dynamics of the microenvironment; there is then a high probability that it is transferred to other species or to an avirulent strain of the same species. A well understood model for studying emerging antibiotic resistance and its impact is Pseudomonas aeruginosa, an opportunistic pathogen which is able to cause acute and chronic infections in nosocomial settings. This bacterium has a huge genetic repertoire consisting of genes that encode both innate and acquired antibiotic resistance traits. Besides acute infections, chronic colonization of P. aeruginosa in the lungs of cystic fibrosis (CF) patients plays a significant role in morbidity and mortality. Antibiotics used in the treatment of such infections has increased the longevity of patients over the last several decades. However, emerging multidrug resistant strains and the eventual increase in the dosage of antibiotic(s) is of major concern. Though there are various infections that are treated by single/combined antibiotics, the particular case of P. aeruginosa infection in CF patients serves as a reference for understanding the impact of overuse of antibiotics and emerging antibiotic resistant strains. This mini review presents the need for judicious use of antibiotics to treat various types of infections, protecting patients and the environment, as well as achieving a better treatment outcome. PMID:24826072

Sriramulu, Dinesh

2013-01-01

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

Who possesses drug resistance genes in the aquatic environment?: sulfamethoxazole (SMX) resistance genes among the bacterial community in water environment of Metro-Manila, Philippines  

PubMed Central

Recent evidence has shown that antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) are ubiquitous in natural environments, including sites considered pristine. To understand the origin of ARGs and their dynamics, we must first define their actual presence in the natural bacterial assemblage. Here we found varying distribution profiles of sul genes in colony forming bacterial assemblages and natural bacterial assemblages. Our monitoring for antibiotic contamination revealed that sulfamethoxazole (SMX) is a major contaminant in aquatic environments of Metro-Manila, which would have been derived from human and animal use, and subsequently decreased through the process of outflow from source to the sea. The SMX-resistant bacterial rate evaluated by the colony forming unit showed 10 to 86% of the total colony numbers showed higher rates from freshwater sites compared to marine sites. When sul genes were quantified by qPCR, colony-forming bacteria conveyed sul1 and sul2 genes in freshwater and seawater (10?510?2 copy/16S) but not sul3. Among the natural bacterial assemblage, all sul1, sul2, and sul3 were detected (10?510?3 copy/16S), whereas all sul genes were at an almost non-detectable level in the freshwater assemblage. This study suggests that sul1 and sul2 are main sul genes in culturable bacteria, whereas sul3 is conveyed by non-culturable bacteria in the sea. As a result marine bacteria possess sul1, sul2 and sul3 genes in the marine environment. PMID:23641240

Suzuki, Satoru; Ogo, Mitsuko; Miller, Todd W.; Shimizu, Akiko; Takada, Hideshige; Siringan, Maria Auxilia T.

2013-01-01

15

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

16

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

17

Drug Abuse Resistance  

NSDL National Science Digital Library

STUDENTS NEED TO BE AWARE OF THE DANGERS OF DRUGS! The following includes helpful ways to learn about drug abuse resistance. Please finish the smoking quiz for class discussion on Friday! If parents would like a helpful resource on how to teach their children to say no to drugs and alcohol. See NIDA for Teens : The Science Behind Drug Abuse Click on the following link ...

Koyle, Mrs.

2005-03-22

18

Drug Resistance in Leishmaniasis  

PubMed Central

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

Chakravarty, Jaya; Sundar, Shyam

2010-01-01

19

Antibiotic resistance of bacterial biofilms.  

PubMed

A biofilm is a structured consortium of bacteria embedded in a self-produced polymer matrix consisting of polysaccharide, protein and DNA. Bacterial biofilms cause chronic infections because they show increased tolerance to antibiotics and disinfectant chemicals as well as resisting phagocytosis and other components of the body's defence system. The persistence of, for example, staphylococcal infections related to foreign bodies is due to biofilm formation. Likewise, chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is caused by biofilm-growing mucoid strains. Characteristically, gradients of nutrients and oxygen exist from the top to the bottom of biofilms and these gradients are associated with decreased bacterial metabolic activity and increased doubling times of the bacterial cells; it is these more or less dormant cells that are responsible for some of the tolerance to antibiotics. Biofilm growth is associated with an increased level of mutations as well as with quorum-sensing-regulated mechanisms. Conventional resistance mechanisms such as chromosomal beta-lactamase, upregulated efflux pumps and mutations in antibiotic target molecules in bacteria also contribute to the survival of biofilms. Biofilms can be prevented by early aggressive antibiotic prophylaxis or therapy and they can be treated by chronic suppressive therapy. A promising strategy may be the use of enzymes that can dissolve the biofilm matrix (e.g. DNase and alginate lyase) as well as quorum-sensing inhibitors that increase biofilm susceptibility to antibiotics. PMID:20149602

Hiby, Niels; Bjarnsholt, Thomas; Givskov, Michael; Molin, Sren; Ciofu, Oana

2010-04-01

20

Drug Resistance in Leishmaniasis  

PubMed Central

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

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

2006-01-01

21

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

Microsoft Academic Search

INTRODUCTION: The objective of the present study was to analyse secular trends in antibiotic consumption and resistance data from a network of 53 intensive care units (ICUs). METHODS: The study involved prospective unit and laboratory-based surveillance in 53 German ICUs from 2001 through 2008. Data were calculated on the basis of proportions of nonduplicate resistant isolates, resistance densities (that is,

Elisabeth Meyer; Frank Schwab; Barbara Schroeren-Boersch; Petra Gastmeier

2010-01-01

22

Antimicrobial (Drug) Resistance  

MedlinePLUS

... Resistance Antibiotic-Resistant Mycobacterium tuberculosis (TB) Methicillin-Resistant Staphylococcus aureus (MRSA) Vancomycin-Resistant Enterococci (VRE) Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) Gram- ...

23

Coevolution and HBV drug resistance.  

PubMed

A high rate of mutation sets a strong foundation for the development of resistance to antiviral drugs. However, the ubiquitous presence of drug resistance mutations in the HBV population does not explain variations in the rate and specific types of drug resistance among patients. These variations can be explained by consideration of coevolution among individual sites in the HBV genome, viral variants and subpopulations, as well as coevolution between the entire intrahost HBV population and the host. The concept of coevolution offers a more complete framework for understanding drug resistance. PMID:20516572

Khudyakov, Yury

2010-01-01

24

Tumor Physiology and Drug Resistance  

Microsoft Academic Search

Clinical resistance is usually assumed to be due to the initial presence or selection of drug-resistant cells in tumors. While important, it is suggested in this review that genetically-determined causes of cellular resistance represent but one cause (and possibly not the major cause) of effective clinical resistance of solid tumors. Factors that depend on tumor physiology, and on the microenvironment

Ian F. Tannock

2001-01-01

25

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.

Fair, Richard J; Tor, Yitzhak

2014-01-01

26

Membrane active vancomycin analogues: a strategy to combat bacterial resistance.  

PubMed

The alarming growth of antibiotic resistant superbugs such as vancomycin-resistant Enterococci and Staphylococci has become a major global health hazard. To address this issue, we report the development of lipophilic cationic vancomycin analogues possessing excellent antibacterial activity against several drug-resistant strains. Compared to vancomycin, efficacy greater than 1000-fold was demonstrated against vancomycin-resistant Enterococci (VRE). Significantly, unlike vancomycin, these compounds were shown to be bactericidal at low concentrations and did not induce bacterial resistance. An optimized compound in the series, compared to vancomycin, showed higher activity in methicillin-resistant Staphylococcus aureus (MRSA) infected mouse model and exhibited superior antibacterial activity in whole blood with no observed toxicity. The remarkable activity of these compounds is attributed to the incorporation of a new membrane disruption mechanism into vancomycin and opens up a great opportunity for the development of novel antibiotics. PMID:24846441

Yarlagadda, Venkateswarlu; Akkapeddi, Padma; Manjunath, Goutham B; Haldar, Jayanta

2014-06-12

27

Bacterial resistance to silver in wound care.  

PubMed

Ionic silver exhibits antimicrobial activity against a broad range of micro-organisms. As a consequence, silver is included in many commercially available healthcare products. The use of silver is increasing rapidly in the field of wound care, and a wide variety of silver-containing dressings are now commonplace (e.g. Hydrofiber dressing, polyurethane foams and gauzes). However, concerns associated with the overuse of silver and the consequent emergence of bacterial resistance are being raised. The current understanding of the biochemical and molecular basis behind silver resistance has been documented since 1998. Despite the sporadic evidence of bacterial resistance to silver, there have been very few studies undertaken and documented to ascertain its prevalence. The risks of antibacterial resistance developing from the use of biocides may well have been overstated. It is proposed that hygiene should be emphasized and targeted towards those applications that have demonstrable benefits in wound care. It is the purpose of this review to assess the likelihood of widespread resistance to silver and the potential for silver to induce cross-resistance to antibiotics, in light of its increasing usage within the healthcare setting. PMID:15823649

Percival, S L; Bowler, P G; Russell, D

2005-05-01

28

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

29

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

30

Drug resistance in Chromobacterium violaceum.  

PubMed

Chromobacterium violaceum is a free-living bacterium commonly found in aquatic habitats of tropical and subtropical regions of the world. This bacterium is able to produce a large variety of products of biotechnological and pharmacological use. Although C. violaceum is considered to be non-pathogenic, some cases of severe infections in humans and other animals have been reported. Genomic data on the type strain ATCC 12472(T) has provided a comprehensive basis for detailed studies of pathogenicity, virulence and drug resistance genes. A large number of open reading frames associated with various mechanisms of drug resistance were found, comprising a remarkable feature of this organism. Amongst these, beta-lactam (penicillin and cephalosporin) and multidrug resistance genes (drug efflux pumps) were the most numerous. In addition, genes associated with bacitracin, bicyclomycin, chloramphenicol, kasugamycin, and methylenomycin were also found. It is postulated that these genes contribute to the ability of C. violaceum to compete with other bacteria in the environment, and also may help to explain the common drug resistance phenotypes observed in infections caused by this bacterium. PMID:15100994

Fantinatti-Garboggini, Fabiana; Almeida, Rosana de; Portillo, Vincius do Amaral; Barbosa, Trcio A P; Trevilato, Peterson Beltramini; Neto, Ccero Eduardo Ramalho; Colho, Rosngela Duarte; Silva, Denise Wanderlei; Bartoleti, Luciana Aparecida; Hanna, Ebert Seixas; Brocchi, Marcelo; Manfio, Gilson P

2004-01-01

31

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

32

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

33

Increasing Drug Resistance in Extensively Drug-Resistant Tuberculosis, South Africa  

PubMed Central

We expanded second-line tuberculosis (TB) drug susceptibility testing for extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa. Of 19 patients with extensively drug-resistant TB identified during February 2008April 2009, 13 (68%) had isolates resistant to all 8 drugs tested. This resistance leaves no effective treatment with available drugs in South Africa. PMID:21392446

Richardson, Jessica; Moodley, Prashini; Moodley, Salona; Babaria, Palav; Ramtahal, Melissa; Heysell, Scott K.; Li, Xuan; Moll, Anthony P.; Friedland, Gerald; Sturm, A. Willem; Gandhi, Neel R.

2011-01-01

34

Drug-Resistant Tuberculosis Transmission and Resistance Amplification within Families  

PubMed Central

Drug-resistant tuberculosis is caused by transmission of resistant strains of Mycobacterium tuberculosis and by acquisition of resistance through inadequate treatment. We investigated the clinical and molecular features of the disease in 2 families after drug-resistant tuberculosis was identified in 2 children. The findings demonstrate the potential for resistance to be transmitted and amplified within families. PMID:22840848

Warren, Rob M.; Enarson, Donald A.; Beyers, Nulda; Schaaf, H. Simon

2012-01-01

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

Drug Resistance in Visceral Leishmaniasis  

PubMed Central

Visceral leishmaniasis remains a public health problem worldwide. This illness was included by the World Health Organization in the list of neglected tropical diseases targeted for elimination by 2015. The widespread emergence of resistance to pentavalent antimonials in India where half cases occur globally and the unavailability of a vaccine in clinical use constitute major obstacles in achieving this goal. The last decade new antileishmanials became available, including the oral agent miltefosine. However, in poor endemic countries their wide use was curtailed because of the high costs, and also due to concerns of toxicity and emergence of resistance. Various mechanisms of antileishmanial resistance were identified recently in field isolates. Their elucidation will boost the design of new drugs and the molecular surveillance of resistance. Combination regimens should be evaluated in large trials. Overall, the development of antileishmanials has been generally slow; new drugs are needed. In order to control visceral leishmaniasis worldwide, treatment advances should become affordable in the poorest countries, where they are needed most. PMID:19888437

Maltezou, Helena C.

2010-01-01

37

Effect of Mutation and Genetic Background on Drug Resistance in Mycobacterium tuberculosis  

PubMed Central

Bacterial factors may contribute to the global emergence and spread of drug-resistant tuberculosis (TB). Only a few studies have reported on the interactions between different bacterial factors. We studied drug-resistant Mycobacterium tuberculosis isolates from a nationwide study conducted from 2000 to 2008 in Switzerland. We determined quantitative drug resistance levels of first-line drugs by using Bactec MGIT-960 and drug resistance genotypes by sequencing the hot-spot regions of the relevant genes. We determined recent transmission by molecular methods and collected clinical data. Overall, we analyzed 158 isolates that were resistant to isoniazid, rifampin, or ethambutol, 48 (30.4%) of which were multidrug resistant. Among 154 isoniazid-resistant strains, katG mutations were associated with high-level and inhA promoter mutations with low-level drug resistance. Only katG(S315T) (65.6% of all isoniazid-resistant strains) and inhA promoter ?15C/T (22.7%) were found in molecular clusters. M. tuberculosis lineage 2 (includes Beijing genotype) was associated with any drug resistance (adjusted odds ratio [OR], 3.0; 95% confidence interval [CI], 1.7 to 5.6; P < 0.0001). Lineage 1 was associated with inhA promoter ?15C/T mutations (OR, 6.4; 95% CI, 2.0 to 20.7; P = 0.002). We found that the genetic strain background influences the level of isoniazid resistance conveyed by particular mutations (interaction tests of drug resistance mutations across all lineages; P < 0.0001). In conclusion, M. tuberculosis drug resistance mutations were associated with various levels of drug resistance and transmission, and M. tuberculosis lineages were associated with particular drug resistance-conferring mutations and phenotypic drug resistance. Our study also supports a role for epistatic interactions between different drug resistance mutations and strain genetic backgrounds in M. tuberculosis drug resistance. PMID:22470121

Egger, Matthias; Bodmer, Thomas; Altpeter, Ekkehardt; Zwahlen, Marcel; Jaton, Katia; Pfyffer, Gaby E.; Borrell, Sonia; Dubuis, Olivier; Bruderer, Thomas; Siegrist, Hans H.; Furrer, Hansjakob; Calmy, Alexandra; Fehr, Jan; Stalder, Jesica Mazza; Ninet, Beatrice; Bottger, Erik C.; Gagneux, Sebastien

2012-01-01

38

Inhibitors of Bacterial Efflux Pumps as Adjuvants in Antibiotic Treatments and Diagnostic Tools for Detection of Resistance by Efflux  

Microsoft Academic Search

Active efflux is a widespread mechanism for bacterial resistance to antibiotics, which contributes to poor intrinsic susceptibility, cross-resistance to structurally diverse classes of drugs, or selection of other mechanisms of resistance. Thus, inhibition of efflux pumps appears to be (i) a promising strategy for restoring the activity of existing antibiotics, and (ii) a useful method to detect the presence of

Francoise Van Bambeke; Jean-Marie Pages; Ving J. Lee

2006-01-01

39

Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance  

Microsoft Academic Search

BACKGROUND: Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated

Stacey L Hembruff; Monique L Laberge; David J Villeneuve; Baoqing Guo; Zachary Veitch; Melanie Cecchetto; Amadeo M Parissenti

2008-01-01

40

Drug Abuse Resistance Education. Administrative Orientation. Revised.  

ERIC Educational Resources Information Center

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

North Carolina State Dept. of Justice, Raleigh.

41

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

42

Multiple Drug Resistance Mechanisms in Cancer  

Microsoft Academic Search

Multiple drug resistance (multidrug resistance; MDR), a phenomenon whereby human tumours that acquire resistance to one type\\u000a of therapy are found to be resistant to several other drugs that are often quite different in both structure and mode of action,\\u000a has been recognised clinically for several decades. An important advance in our understanding of MDR came with the identification\\u000a of

Bruce C. Baguley

2010-01-01

43

Drug resistance in leishmaniasis: Newer developments.  

PubMed

Leishmaniasis is a vector borne protozoan disease and it remains a major public health problem world-wide. Lack of an effective vaccine and vector control program makes the chemotherapy as the primary tool for leishmaniasis. Antimonials were used as the first line of treatment for many years. Emergence of resistance against this drug has become a major concern. Literatures and studies published on anti-leishmanial drug resistance, newer drug discovery for leishmanial resistance etc., in PubMed, Medline and Google search and reviewed thoroughly. Various newer drugs have been identified but, are in limited use because of high cost, toxicity, resistance etc., Recently, many newer mechanisms of drug resistance have been identified which may boost in future designing and development of drugs. PMID:24754020

Mohapatra, Sarita

2014-01-01

44

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

45

Selection and evolution of resistance to antimicrobial drugs.  

PubMed

The overuse and misuse of antibiotics over many years has selected a high frequency of resistance among medically important bacterial pathogens. The evolution of resistance is complex, frequently involving multiple genetic alterations that minimize biological fitness costs and/or increase the resistance level. Resistance is selected at very low drug concentrations, such as found widely distributed in the environment, and this selects for resistant mutants with a high fitness. Once resistance with high fitness is established in a community it is very difficult to reduce its frequency. Addressing the problem of resistance is essential if we are to ensure a future where we can continue to enjoy effective medical control of bacterial infections. This will require several actions including the discovery and development of novel antibiotics, the creation of a continuous pipeline of drug discovery, and the implementation of effective global antibiotic stewardship to reduce the misuse of antibiotics and their release into the environment. 2014 IUBMB Life, 66(8):521-529, 2014. PMID:24933583

Hughes, Diarmaid

2014-08-01

46

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

PubMed Central

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

2014-01-01

47

Computational Analysis of HIV Drug Resistance Data  

E-print Network

and the use of combination therapy, successful treatment of HIV-infections is hampered by the emergence of drug-resistant genetic variants in response to therapy. Finding a new potent drug combination af- ter treatment failure is considered challenging, because most accumulated mutations confer resistance

48

Bacterial cheating limits the evolution of antibiotic resistance  

Microsoft Academic Search

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

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

2011-01-01

49

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 is an increasing threat to society, especially in hospital settings. Many antibiotics that were formerly effective environments and to provide understanding of mea- sures to avoid the endemicity of resistant antibiotic strains

Ruan, Shigui

50

Bacterial resistance mechanisms for heavy metals of environmental concern  

Microsoft Academic Search

Summary Bacterial species have genetically-determined systems for resistances to toxic heavy metals. Those for metals of environmental concern including mercury cadmium, arsenic and others are briefly summarized, considering the genes of the systems and the biochemical mechanisms by which the resistance proteins function.

Guangyong Ji; Simon Silver

1995-01-01

51

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

52

MicroRNA and drug resistance  

Microsoft Academic Search

Chemotherapy is the preferred treatment for malignancies. However, a successful long-term use of chemotherapy is often prevented by the development of drug resistance. Many mechanisms such as gene mutation, DNA methylation and histone modification have important roles in the resistance of cancer cells to chemotherapeutic agents. Climent suggested miR-125b was involved in the development of drug resistance by microRNA (miRNA)

J Ma; C Dong; C Ji

2010-01-01

53

Assessment of Bacterial Antibiotic Resistance Transfer in the Gut  

PubMed Central

We assessed horizontal gene transfer between bacteria in the gastrointestinal (GI) tract. During the last decades, the emergence of antibiotic resistant strains and treatment failures of bacterial infections have increased the public awareness of antibiotic usage. The use of broad spectrum antibiotics creates a selective pressure on the bacterial flora, thus increasing the emergence of multiresistant bacteria, which results in a vicious circle of treatments and emergence of new antibiotic resistant bacteria. The human gastrointestinal tract is a massive reservoir of bacteria with a potential for both receiving and transferring antibiotic resistance genes. The increased use of fermented food products and probiotics, as food supplements and health promoting products containing massive amounts of bacteria acting as either donors and/or recipients of antibiotic resistance genes in the human GI tract, also contributes to the emergence of antibiotic resistant strains. This paper deals with the assessment of antibiotic resistance gene transfer occurring in the gut. PMID:21318188

Schj?rring, Susanne; Krogfelt, Karen A.

2011-01-01

54

Plasmids and evolutionary rescue by drug resistance.  

PubMed

Antibiotic resistance provides evolutionary rescue for bacterial populations under the threat of extinction through antibiotics. It can arise de novo through mutation in the population, or be obtained from other bacterial populations via the transfer of a resistance-conferring plasmid. We use stochastic modeling methods to establish whether the most likely source of rescue is via a plasmid or via the chromosome, and show that contrary to what is assumed plasmids are not necessarily beneficial locations for resistance genes. Competition at the plasmid level of selection is of great importance-the spread of a resistant plasmid in the population can be slowed or entirely stopped by a nonresistant version of the same plasmid. We suggest that future studies on antibiotic-resistant plasmids should explicitly consider competition at this level of selection. PMID:24749717

Tazzyman, Samuel J; Bonhoeffer, Sebastian

2014-07-01

55

Innate and Induced Resistance Mechanisms of Bacterial Biofilms  

Microsoft Academic Search

Bacterial biofilms are highly recalcitrant to antibiotic treatment, which holds serious consequences for therapy of infections\\u000a that involve biofilms. The genetic mechanisms of this biofilm antibiotic resistance appear to fall into two general classes:\\u000a innate resistance factors and induced resistance factors. Innate mechanisms are activated as part of the biofilm developmental\\u000a pathway, the factors being integral parts of biofilm structure

G. G. Anderson; G. A. O'Toole

56

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

57

Bacterial resistance to antimicrobials in urinary isolates  

Microsoft Academic Search

Escherichia coli accounted for about 80% of organisms in uncomplicated urinary tract infections (UTIs), followed by Staphylococcus spp. especially Staphylococcus saprophyticus, and Proteus mirabilis. Against E. coli isolates from patients with uncomplicated UTI, faropenem was the most effective. Up to 1999, fluoroquinolone-resistant isolates were not observed in patients with uncomplicated UTI, but in 2001 fluoroquinolone-resistant E. coli isolates emerged and

Tetsuro Muratani; Tetsuro Matsumoto

2004-01-01

58

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

59

Infectious Multiple Drug Resistance in the Enterobacteriaceae.  

National Technical Information Service (NTIS)

Tobramycin-resistant burn wound isolates from five different bacterial genera contained a common 68 x 10 to the 6th power dalton R plasmid that could be transmitted by conjugation to Escherichia coli K-12. It was possible by a variety of newly developed m...

S. Falkow

1977-01-01

60

Emergence of drug resistance in India.  

PubMed

Chloroquine resistance in Plasmodium malaria is an emerging problem globally. In India resistance of Plasmodium falciparum to choloroquine, the cheapest and the most used drug was first reported in the year 1973 from Diphu of Karbi-Anglong district in Assam state. Systematic monitoring of drug resistance is being undertaken in the country from 1978 by the Directorate of National Vector Borne Disease Control Programme (NVBDCP) through its 13 Pf monitoring teams. The findings of these drug resistance studies has helped the programme for the revision of the drug policy and update it from time to time thereby facilitating appropriate measures for not only individual cases but also to contain and prevent further spread of resistant foci. This article summarises therapeutic efficacy studies conducted by the Pf monitoring teams in the country between 2001 and 2007 related to efficacy of chloroquine and other antimalarials drugs. As per the results available, the efficacy of chloroquine for treating uncomplicated falciparum at most of the study sites is much lower than the desired cut off levels of 10% (83% studies have shown treatment failure more than 10%). Total of 4273, 168 and 137 P. falciparum cases have been tested against chloroquine, sulphadoxine/pyrimethamine and ACT(AS+SP) combination. During the period under report, 85 new chloroquine resistant PHCs/foci from 64 districts were qualified warranting change of drug policy as per the national guidelines. These studies show that chloroquine resistance in P. falciparum is widespread in the country. To combat the drug resistant in malaria, the use of combination therapy ie, artesunate plus sulfadoxine/pyrimethamine has been recommended for treatment of all confirmed P. falciparum cases in all the qualified areas as per the criteria laid down in National Drug Policy on malaria. PMID:19552104

Arora, Usha; Sonal, G S; Dhillon, G P S; Thakor, Hitendrasinh G

2008-10-01

61

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

PubMed Central

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

Labby, Kristin J; Garneau-Tsodikova, Sylvie

2013-01-01

62

Drug Resistance Mutations in HIV1  

Microsoft Academic Search

pressure), resistant strains may be pre- sent at levels below the limit of detec- tion of the test; analyzing stored sam- ples (collected under selection pressure) could be useful in this setting; and (3) recognizing that virologic failure of the first regimen typically involves HIV-1 isolates with resistance to only 1 or 2 of the drugs in the regimen; in

Victoria A. Johnson; Franoise Brun-Vzinet; Bonaventura Clotet; Brian Conway; Richard T. D'Aquila; Lisa M. Demeter; Daniel R. Kuritzkes; Deenan Pillay; Jonathan M. Schapiro; Amalio Telenti; Douglas D. Richman

63

Legal issues associated with antimicrobial drug resistance.  

PubMed Central

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

Fidler, D. P.

1998-01-01

64

Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance  

Microsoft Academic Search

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

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

2011-01-01

65

Bacterial resistance to oxytetracycline in Chilean salmon farming  

Microsoft Academic Search

The use of oxytetracycline for preventing and controlling bacterial pathogens in salmon farming is frequent in Chile, yet no studies have been performed to evaluate the ecological impact of its intensive and prolonged use. In this work, the frequency of oxytetracycline-resistant bacteria from water, pelletized feed and fingerlings from four Chilean freshwater Atlantic salmon farms, as well as the level

Claudio D. Miranda; Raul Zemelman

2002-01-01

66

Resistance to echinocandin-class antifungal drugs.  

PubMed

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking beta-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical failure and elevated MIC values for the echinocandin drugs. Fungi display several adaptive physiological mechanisms that result in elevated MIC values. However, resistance to echinocandin drugs among clinical isolates is associated with amino acid substitutions in two "hot-spot" regions of Fks1, the major subunit of glucan synthase. The mutations, yielding highly elevated MIC values, are genetically dominant and confer cross-resistance to all echinocandin drugs. Prominent Fks1 mutations decrease the sensitivity of glucan synthase for drug by 1000-fold or more, and strains harboring such mutations may require a concomitant increase in drug to reduce fungal organ burdens in animal infection models. The Fks1-mediated resistance mechanism is conserved in a wide variety of Candida spp. and can account for intrinsic reduced susceptibility of certain species. Fks1 mutations confer resistance in both yeasts and moulds suggesting that this mechanism is pervasive in the fungal kingdom. PMID:17569573

Perlin, David S

2007-06-01

67

Drug-resistant tuberculosis: emerging treatment options  

PubMed Central

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

Adhvaryu, Meghna; Vakharia, Bhasker

2011-01-01

68

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

EPA Science Inventory

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

69

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

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

2014-01-01

70

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

71

[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

Bektre, Bayhan; Haznedaro?lu, Tuner; Baylan, Orhan; Ozyurt, Mustafa; Ozktk, Nuri; Satana, Dilek; Cavu?o?lu, Cengiz; Seber, Engin

2013-01-01

72

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

73

Geographical variation in cloacal microflora and bacterial antibiotic resistance in a threatened  

E-print Network

Geographical variation in cloacal microflora and bacterial antibiotic resistance in a threatened to antibiotics in nest- lings and full-grown Egyptian vultures Neophron per- cnopterus were assessed in four of stabled livestock carrion and bacterial resistance to multiple antibiotics was found. Bacterial resistance

Donázar, José A.

74

HIV resistance to anti-viral drugs.  

PubMed

The use of zidovudine (ZDV) and other forms of nucleoside therapy, including dideoxyinosine (ddI), to treat HIV-infected individuals has led to both longer survival and improved quality of life. However, ZDV-resistant variants of HIV-1 can be isolated from patients undergoing prolonged therapy with this drug. HIV drug resistance against ZDV, ddI and other nucleosides is attributable to a series of point mutations within the pol gene of HIV-1 that encodes the viral enzyme, reverse transcriptase (RT). This is not surprising, since the virus is known to replicate at high rates in infected individuals; moreover the RT which mediates transcription of proviral DNA from viral genomic RNA is known to be highly error-prone. Thus, mutants of HIV-1, which possess a drug resistance phenotype and genotype, may be expected to emerge under the selective pressure of long-term anti-viral chemotherapy. HIV drug resistance occurs most commonly in individuals with low CD4 counts, who have progressed to more serious forms of disease. Moreover, viruses obtained from patients with AIDS generally display higher levels of resistance, relative to pre-treatment isolates, than do viruses from patients with more limited illness. Although observations of drug resistance can be correlated with disease progression and a weakened immune system, it is still unclear whether a cause and effect relationship exists. Current clinical research is designed to answer this question while testing the notion that combinations of nucleosides and immuno-stimulatory drugs may provide important clinical benefits. PMID:7504966

Wainberg, M A; Salomon, H; Spira, B; Mercure, L; Wainberg, J; Nagai, K; Bentwich, Z; Montaner, J

1993-03-01

75

Drug-resistant Neisseria gonorrhoeae in Michigan  

PubMed Central

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

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

2005-01-01

76

Drug Resistance Assays for Mycobacterium tuberculosis  

Microsoft Academic Search

The introduction of antimicrobial therapy of tuberculosis during the second half of the last century was a turning point in\\u000a the millennium-old history of this disease. However, the problem of drug resistance emerged, and with it, two levels of concern.\\u000a First, such resistance not only poses a public health threat to successful control of TB epidemics, but it also complicates

Leonid Heifets; Gerard Cangelosi

77

Drug resistance confounding prion therapeutics  

PubMed Central

There is not a single pharmaceutical that halts or even slows any neurodegenerative disease. Mounting evidence shows that prions cause many neurodegenerative diseases, and arguably, scrapie and CreutzfeldtJakob disease prions represent the best therapeutic targets. We report here that the previously identified 2-aminothiazoles IND24 and IND81 doubled the survival times of scrapie-infected, wild-type mice. However, mice infected with Rocky Mountain Laboratory (RML) prions, a scrapie-derived strain, and treated with IND24 eventually exhibited neurological dysfunction and died. We serially passaged their brain homogenates in mice and cultured cells. We found that the prion strain isolated from IND24-treated mice, designated RML[IND24], emerged during a single passage in treated mice. Although RML prions infect both the N2a and CAD5 cell lines, RML[IND24] prions could only infect CAD5 cells. When passaged in CAD5 cells, the prions remained resistant to high concentrations of IND24. However, one passage of RML[IND24] prions in untreated mice restored susceptibility to IND24 in CAD5 cells. Although IND24 treatment extended the lives of mice propagating different prion strains, including RML, another scrapie-derived prion strain ME7, and chronic wasting disease, it was ineffective in slowing propagation of CreutzfeldtJakob disease prions in transgenic mice. Our studies demonstrate that prion strains can acquire resistance upon exposure to IND24 that is lost upon passage in mice in the absence of IND24. These data suggest that monotherapy can select for resistance, thus intermittent therapy with mixtures of antiprion compounds may be required to slow or stop neurodegeneration. PMID:24128760

Berry, David B.; Lu, Duo; Geva, Michal; Watts, Joel C.; Bhardwaj, Sumita; Oehler, Abby; Renslo, Adam R.; DeArmond, Stephen J.; Prusiner, Stanley B.; Giles, Kurt

2013-01-01

78

[Bacterial infections and resistance to antibiotics in cystic fibrosis].  

PubMed

Knowledge of the microbiology of pulmonary infections is critical for treatment of cystic fibrosis because sickness and mortality in this disease are mainly due to relapse occurring in the respiratory tract. The microbiology of pulmonary infections presents several singular aspects. Respiratory tract infections are caused by bacteria such as Staphylococcus aureus in the early years of life and Pseudomonas aeruginosa and Burkholderia cepacia thereafter. The patients, who are not immune compromised, are predisposed to chronic colonization and highly transmissible bacterial strains can cause cross-infections. Bacterial also develop resistance mechanisms which make them difficult to treat. Until recently the relationship between genetic defects and a predisposition to colonization was not noted, but recent studies have allowed us to form some interesting hypothesis. The present work analyzes the principal mechanisms of antibiotic resistance, with particular reference to classic cystic fibrosis pathogens, and looks at future prospects of respiratory tract infection treatment. PMID:10963010

Taccetti, G; Repetto, T; Procopio, E; Marianelli, L; Campana, S

1999-01-01

79

Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides  

Microsoft Academic Search

Cationic antimicrobial peptides (CAMPs) are integral compounds of the antimicrobial arsenals in virtually all kinds of organisms,\\u000a with important roles in microbial ecology and higher organisms host defense. Many bacteria have developed countermeasures\\u000a to limit the efficacy of CAMPs such as defensins, cathelicidins, kinocidins, or bacteriocins. The best-studied bacterial CAMP\\u000a resistance mechanisms involve electrostatic repulsion of CAMPs by modification of

D. Kraus; A. Peschel

80

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.

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

2014-01-01

81

[Bacterial enteric pathogens' resistance to fluoroquinolones and last generation cephalosporines].  

PubMed

The increase of incidence of resistance to the antibiotics became the most worrisome subject within the clinical and research communities in the medical fields. Intrinsic resistance genetic mutations, horizontal transfer of mobile structures carrying genes coding for resistance to the antibiotics within the pan-microbial genome are representing the bacterial resistome which is bearing the genetic information regarding the defensive mechanisms developed by micro-organisms to protect themselves against antibiotics. Rice in the resistance of enteric bacteria, pathogens involved in a large number of human infections, to the cephalosporin of last generation and to the fluoroquinolones is a very actual subject in the medical area. Production of beta-lactamases with extended spectrum is the most important enzymatic defence system, developed by micro-organisms, consisting in the inactivation of beta-lactam antibiotics by destroying the beta-lactam ring. Enterobacteria are able to produce beta-lactamases of type TEM, SHV and/or CTX-M. Punctual mutations in nucleotide structure of bla genes, coding for beta-lactamases synthesis, are leading on production of a large diversity of enzymes with enlarged spectrum of activity (ESBL). At the beginning of 90's the first beta-lactamases resistance to clavulanic acid were detected and in our days more then 170 TEM, 120 SVH and 90 CTX-MESBLs are known. Escherichia coli strains are producing, firstly, TEM ESBLs, Klebsiella pneumoniae SHV ESBLs. and both are producing CTX-M type ESBLs, are resistant to the fluoroquinolones due to punctual mutations in nucleotide structure of gyr gene coding for gyrases production, enzymes involved in nucleic acids replication. Resistance to the antibiotics with extended activity is a public health threat due to their capacity of large spreading within bacterial population, when the coding structures are located on mobile genetic structures. The menace increase when genes coding for fluoroquinolones resistance (qnr) are identified on such of structures. PMID:21553476

Damian, Maria; Usein, Codru?a-Romanita; Palade, Andi Marian; B?ltoiu, M?d?lina; Condei, Maria; Ciontea, Simona; Tatu-Chi?oiu, Dorina

2010-01-01

82

Mechanisms of Candida biofilm drug resistance.  

PubMed

Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, ?-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

2013-10-01

83

Mechanisms of Candida biofilm drug resistance  

PubMed Central

Candida commonly adheres to implanted medical devices, growing as a resilient biofilm capable of withstanding extraordinarily high antifungal concentrations. As currently available antifungals have minimal activity against biofilms, new drugs to treat these recalcitrant infections are urgently needed. Recent investigations have begun to shed light on the mechanisms behind the profound resistance associated with the biofilm mode of growth. This resistance appears to be multifactorial, involving both mechanisms similar to conventional, planktonic antifungal resistance, such as increased efflux pump activity, as well as mechanisms specific to the biofilm lifestyle. A unique biofilm property is the production of an extracellular matrix. Two components of this material, ?-glucan and extracellular DNA, promote biofilm resistance to multiple antifungals. Biofilm formation also engages several stress response pathways that impair the activity of azole drugs. Resistance within a biofilm is often heterogeneous, with the development of a subpopulation of resistant persister cells. In this article we review the molecular mechanisms underlying Candida biofilm antifungal resistance and their relative contributions during various growth phases. PMID:24059922

Taff, Heather T; Mitchell, Kaitlin F; Edward, Jessica A; Andes, David R

2013-01-01

84

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

PubMed Central

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

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

2013-01-01

85

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

86

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 CambodiaThailand 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

87

Understanding the metabolic basis of drug resistance  

PubMed Central

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

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

2011-01-01

88

Genomewide Identification of Genetic Determinants of Antimicrobial Drug Resistance in Pseudomonas aeruginosa  

Microsoft Academic Search

The emergence of antimicrobial drug resistance is of enormous public concern due to the increased risk of delayed treatment of infections, the increased length of hospital stays, the substantial increase in the cost of care, and the high risk of fatal outcomes. A prerequisite for the development of effective therapy alternatives is a detailed understanding of the diversity of bacterial

Andreas Dotsch; Tanja Becker; Claudia Pommerenke; Zofia Magnowska; Lothar Jansch; Susanne Haussler

2009-01-01

89

Managing multiple and extensively drug-resistant tuberculosis and HIV.  

E-print Network

??Global increases in multi-drug-resistant and extensively drug-resistant tuberculosis (TB), are threatening both TB and HIV treatment programs worldwide. Together, they raise concerns of a global (more)

Friedland, Gerald H.

2007-01-01

90

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

91

Functional Gold Nanoparticles as Potent Antimicrobial Agents against Multi-Drug-Resistant Bacteria.  

PubMed

We present the use of functionalized gold nanoparticles (AuNPs) to combat multi-drug-resistant pathogenic bacteria. Tuning of the functional groups on the nanoparticle surface provided gold nanoparticles that were effective against both Gram-negative and Gram-positive uropathogens, including multi-drug-resistant pathogens. These AuNPs exhibited low toxicity to mammalian cells, and bacterial resistance was not observed after 20 generations. A strong structure-activity relationship was observed as a function of AuNP functionality, providing guidance to activity prediction and rational design of effective antimicrobial nanoparticles. PMID:25232643

Li, Xiaoning; Robinson, Sandra M; Gupta, Akash; Saha, Krishnendu; Jiang, Ziwen; Moyano, Daniel F; Sahar, Ali; Riley, Margaret A; Rotello, Vincent M

2014-10-28

92

Drug resistance mechanism of PncA in Mycobacterium tuberculosis.  

PubMed

Tuberculosis continues to be a global health threat. Pyrazinamide (PZA) is an important first-line drug in multidrug-resistant tuberculosis treatment. The emergence of strains resistant to PZA represents an important public health problem, as both first- and second-line treatment regimens include PZA. It becomes toxic to Mycobacterium tuberculosis when converted to pyrazinoic acid by the bacterial pyrazinamidase (PncA) enzyme. Resistance to PZA is caused mainly by the loss of enzyme activity by mutation, the mechanism of resistance is not completely understood. In our studies, we analysed three mutations (D8G, S104R and C138Y) of PncA which are involved in resistance towards PZA. Binding pocket analysis solvent accessibility analysis, molecular docking and interaction analysis were performed to understand the interaction behaviour of mutant enzymes with PZA. Molecular dynamics simulations were conducted to understand the three-dimensional (3D) conformational behaviour of native and mutants PncA. Our analysis clearly indicates that the mutation (D8G, S104R and C138Y) in PncA is responsible for rigid binding cavity which in turn abolishes conversion of PZA to its active form and is the sole reason for PZA resistance. Excessive hydrogen bonding between PZA binding cavity residues and their neighbouring residues are the reason of rigid binding cavity during simulation. We present an exhaustive analysis of the binding site flexibility and its 3D conformations that may serve as new starting points for structure-based drug design and helps the researchers to design new inhibitors with consideration of rigid criterion of binding residues due to mutation of this essential target. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:11. PMID:23383724

Rajendran, Vidya; Sethumadhavan, Rao

2014-01-01

93

Identifying co-targets to fight drug resistance based on a random walk model  

PubMed Central

Background Drug resistance has now posed more severe and emergent threats to human health and infectious disease treatment. However, wet-lab approaches alone to counter drug resistance have so far still achieved limited success due to less knowledge about the underlying mechanisms of drug resistance. Our approach apply a heuristic search algorithm in order to extract active network under drug treatment and use a random walk model to identify potential co-targets for effective antibacterial drugs. Results We use interactome network of Mycobacterium tuberculosis and gene expression data which are treated with two kinds of antibiotic, Isoniazid and Ethionamide as our test data. Our analysis shows that the active drug-treated networks are associated with the trigger of fatty acid metabolism and synthesis and nicotinamide adenine dinucleotide (NADH)-related processes and those results are consistent with the recent experimental findings. Efflux pumps processes appear to be the major mechanisms of resistance but SOS response is significantly up-regulation under Isoniazid treatment. We also successfully identify the potential co-targets with literature confirmed evidences which are related to the glycine-rich membrane, adenosine triphosphate energy and cell wall processes. Conclusions With gene expression and interactome data supported, our study points out possible pathways leading to the emergence of drug resistance under drug treatment. We develop a computational workflow for giving new insights to bacterial drug resistance which can be gained by a systematic and global analysis of the bacterial regulation network. Our study also discovers the potential co-targets with good properties in biological and graph theory aspects to overcome the problem of drug resistance. PMID:22257493

2012-01-01

94

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

PubMed Central

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

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

2011-01-01

95

Adherence and drug resistance: predictions for therapy outcome  

E-print Network

Adherence and drug resistance: predictions for therapy outcome Lindi M. Wahl and Martin A. Nowak to the drug regimen. We consider two types of treatment failure: failure to eliminate the wild-type virus, and the emergence of drug-resistant virus. Speci¢cally, we determine the conditions under which resistance dominates

Nowak, Martin A.

96

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

97

Best drug treatment for multidrug-resistant and extensively drug-resistant tuberculosis.  

PubMed

Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis are generally thought to have high mortality rates. However, many cases can be treated with the right combination and rational use of available antituberculosis drugs. This Review describes the evidence available for each drug and discusses the basis for recommendations for the treatment of patients with MDR and XDR tuberculosis. The recommended regimen is the combination of at least four drugs to which the Mycobacterium tuberculosis isolate is likely to be susceptible. Drugs are chosen with a stepwise selection process through five groups on the basis of efficacy, safety, and cost. Among the first group (the oral first-line drugs) high-dose isoniazid, pyrazinamide, and ethambutol are thought of as an adjunct for the treatment of MDR and XDR tuberculosis. The second group is the fluoroquinolones, of which the first choice is high-dose levofloxacin. The third group are the injectable drugs, which should be used in the following order: capreomycin, kanamycin, then amikacin. The fourth group are called the second-line drugs and should be used in the following order: thioamides, cycloserine, then aminosalicylic acid. The fifth group includes drugs that are not very effective or for which there are sparse clinical data. Drugs in group five should be used in the following order: clofazimine, amoxicillin with clavulanate, linezolid, carbapenems, thioacetazone, then clarithromycin. PMID:20797644

Caminero, Jos A; Sotgiu, Giovanni; Zumla, Alimuddin; Migliori, Giovanni Battista

2010-09-01

98

Antimalarial dosing regimens and drug resistance.  

PubMed

The contribution of underdosing to antimalarial treatment failure has been underappreciated. Most recommended dosage regimens are based on studies in non-pregnant adult patients. Young children and pregnant women, who bear the heaviest malaria burden, have the highest treatment failure rates. This has been attributed previously to lower immunity, although blood concentrations of many antimalarial drugs are significantly lower in pregnant women and young children than in non-pregnant adults. Nevertheless, there have been no studies of higher dosages. Sub-therapeutic concentrations will certainly contribute to poorer responses to treatment and will fuel the emergence and spread of antimalarial drug resistance. There is an urgent need for studies to optimise antimalarial dosage regimens in infants, young children and pregnant women, both to improve cure rates and to prolong the useful therapeutic lives of antimalarial drugs. PMID:18262470

Barnes, Karen I; Watkins, William M; White, Nicholas J

2008-03-01

99

Recent Trends in HIV-1 Drug Resistance  

PubMed Central

Once considered an inevitable consequence of HIV treatment, drug resistance is declining. This decline supports the hypothesis that antiretroviral therapy can arrest replication and prevent the evolution of resistance. Further support comes from excellent clinical outcomes, the failure of treatment intensification to reduce residual viremia, the lack of viral evolution in patients on optimal therapy, pharmacodynamics studies explaining the extraordinarily high antiviral activity of modern regimens, and recent reports of potential cures. Evidence supporting ongoing replication includes higher rates of certain complications in treated patients and an increase in circular forms of the viral genome after intensification with integrase inhibitors. Recent studies also provide an explanation for the observation that some patients fail protease-inhibitor based regimens without evidence for resistance. PMID:24021560

Siliciano, Janet D.; Siliciano, Robert F.

2014-01-01

100

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; Prez-Guzmn, 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

101

Drug resistance in patients with leprosy in the United States.  

PubMed

Molecular drug susceptibility testing was performed on 39 US patients with leprosy. Of these, 2 had dapsone-resistant Mycobacterium leprae and 1 of these patients also had rifampin-resistant M. leprae. Even though antileprosy drug resistance occurs in this leprosy population, resistance does not appear to be a major problem. PMID:24065328

Williams, Diana L; Lewis, Cheryl; Sandoval, Felipe G; Robbins, Naoko; Keas, Stephen; Gillis, Thomas P; Scollard, David M

2014-01-01

102

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

E-print Network

that these germs are making the person sick. Who gets Drug Resistant Bacteria? Anyone can get Drug Resistant, people in the community can get Drug Resistant Bacteria usually those with close contact to people with the germ. Healthy people rarely get these infections (but they may). How does the doctor know that someone

Oliver, Douglas L.

103

Drug resistance in chemotherapy for breast cancer.  

PubMed

Recent developments with chemotherapy for breast cancer have improved patient survival. However, there continue to be nonresponders to conventional anticancer agents. Multidrug resistance (MDR) is caused by the expression of P-glycoprotein (P-gp) on the cell membrane. The expression of P-gp is encoded by MDR1 mRNA in tumors and is associated with clinical drug resistance. Since P-gp appears to be involved in both acquired and congenital MDR in human cancers, P-gp could be an important target for improving the efficacy of chemotherapy. Recently, we have focused on a therapeutic approach to reduce drug resistance in chemotherapy for breast cancer. Dofequidar fumarate (Dof) is a novel, orally active quinoline derivative that reverses multidrug resistance. In preclinical studies, the inhibition of doxorubicin-resistant cancer cell lines was observed in the presence of Dof + doxorubicin. We conducted clinical trials including Dof + cyclophosphamide (C), doxorubicin (A), and fluorouracil therapy (F) for patients with advanced or recurrent breast cancer. We compared the efficacy and tolerability of Dof + CAF with CAF alone. In this randomized, placebo-controlled trial, all patients were treated with six cycles of CAF therapy. Patients received Dof (900 mg p.o.) 30 min before doxorubicin. The primary endpoint was overall response rate (partial or complete response). In total, 221 patients were evaluable. The overall response rate was 42.6% for CAF alone versus 53.1% for Dof + CAF. Although the response rate improved by more than 10% with the combination of Dof + CAF, it was not statistically significant. Initially, we were expecting more than 20% improvement in the overall response rate. However, Dof significantly improved progression-free survival in patients who were premenopausal (P=0.046), who had received no prior therapy (P<0.01), or patients with advanced (stage IV) primary tumors (P=0.017). In addition, treatment with Dof did not affect the plasma concentration of doxorubicin in patients. These clinical studies indicate that Dof was well tolerated and displayed promising efficacy in patients who had not received prior therapy. The antiestrogens, tamoxifen, and toremifene, may moderate P-gp-related drug resistance in vitro. Toremifene demonstrated a synergistic effect in combination with paclitaxel on various human breast cancer cell lines. Furthermore, a synergistic effect was observed on a multidrug-resistant cell line. This synergistic effect was more potent when paclitaxel was combined with toremifene than with tamoxifen. Clinical benefits in some patients with recurrent breast cancer were reported. PMID:16273361

Saeki, Toshiaki; Tsuruo, Takashi; Sato, Wakao; Nishikawsa, Kiyoshiro

2005-11-01

104

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

105

Neurostimulation for Drug-Resistant Epilepsy  

PubMed Central

Purpose of Review: The purpose of this review is to provide an evidence-based update on the neurostimulation options available for patients with drug-resistant epilepsy in the United States and in European countries. Recent Findings: The field of neurostimulation for epilepsy has grown dramatically since 1997, when vagus nerve stimulation became the first device to be approved for epilepsy by the US Food and Drug Administration (FDA). New data from recently completed randomized controlled trials are available for deep brain stimulation of the anterior thalamus, responsive neurostimulation, and trigeminal nerve stimulation. Although vagus nerve stimulation is the only device currently approved in the United States, deep brain stimulation and responsive neurostimulation devices are awaiting FDA approval. Deep brain stimulation, trigeminal nerve stimulation, and transcutaneous vagus nerve stimulation are now approved for epilepsy in the European Union. In this article, the mechanisms of action, safety, and efficacy of new neurostimulation devices are reviewed, and the key advantages and disadvantages of each are discussed. Summary: The exponential growth of the field of neuromodulation for epilepsy is an exciting development; these new devices provide physicians with new options for patients with drug-resistant epilepsy. PMID:23739108

DeGiorgio, Christopher M.; Krahl, Scott E.

2013-01-01

106

Plasmid coding for transferable drug resistance in bacteria isolated from cultured rainbow trout.  

PubMed Central

The occurrence of drug resistance and plasmid-mediated transferability was investigated in 170 strains belonging to eight bacterial groups isolated from cultured rainbow trout. It was found that 87.6% of the strains were resistant to at least one drug, with the highest percentages of resistance being detected for ampicillin (54.7%), sulfadiazine (46.5%), nitrofurantoin (38.2%), and chloramphenicol (37.0%). Six enterobacteria, two Vibrio, and one Aeromonas isolate transferred resistance factors to Escherichia coli K-12. The most common transmissible R factor determined resistance to chloramphenicol and sulfadiazine, demonstrating an association between a specific plasmid and the resistance pattern transferred. The presence of chloramphenicol in fish food was detected by bioassay. In general, transfer frequencies were similar in primary and secondary matings, which indicate the potential water-borne dissemination of these R plasmids. Images PMID:6508296

Toranzo, A E; Combarro, P; Lemos, M L; Barja, J L

1984-01-01

107

Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis  

PubMed Central

In March 2012, in response to reports of tuberculosis (TB) resistant to all anti-TB drugs, the World Health Organization convened an expert consultation that identified issues to be resolved before defining a new category of highly drug-resistant TB. Proposed definitions are ambiguous, and extensive drug resistance is encompassed by the already defined extensively drug-resistant (XDR) TB. There is no evidence that proposed totally resistant TB differs from strains encompassed by XDR TB. Susceptibility tests for several drugs are poorly reproducible. Few laboratories can test all drugs, and there is no consensus list of all anti-TB drugs. Many drugs are used off-label for highly drug resistant TB, and new drugs formulated to combat resistant strains would render the proposed category obsolete. Labeling TB strains as totally drug resistant might lead providers to think infected patients are untreatable. These challenges must be addressed before defining a new category for highly drug-resistant TB. PMID:23092736

Nunn, Paul; Kurbatova, Ekaterina V.; Weyer, Karin; Dalton, Tracy L.; Wares, Douglas F.; Iademarco, Michael F.; Castro, Kenneth G.; Raviglione, Mario

2012-01-01

108

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

Fernandez, Lucia

2012-01-01

109

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

PubMed Central

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

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

2013-01-01

110

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

111

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

112

Emerging Roles of SIRT1 in Cancer Drug Resistance  

PubMed Central

Innate resistance to various therapeutic interventions is a hallmark of cancer. In recent years, acquired resistance has emerged as a daunting challenge to targeted cancer therapy, which abolishes the efficacy of otherwise successful targeting drugs. Cancer cells gain the resistance property through a variety of mechanisms in primary and metastatic cancers, involving cellular intrinsic and extrinsic factors. Increasing evidence suggests that the mammalian stress response gene sirtuin 1 (SIRT1) plays a critical role in multiple aspects of cancer drug resistance. SIRT1 decreases drug penetration, confers proliferation and antiapoptotic survival advantages to cancer cells, facilitates acquired resistance through genetic mutations, promotes the survival of cancer stem cells, and changes the tumor microenvironment for resistance in cell-autonomous and -nonautonomous manners. This article provides an overview of research advances in the roles of SIRT1 in cancer drug resistance and highlights the prospect of targeting SIRT1 as a new strategy to overcome cancer drug resistance and improve therapeutic outcomes. PMID:24019998

Wang, Zhiqiang

2013-01-01

113

Bacterial drug tolerance under clinical conditions is governed by anaerobic adaptation but not anaerobic respiration.  

PubMed

Noninherited antibiotic resistance is a phenomenon whereby a subpopulation of genetically identical bacteria displays phenotypic tolerance to antibiotics. We show here that compared to Escherichia coli, the clinically relevant genus Burkholderia displays much higher levels of cells that tolerate ceftazidime. By measuring the dynamics of the formation of drug-tolerant cells under conditions that mimic in vivo infections, we show that in Burkholderia bacteria, oxygen levels affect the formation of these cells. The drug-tolerant cells are characterized by an anaerobic metabolic signature and can be eliminated by oxygenating the system or adding nitrate. The transcriptome profile suggests that these cells are not dormant persister cells and are likely to be drug tolerant as a consequence of the upregulation of anaerobic nitrate respiration, efflux pumps, ?-lactamases, and stress response proteins. These findings have important implications for the treatment of chronic bacterial infections and the methodologies and conditions that are used to study drug-tolerant and persister cells in vitro. PMID:25049258

Hemsley, Claudia M; Luo, Jamie X; Andreae, Clio A; Butler, Clive S; Soyer, Orkun S; Titball, Richard W

2014-10-01

114

Bacterial Drug Tolerance under Clinical Conditions Is Governed by Anaerobic Adaptation but not Anaerobic Respiration  

PubMed Central

Noninherited antibiotic resistance is a phenomenon whereby a subpopulation of genetically identical bacteria displays phenotypic tolerance to antibiotics. We show here that compared to Escherichia coli, the clinically relevant genus Burkholderia displays much higher levels of cells that tolerate ceftazidime. By measuring the dynamics of the formation of drug-tolerant cells under conditions that mimic in vivo infections, we show that in Burkholderia bacteria, oxygen levels affect the formation of these cells. The drug-tolerant cells are characterized by an anaerobic metabolic signature and can be eliminated by oxygenating the system or adding nitrate. The transcriptome profile suggests that these cells are not dormant persister cells and are likely to be drug tolerant as a consequence of the upregulation of anaerobic nitrate respiration, efflux pumps, ?-lactamases, and stress response proteins. These findings have important implications for the treatment of chronic bacterial infections and the methodologies and conditions that are used to study drug-tolerant and persister cells in vitro. PMID:25049258

Hemsley, Claudia M.; Luo, Jamie X.; Andreae, Clio A.; Butler, Clive S.; Soyer, Orkun S.

2014-01-01

115

Antimicrobial resistance of bacterial enteropathogens isolated from stools in Madagascar  

PubMed Central

Background Diarrheal diseases are a major public health problem in developing countries, and are one of the main causes of hospital admissions in Madagascar. The Pasteur Institute of Madagascar undertook a study to determine the prevalence and the pathogenicity of bacterial, viral and protozoal enteropathogens in diarrheal and non-diarrheal stools of children aged less than 5years in Madagascar. We present here the results of the analysis of antimicrobial susceptibility of the bacteria isolated during this study. Methods The study was conducted in the community setting in 14 districts of Madagascar from October 2008 to May 2009. Conventional methods and PCR were used to identify the bacteria; antimicrobial susceptibility was determined using an agar diffusion method for enterobacteriaceae and MICs were measured by an agar dilution method for Campylobacter sp. In addition to the strains isolated during this study, Salmonella sp and Shigella sp isolated at the Pasteur Institute of Madagascar from 2005 to 2009 were included in the analysis to increase the power of the study. Results Twenty-nine strains of Salmonella sp, 35 strains of Shigella sp, 195 strains of diarrheagenic E. coli, 203 strains of C. jejuni and 71 strains of C. coli isolated in the community setting were tested for antibiotic resistance. Fifty-five strains of Salmonella sp and 129 strains of Shigella sp isolated from patients referred to the Pasteur Institute of Madagascar were also included in the study. Many E. coli and Shigella isolates (around 80%) but fewer Salmonella isolates were resistant to ampicillin and trimethoprim/sulfamethoxazole. A small proportion of strains of each species were resistant to ciprofloxacin and only 3% of E. coli strains presented a resistance to third generation cephalosporins due to the production of extended-spectrum beta-lactamases. The resistance of Campylobacter sp to ampicillin was the most prevalent, whereas less than 5% of isolates were resistant to each of the other antibiotics. Conclusion The highest prevalence of antimicrobial resistance was to ampicillin and trimethoprim/sulfamethoxazole. Antibiotic treatment is not recommended for children with diarrhea in Madagascar and the emphasis should be placed on oral rehydration. PMID:24568189

2014-01-01

116

Rhabdomyolysis Associated with Antimicrobial DrugResistant Mycoplasma pneumoniae  

PubMed Central

We describe a case of rhabdomyolysis in a patient infected with antimicrobial drugresistant Mycoplasma pneumoniae The patients acute-phase serum levels of interleukin-18 and tumor necrosis factor? were high, which suggests a pathogenic role for M. pneumoniae. In an era of increasing antimicrobial drug resistance, a system for rapidly identifying resistant M. pneumoniae would be beneficial. PMID:22515975

Narita, Mitsuo; Ohya, Hitomi; Yamanaka, Takayuki; Aizawa, Yuta; Matsuo, Mai; Matsunaga, Masamichi; Tsukano, Shinya; Taguchi, Testuo

2012-01-01

117

Drug and radiation resistance in spheroids: cell contact and kinetics  

Microsoft Academic Search

Cells from multicellular spheroids are often more resistant than monolayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the drug to penetrate the spheroid, or the presence of hypoxic cells, these mechanisms do not adequately explain resistance to all agents. Small spheroids (containing about 2550 cells) exposed to ionizing

Peggy L. Olive; Ralph E. Durand

1994-01-01

118

Bacterial ghosts (BGs)Advanced antigen and drug delivery system  

Microsoft Academic Search

Bacterial ghosts (BGs) are empty bacterial envelopes of Gram-negative bacteria produced by controlled expression of cloned gene E, forming a lysis tunnel structure within the envelope of the living bacteria. BGs are devoid of cytoplasmic content and possess all bacterial bio-adhesive surface properties in their original state while not posing any infectious threat. BGs are ideally suited as an advanced

Pavol Kudela; Verena Juliana Koller; Werner Lubitz

2010-01-01

119

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

120

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 the world, and the resulting failures of antibiotic ther- apy cause hundreds of thousands of deaths annually

Kishony, Roy

121

Application of hordothionins and cecropin B for engineering bacterial disease resistance into plants  

Microsoft Academic Search

Bacterial diseases can cause a drastic decrease of yield in certain crops. Breeding for bacterial disease resistance therefore is of utmost necessity. Up to now, traditional plant breeding was the only method to reach this goal. Recent developments in genetic engineering technology however provide novel ways for the production of disease resistant plants. This thesis describes the results of two

D. Florack

1994-01-01

122

Bacterial Resistance to Antisense Peptide Phosphorodiamidate Morpholino Oligomers  

PubMed Central

Peptide phosphorodiamidate morpholino oligomers (PPMOs) are synthetic DNA mimics that bind cRNA and inhibit bacterial gene expression. The PPMO (RFF)3RXB-AcpP (where R is arginine, F, phenylalanine, X is 6-aminohexanoic acid, B is ?-alanine, and AcpP is acyl carrier protein) is complementary to 11 bases of the essential gene acpP (which encodes acyl carrier protein). The MIC of (RFF)3RXB-AcpP was 2.5 ?M (14 ?g/ml) in Escherichia coli W3110. The rate of spontaneous resistance of E. coli to (RFF)3RXB-AcpP was 4 10?7 mutations/cell division. A spontaneous (RFF)3RXB-AcpP-resistant mutant (PR200.1) was isolated. The MIC of (RFF)3RXB-AcpP was 40 ?M (224 ?g/ml) for PR200.1. The MICs of standard antibiotics for PR200.1 and W3110 were identical. The sequence of acpP was identical in PR200.1 and W3110. PR200.1 was also resistant to other PPMOs conjugated to (RFF)3RXB or peptides with a similar composition or pattern of cationic and nonpolar residues. Genomic sequencing of PR200.1 identified a mutation in sbmA, which encodes an active transport protein. In separate experiments, a (RFF)3RXB-AcpP-resistant isolate (RR3) was selected from a transposome library, and the insertion was mapped to sbmA. Genetic complementation of PR200.1 or RR3 with sbmA restored susceptibility to (RFF)3RXB-AcpP. Deletion of sbmA caused resistance to (RFF)3RXB-AcpP. We conclude that resistance to (RFF)3RXB-AcpP was linked to the peptide and not the phosphorodiamidate morpholino oligomer, dependent on the composition or repeating pattern of amino acids, and caused by mutations in sbmA. The data further suggest that (RFF)3R-XB PPMOs may be transported across the plasma membrane by SbmA. PMID:22985881

Puckett, Susan E.; Reese, Kaleb A.; Mitev, Georgi M.; Mullen, Valerie; Johnson, Rudd C.; Pomraning, Kyle R.; Mellbye, Brett L.; Tilley, Lucas D.; Iversen, Patrick L.; Freitag, Michael

2012-01-01

123

Drug Resistance of Coliform Bacteria in Hospital and City Sewage  

PubMed Central

The number and properties of drug-resistant coliform bacteria in hospital and city sewage were compared. There was little difference in the counts of organisms with nontransferable resistance to one or more of 13 commonly used drugs. An average of 26% of coliforms in hospital waste water had transferable resistance to at least one of the drugs ampicillin, chloramphenicol, streptomycin, sulfonamide, or tetracycline as compared to an average of 4% in city sewage. R+ bacteria in the hospital discharge were also resistant to a broader spectrum of drugs than those in city sewage. In both effluents, the occurrence of fecal Escherichia coli among R+ coliforms was twice as high as among coliforms with nontransferable resistance. Resistance was transferable to Salmonella typhi, and such drug-resistant pathogens in the water environment could be of particular concern. The significance of the results with regard to environmental pollution with R+ bacteria and the dissemination of these organisms is discussed. PMID:4597713

Grabow, W. O. K.; Prozesky, O. W.

1973-01-01

124

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; Bnard, Antoine; Peytavin, Gilles; Damond, Florence; Roy, Cline; Taieb, Audrey; Chne, Genevive; Matheron, Sophie; Brun-Vzinet, Franoise; Descamps, Diane

2013-06-19

125

Animal Health Advisory Multi-drug Resistant Salmonella in Horses  

E-print Network

Animal Health Advisory Multi-drug Resistant Salmonella in Horses The NYS Veterinary Diagnostic for identification. Since no commercially available vaccine exists against Salmonella, disinfection and other

Keinan, Alon

126

Proteomic insights into Acinetobacter baumannii drug resistance and pathogenesis.  

PubMed

Acinetobacter baumannii is an important opportunist pathogen, due to severe antibiotic resistance and nosocomial infection. The epidemiology and antibiotic resistance of A.baumannii have been extensively reviewed, but the pathogenesis and virulence remain unclear. Proteomics analysis has been applied to study the mechanism of drug resistance, biofilm, micronutrient acquisition, and the extracellular compartment. This review summarizes applications of proteomics in A. baumannii, aiming to summarize novel insights into the mechanism of A. baumannii pathogenesis and drug resistance. PMID:23879539

Long, Quanxin; Huang, Changwu; Liao, Pu; Xie, Jianping

2013-01-01

127

Microbial pollution in wildlife: Linking agricultural manuring and bacterial antibiotic resistance in red-billed choughs.  

PubMed

The spread of pathogens in the environment due to human activities (pathogen pollution) may be involved in the emergence of many diseases in humans, livestock and wildlife. When manure from medicated livestock and urban effluents is spread onto agricultural land, both residues of antibiotics and bacteria carrying antibiotic resistance may be introduced into the environment. The transmission of bacterial resistance from livestock and humans to wildlife remains poorly understood even while wild animals may act as reservoirs of resistance that may be amplified and spread in the environment. We determined bacterial resistance to antibiotics in wildlife using the red-billed chough Pyrrhocorax pyrrhocorax as a potential bioindicator of soil health, and evaluated the role of agricultural manuring with waste of different origins in the acquisition and characteristics of such resistance. Agricultural manure was found to harbor high levels of bacterial resistance to multiple antibiotics. Choughs from areas where manure landspreading is a common agricultural practice harbor a high bacterial resistance to multiple antibiotics, resembling the resistance profile found in the waste (pig slurry and sewage sludge) used in each area. The transfer of bacterial resistance to wildlife should be considered as an important risk for environmental health when agricultural manuring involves fecal material containing multiresistant enteric bacteria including pathogens from livestock operations and urban areas. The assessment of bacterial resistance in wild animals may be valuable for the monitoring of environmental health and for the management of emergent infectious diseases influenced by the impact of different human activities in the environment. PMID:19264302

Blanco, Guillermo; Lemus, Jess A; Grande, Javier

2009-05-01

128

Resistance and susceptibility of mice to bacterial infection: course of listeriosis in resistant or susceptible mice.  

PubMed Central

Resistance and susceptibility to Listeria monocytogenes in mice was found to be related to (i) the innate ability of the nonimmune macrophages to kill or inhibit the growth of the organism during the first 24 to 48 h after infection, and (ii) the time of onset of acquired cell-mediated resistance. Resistant C57Bl/6 mice were 10 times more efficient than susceptible BALB/c mice at suppressing the early growth of Listeria in the liver. Furthermore, the onset of acquired immunity occurred 24 to 48 h earlier in C57Bl/6 than in BALB/c mice. Acquired immunity was measured by (i) fall in bacterial numbers in spleen and livers of infected mice (ii) adoptive transfer of immunity to normal mice by using spleen cells from infected mice, (iii) delayed-type hypersensitivity skin testing, and (iv) uptake of tritiated thymidine by lymphocytes in the spleen. PMID:417029

Cheers, C; McKenzie, I F; Pavlov, H; Waid, C; York, J

1978-01-01

129

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

130

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

NASA Astrophysics Data System (ADS)

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

Greulich, Philip; Waclaw, Bart?omiej; Allen, Rosalind J.

2012-08-01

131

Interplay between mutational pathway and spatial drug distribution controls time to evolution of drug resistance  

E-print Network

Spatial gradients of drug concentration are believed to play an important role in the evolution of drug resistance. We use a stochastic model to show that in a growing population of malignant cells the effect of a spatially non-uniform drug distribution depends critically on the mutational pathway leading to resistance. A non-uniform drug concentration can strongly accelerate the emergence of resistance when the pathway involves a sequence of mutants with increasing resistance, but slows it down if the pathway crosses a fitness valley. Our results suggest that the design of better strategies to combat the emergence of resistance may require detailed knowledge of the mutational pathways involved.

Greulich, Philip; Allen, Rosalind J

2012-01-01

132

Effects of antimutagens on development of drug\\/antibiotic resistance in microorganisms  

Microsoft Academic Search

The effects of polyamines and related compounds on the development of drug\\/antibiotic resistance in a variety of bacterial strains were studied. Methods employed included standard toxicity assays, modified Ames tests for mutation frequencies and antimutagenic effects, prophage induction assays, and recA-lacZ and ada-lacZ induction assays. Using these methods, we have shown that the polyamines produce strong antimutagenic effects against EMS

Segaran P. Pillai; Delbert M. Shankel

1998-01-01

133

Drug resistance in brain diseases and the role of drug efflux transporters  

Microsoft Academic Search

Resistance to drug treatment is an important hurdle in the therapy of many brain disorders, including brain cancer, epilepsy, schizophrenia, depression and infection of the brain with HIV. Consequently, there is a pressing need to develop new and more effective treatment strategies. Mechanisms of resistance that operate in cancer and infectious diseases might also be relevant in drug-resistant brain disorders.

Heidrun Potschka; Wolfgang Lscher

2005-01-01

134

Thermal resistance of naturally occurring airborne bacterial spores.  

PubMed Central

Simulation of a heat process used in the terminal dry-heat decontamination of the Viking spacecraft is reported. Naturally occurring airborne bacterial spores were collected on Teflon ribbons in selected spacecraft assembly areas and subsequently subjected to dry heat. Thermal inactivation experiments were conducted at 105, 111.7, 120, 125, 130, and 135 degrees C with a moisture level of 1.2 mg of water per liter. Heat survivors were recovered at temperatures of 135 degrees C when a 30-h heating cycle was employed. Survivors were recovered from all cycles studied and randomly selected for identification. The naturally occurring spore population was reduced an average of 2.2 to 4.4 log cycles from 105 to 135 degrees C. Heating cycles of 5 and 15 h at temperature were compared with the standard 30-h cycle at 111.7, 120, and 125 degrees C. No significant differences in inactivation (alpha = 0.05) were observed between 111.7 and 120 degrees C. The 30-h cycle differs from the 5-and 15-h cycles at 125 degrees C. Thus, the heating cycle can be reduced if a small fraction (about 10-3 to 10-4) of very resistant spores can be tolerated. PMID:727780

Puleo, J R; Bergstrom, S L; Peeler, J T; Oxborrow, G S

1978-01-01

135

Rapid Development of Drug-Resistant Mutants of Poliovirus  

Microsoft Academic Search

Guanidine hydrochloride is a potent inhibitor of poliovirus synthesis in cell culture. However, the viral progeny which do grow in the presence of guanidine may become approximately 10,000 times more resistant to the drug. The phenomenon of drug resistance poses yet another problem in the search for a satisfactory viral chemotherapeutic agent.

Joseph L. Melnick; Derek Crowther; Julio Barrera-Oro

1961-01-01

136

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.

137

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 of antimalarial chemotherapy and priorities moving forward. The search for new antimalarials For decades, malaria

Symington, Lorraine S.

138

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

PubMed

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

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

2014-11-12

139

Antiviral Drug Resistance Testing in Patients with Chronic Hepatitis B  

Microsoft Academic Search

BackgroundAntiviral drugs against hepatitis B virus are limited by the emergence of drug resistance.\\u000a \\u000a \\u000a \\u000a AimsWe aimed to study the impact of drug resistance testing on treatment decisions.\\u000a \\u000a \\u000a \\u000a MethodsIn part 1 of this study, consecutive patients with chronic hepatitis B who had antiviral drug resistance testing were studied.\\u000a Part 2 was a two-step questionnaire survey including ten characteristic case scenarios. Hepatologists

Vincent Wai-Sun Wong; Grace Lai-Hung Wong; Chi-Hang Tse; Lilly K. W. Yuen; Hoi-Yun Chan; Stephen A. Locarnini; Henry Lik-Yuen Chan

140

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

141

Transcriptional Analyses of Antifungal Drug Resistance in Candida albicans  

Microsoft Academic Search

Oral infections with the pathogenic yeast Candida albicans are one of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug-resistant isolates. Several molecular mechanisms that contribute to drug resistance have been identified, including increased mRNA levels for two types of efflux pump genes:

CHRIS N. LYONS; THEODORE C. WHITE

2000-01-01

142

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

143

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

144

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. Aggressive chemotherapy thus generates opposing evolutionary forces which together determine the rate of drug, Bell AS, Sim DG, Tomasello D, Mideo N, et al. (2013) Aggressive Chemotherapy and the Selection of Drug

Day, Troy

145

Antimalarial Drugs Clear Resistant Parasites from Partially Immune Hosts  

Microsoft Academic Search

Circumstantial evidence in human malaria suggests that elimination of parasites by drug treatment meets higher success rates in individuals having some background immunity. In this study, using the rodent malaria model Plasmodium chabaudi, we show that drug-resistant parasites can be cleared by drugs when the host is partially immune. Malaria due to Plasmodium falciparum is still a major cause of

PEDRO CRAVO; RICHARD CULLETON; PAUL HUNT; DAVID WALLIKER; MARGARET J. MACKINNON

2001-01-01

146

Antimalarial drugs clear resistant parasites from partially immune hosts.  

PubMed

Circumstantial evidence in human malaria suggests that elimination of parasites by drug treatment meets higher success rates in individuals having some background immunity. In this study, using the rodent malaria model Plasmodium chabaudi, we show that drug-resistant parasites can be cleared by drugs when the host is partially immune. PMID:11557487

Cravo, P; Culleton, R; Hunt, P; Walliker, D; Mackinnon, M J

2001-10-01

147

HIV Drug Resistance and the importance of adherence  

NSDL National Science Digital Library

This animation is comprised of five sections and outlines the specifics of drug resistant HIV, drugs that are available to stop HIV, and more information relating to HIV Medication. The animation goes to the level of cell biology and discusses multiple types of drugs used in fighting HIV.

2005-01-01

148

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]: 159204) 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

149

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

150

Drug-Resistant Malaria: The Era of ACT  

PubMed Central

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

Lin, Jessica T.; Juliano, Jonathan J.

2010-01-01

151

Mycobacterium tuberculosis interactome analysis unravels potential pathways to drug resistance  

Microsoft Academic Search

BackgroundEmergence of drug resistant varieties of tuberculosis is posing a major threat to global tuberculosis eradication programmes.\\u000a Although several approaches have been explored to counter resistance, there has been limited success due to a lack of understanding\\u000a of how resistance emerges in bacteria upon drug treatment. A systems level analysis of the proteins involved is essential\\u000a to gain insights into

Karthik Raman; Nagasuma Chandra

2008-01-01

152

Phytol derivatives as drug resistance reversal agents.  

PubMed

Phytol was chemically transformed into fifteen semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with nalidixic acid against E.?coli strains CA8000 and DH5?. The pivaloyl (4), 3,4,5-trimethoxybenzoyl (9), 2,3-dichlorobenzoyl (10), cinnamoyl (11), and aldehyde (14) derivatives of phytol ((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol) were evaluated by using another antibiotic, tetracycline, against the MDREC-KG4 clinical isolate of E.?coli. Derivative 4 decreased the maximal inhibitory concentration (MIC) of the antibiotics by 16-fold, while derivatives 9, 10, 11, and 14 reduced MIC values of the antibiotics up to eightfold against the E.?coli strains. Derivatives 4, 9, 10, 11, and 14 inhibited the ATP-dependent efflux pump; this was also supported by their in silico binding affinity and down-regulation of the efflux pump gene yojI, which encodes the multidrug ATP-binding cassette transporter protein. This study supports the possible use of phytol derivatives in the development of cost-effective antibacterial combinations. PMID:24891085

Upadhyay, Harish C; Dwivedi, Gaurav R; Roy, Sudeep; Sharma, Ashok; Darokar, Mahendra P; Srivastava, Santosh K

2014-08-01

153

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

PubMed Central

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

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

2014-01-01

154

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

155

In vitro antibiotic resistance in bacterial keratitis in London  

Microsoft Academic Search

AIMTo document changes in the profile of bacterial isolates from cases of keratitis and changes in their susceptibility to first line antibiotic therapies.METHODSA 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 KirbyBauer disc diffusion method. The number of isolates, changes in

Stephen J Tuft; Melville Matheson

2000-01-01

156

SUPPLEMENTAL INFORMATION Methicillin-Resistant Staphylococcus aureus Bacterial Nitric Oxide Synthase Affects Antibiotic  

E-print Network

1 SUPPLEMENTAL INFORMATION Methicillin-Resistant Staphylococcus aureus Bacterial Nitric Supplemental Experimental Procedures Page 2 Figures Supplemental Figure S1. Daptomycin killing kinetics Page 4 Supplemental Figure S2. Effect of iron on bacterial growth Page 5 Supplemental Figure S3. SOD activity assay

Nizet, Victor

157

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

158

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

159

Conjunctival bacterial flora and antibiotic resistance pattern in patients undergoing cataract surgery  

Microsoft Academic Search

Purpose: To evaluate the conjunctival bacterial flora and its antibiotic resistance pattern in eyes of patients undergoing cataract surgery. Methods: From August to October 2004, 50 patients undergoing cataract surgery in the \\

Tiago Eugnio Faria e Arantes; Ronald Fonseca Cavalcanti; Maria de Ftima Alves Diniz; Maiara Santos Severo; Joo Lins Neto; Clia Maria Machado Barbosa de Castro

2006-01-01

160

pH and drug resistance. II. turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs  

Microsoft Academic Search

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The primary mechanism leading to a multidrug-resistant phenotype is assumed to be plasma-membrane localized overexpression of drug efflux transporters, such as P-glycoprotein (P-gp). However, acidic intracellular organelles can also participate in resistance to chemotherapeutic drugs. In this study, we investigated, both experimentally and theoretically, the

Natarajan Raghunand; Stephen H Wright; Robert J Gillies

1999-01-01

161

Delamanid: A new armor in combating drug-resistant tuberculosis.  

PubMed

Intense search has been made in the discovery of newer anti-TB drugs to tackle the issues such as drug resistance, HIV co-infection and risk of drug-drug interactions in the management of TB. Delamanid, a newer mycobacterial cell wall synthesis inhibitor, received a conditional approval from European medicines agency (EMA) for the treatment of MDR-TB. Preclinical and clinical studies have shown that delamanid has high potency, least risk for drug-drug interactions and better tolerability. PMID:25210407

Xavier, Alphienes Stanley; Lakshmanan, Mageshwaran

2014-07-01

162

Nanoparticle-based combination therapy toward overcoming drug resistance in cancer  

E-print Network

Review Nanoparticle-based combination therapy toward overcoming drug resistance in cancer Che . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1108 4. Combination strategies against clinical cancer drug resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1110 1. Introduction The long-standing challenge in cancer drug resistance and the urgent need

Zhang, Liangfang

163

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

...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

164

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

165

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

166

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

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

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

Martinez, Jose L.; Baquero, Fernando

2002-01-01

169

Bacterial Magnetosome: A Novel Biogenetic Magnetic Targeted Drug Carrier with Potential Multifunctions  

PubMed Central

Bacterial magnetosomes (BMs) synthesized by magnetotactic bacteria have recently drawn great interest due to their unique features. BMs are used experimentally as carriers for antibodies, enzymes, ligands, nucleic acids, and chemotherapeutic drugs. In addition to the common attractive properties of magnetic carriers, BMs also show superiority as targeting nanoscale drug carriers, which is hardly matched by artificial magnetic particles. We are presenting the potential applications of BMs as drug carriers by introducing the drug-loading methods and strategies and the recent research progress of BMs which has contributed to the application of BMs as drug carriers. PMID:22448162

Sun, Jianbo; Li, Ying; Liang, Xing-Jie; Wang, Paul C.

2012-01-01

170

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

171

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. glabratapositive blood culture at MD Anderson Cancer Center, Houston, Texas, USA, during March 2005September 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

172

Drug-Resistant Candida glabrata Infection in Cancer Patients.  

PubMed

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; Kontoyiannis, Dimitrios P

2014-11-01

173

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

174

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; Lpez, Pilar; Pompo, Marcelo; Armengol, Joan; Barcel, Dami; Balczar, Jose Luis; Rodrguez-Mozaz, Sara; Marc, Rafael

2013-07-01

175

Impact of Bacterial Genetics on the Transmission of Isoniazid-Resistant Mycobacterium tuberculosis  

Microsoft Academic Search

Understanding the ecology of drug-resistant pathogens is essential for devising rational programs to preserve the effective lifespan of antimicrobial agents and to abrogate epidemics of drug-resistant organisms. Mathematical models predict that strain fitness is an important determinant of multidrug-resistant Mycobacterium tuberculosis transmission, but the effects of strain diversity have been largely overlooked. Here we compared the impact of resistance mutations

Sebastien Gagneux; Marcos V. Burgos; Kathryn DeRiemer; Antonio Enciso; Samira Muoz; Phillip C. Hopewell; Peter M. Small; Alexander S. Pym

2006-01-01

176

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

177

pH and drug resistance. II. Turnover of acidic vesicles and resistance to weakly basic chemotherapeutic drugs.  

PubMed

Resistance to chemotherapeutic agents is a major cause of treatment failure in patients with cancer. The primary mechanism leading to a multidrug-resistant phenotype is assumed to be plasma-membrane localized overexpression of drug efflux transporters, such as P-glycoprotein (P-gp). However, acidic intracellular organelles can also participate in resistance to chemotherapeutic drugs. In this study, we investigated, both experimentally and theoretically, the effect of acidic vesicle turnover on drug resistance. We have developed a general model to account for multiple mechanisms of resistance to weakly basic organic cations, e.g. anthracyclines and Vinca alkaloids. The model predicts that lower cytosolic concentrations of drugs can be achieved through a combination of high endosomal turnover rates, a low endosomal pH, and an alkaline-inside pH gradient between cytosol and the extracellular fluid. Measured values for these parameters have been inserted into the model. Computations using conservative values of all parameters indicate that turnover of acidic vesicles can be an important contributor to the drug-resistant phenotype, especially if vesicles contain an active uptake system, such as H+/cation exchange. Even conservative estimates of organic cation-proton antiport activity would be sufficient to make endosomal drug extrusion a potent mechanism of resistance to weakly basic drugs. The effectiveness of such a drug export mechanism would be comparable to drug extrusion via drug pumps such as P-gp. Thus, turnover of acidic vesicles can be an important factor in chemoresistance, especially in cells that do not overexpress plasma membrane-bound drug pumps like P-glycoprotein. PMID:10796075

Raghunand, N; Martnez-Zaguiln, R; Wright, S H; Gillies, R J

1999-05-01

178

Drug Resistance Updates 15 (2012) 9097 Contents lists available at SciVerse ScienceDirect  

E-print Network

Drug Resistance Updates 15 (2012) 90­97 Contents lists available at SciVerse ScienceDirect Drug Resistance Updates journal homepage: www.elsevier.com/locate/drup The dynamics of drug resistance Park, MD, USA a r t i c l e i n f o Keywords: Drug-dependent/independent resistance Drug scheduling

Levy, Doron

179

Drug resistance of Enterococcus faecium clinical isolates and the conjugative transfer of gentamicin and erythromycin resistance traits  

Microsoft Academic Search

Drug resistance and the transferability of resistance were examined in 218 Enterococcus faecium clinical isolates obtained from in-patients of a Japanese university hospital between 1990 and 1999. One hundred and sixty one isolates (73.9%) were drug-resistant and 127 (58.2%) isolates were resistant to two or more drugs. Vancomycin resistant E. faecium (VRE) was not isolated. The transferability of drug-resistance to

Kunio Takeuchi; Haruyoshi Tomita; Shuhei Fujimoto; Michiaki Kudo; Hiroyuki Kuwano; Yasuyoshi Ike

2005-01-01

180

Association of sorcin with drug resistance in L1210 cells.  

PubMed

L1210 sublines independently selected for resistance to teniposide (VM-26), etoposide (VP-16), doxorubicin (DOX), dactinomycin (DACT), or vincristine (VCR) express an anionic, 22-kDa protein that is not observed in extracts of parental L1210 cells. Antibody raised against sorcin, an acidic calcium-binding protein overproduced in many other cells resistant to these agents, cross-reacts with the 22-kDa polypeptide. The levels of the 22-kDa protein (sorcin) increase with the relative levels of drug resistance of the L1210 sublines. The appearance of sorcin in these various sublines further supports the notion that the overproduction of this protein is related to the general phenomenon of multidrug resistance rather than to specific drug resistance and that selection for resistance to teniposide produces L1210 sublines with multidrug resistance. PMID:2909286

Roberts, D; Meyers, M B; Biedler, J L; Wiggins, L G

1989-01-01

181

New resistance mechanisms to azole drugs in Aspergillus fumigatus and emergence of antifungal drugs-resistant A. fumigatus atypical strains  

Microsoft Academic Search

Azole drug resistance in Aspergillus fumigatus is an uncommon but well-known phenomenon. The analysis of resistance mechanisms at molecular level has identified the bases for A. fumigatus azole resistance. To date, the most prevalent mechanism of azole resistance appears to be the modification of Cyp51, specifically mutations in cyp51A gene. These mutations have been associated with three different antifungal susceptibility

E. Mellado; L. Alcazar-Fuoli; G. Garca-Effrn; A. Alastruey-Izquierdo; M. Cuenca-Estrella; J. L. Rodrguez-Tudela

2006-01-01

182

Multidrug-resistant bacterial infections after liver transplantation: An ever-growing challenge  

PubMed Central

Bacterial infections are a leading cause of morbidity and mortality among solid organ transplant recipients. Over the last two decades, various multidrug-resistant (MDR) pathogens have emerged as relevant causes of infection in this population. Although this fact reflects the spread of MDR pathogens in health care facilities worldwide, several factors relating to the care of transplant donor candidates and recipients render these patients particularly prone to the acquisition of MDR bacteria and increase the likelihood of MDR infectious outbreaks in transplant units. The awareness of this high vulnerability of transplant recipients to infection leads to the more frequent use of broad-spectrum empiric antibiotic therapy, which further contributes to the selection of drug resistance. This vicious cycle is difficult to avoid and leads to a scenario of increased complexity and narrowed therapeutic options. Infection by MDR pathogens is more frequently associated with a failure to start appropriate empiric antimicrobial therapy. The lack of appropriate treatment may contribute to the high mortality occurring in transplant recipients with MDR infections. Furthermore, high therapeutic failure rates have been observed in patients infected with extensively-resistant pathogens, such as carbapenem-resistant Enterobacteriaceae, for which optimal treatment remains undefined. In such a context, the careful implementation of preventive strategies is of utmost importance to minimize the negative impact that MDR infections may have on the outcome of liver transplant recipients. This article reviews the current literature regarding the incidence and outcome of MDR infections in liver transplant recipients, and summarizes current preventive and therapeutic recommendations. PMID:24876740

Santoro-Lopes, Guilherme; de Gouvea, Erika Ferraz

2014-01-01

183

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

184

Emergence of Drug-Resistant Influenza Virus: Population Dynamical Considerations  

NSDL National Science Digital Library

Access to the article is free, however registration and sign-in are required: Given the considerable challenges to the rapid development of an effective vaccine against influenza, antiviral agents will play an important role as a first-line defense if a new pandemic occurs. The large-scale use of drugs for chemoprophylaxis and treatment will impose strong selection for the evolution of drug-resistant strains. The ensuing transmission of those strains could substantially limit the effectiveness of the drugs as a first-line defense. Summarizing recent data on the rate at which the treatment of influenza infection generates resistance de novo and on the transmission fitness of resistant virus, we discuss possible implications for the epidemiological spread of drug resistance in the context of an established population dynamic model.

Roland R. Regoes (Institute of Integrative Biology, ETH Z¼rich;); Sebastian Bonhoeffer (Institute of Integrative Biology, ETH Z¼rich;)

2006-04-21

185

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.; Maser, Pascal; Horn, David

2013-01-01

186

Multidrug-resistant and extensively drug-resistant tuberculosis: consequences for the global HIV community  

PubMed Central

Purpose of review Physicians, researchers and policy makers must understand the myriad consequences of multidrug and extensively drug-resistant tuberculosis (TB) within the HIV community in order to guide clinical care, research and resource allocation. Recent findings Extensively drug-resistant TB can no longer be considered as occurring in isolated outbreaks as it has been reported in 45 countries from all regions of the world. HIV has been associated as an independent risk factor for infection with drug-resistant TB. HIV patients appear more likely to suffer from primary, transmitted resistance as opposed to developing acquired resistance during the course of treatment for TB. New rapid diagnostics offer promise of providing clinically useful first-line drug susceptibility information but require validation in HIV patients and smear negative individuals. Demonstration projects of community-based treatment of drug-resistant TB and integration of TB and HIV care provide opportunities to decentralize management of drug-resistant TB. Summary Multidrug-resistant and extensively drug-resistant TB disproportionately affect HIV patients and result in increased morbidity and mortality. In this study, we address these challenging issues and offer some short-term and longer term strategies for their alleviation. PMID:19532076

Shenoi, Sheela; Heysell, Scott; Moll, Anthony; Friedland, Gerald

2009-01-01

187

Electrical Stimulation for Drug-Resistant Epilepsy  

PubMed Central

Objective The objective of this analysis was to evaluate the effectiveness of deep brain stimulation (DBS) and vagus nerve stimulation (VNS) for the treatment of drug-resistant epilepsy in adults and children. Data Sources A literature search was performed using MEDLINE, EMBASE, the Cochrane Library, and the Centre for Reviews and Dissemination database, for studies published from January 2007 until December 2012. Review Methods Systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies (in the absence of RCTs) of adults or children were included. DBS studies were included if they specified that the anterior nucleus of thalamus was the area of the brain stimulated. Outcomes of interest were seizure frequency, health resource utilization, and safety. A cost analysis was also performed. Results The search identified 6 studies that assessed changes in seizure frequency after electrical stimulation: 1 RCT on DBS in adults, 4 RCTs on VNS in adults, and 1 RCT on VNS in children. The studies of DBS and VNS in adults found significantly improved rates of seizure frequency, but the study of VNS in children did not find a significant difference in seizure frequency between the high and low stimulation groups. Significant reductions in hospitalizations and emergency department visits were found for adults and children who received VNS. No studies addressed the use of health resources for patients undergoing DBS. Five studies reported on adverse events, which ranged from serious to transient for both procedures in adults and were mostly transient in the 1 study of VNS in children. Limitations We found no evidence on DBS in children or on health care use related to DBS. The measurement of seizure frequency is self-reported and is therefore subject to bias and issues of compliance. Conclusions Based on evidence of low to moderate quality, both DBS and VNS seemed to reduce seizure frequency in adults. In children, VNS did not appear to be as effective at reducing seizure frequency, but children had significantly fewer hospitalizations and ED visits after VNS implantation. Despite the considerable risks associated with these invasive procedures, long-term adverse events appear to be limited. Plain Language Summary Electrical stimulation of specific areas of the brain is a procedure used to control epileptic seizures when more conventional treatments are not working. Most adults and children with epilepsy are able to control their seizures with medication, but for some patients, drugs are not effective and surgery to remove the part of the brain where the seizures start is not an appropriate option. This study looked at the research available on the effectiveness, safety, and cost of two types of electrical stimulation devices currently licensed for treatment of epilepsy for adults and children in Canada: vagus nerve stimulation (VNS) and deep brain stimulation (DBS). Both approaches appear to be effective at reducing the frequency of seizures in adults. However, the evidence on DBS is limited to a single study with adults; we found no studies of DBS with children. Studies on VNS showed that both adults and children had fewer hospitalizations and emergency department visits after the procedure. Both procedures carry serious risks, but several longer-term studies have found that adverse events appear to be limited. The cost of VNS, including the process of assessing whether or not patients are good candidates for the procedure, is estimated to be about $40,000 per person (and higher for DBS because the device is more expensive and the operating time is longer). Of the 70,000 people in Ontario with epilepsy, about 1,400 (300 children and 1,110 adults) may be candidates for VNS to reduce their seizures. PMID:24228081

Chambers, A; Bowen, JM

2013-01-01

188

Team finds gene that promotes drug resistance in cancer  

Cancer.gov

Scientists from the University of Iowa and Brigham Young University have identified a gene that may be a target for overcoming drug resistance in cancer. The finding could not only improve prognostic and diagnostic tools for evaluating cancer and monitoring patients' response to treatment but also could lead to new therapies directed at eradicating drug-resistant cancer cells. The University of Iowa is home to the Holden Comprehensive Cancer Center.

189

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

190

Human Immunodeficiency Virus: Resistance to Antiretroviral Drugs in Developing Countries  

Microsoft Academic Search

\\u000a This chapter reviews issues central to understanding the emergence and transmission of drug-resistant human immunodeficiency\\u000a virus (HIV) and its impact on developing countries. We first give an overview of HIV, HIV treatment using antiretroviral drugs,\\u000a and access to treatment in developing countries. Then we review current understanding of the impact of adherence and treatment\\u000a interruption on the emergence of resistance

Rebecca F. Baggaley; Maya L. Petersen; Marcelo A. Soares; Marie-Claude Boily; Francisco I. Bastos

191

Extensively drug-resistant tuberculosis: epidemiology and management  

PubMed Central

The advent of antibiotics for the treatment of tuberculosis (TB) represented a major breakthrough in the fight against the disease. However, since its first use, antibiotic therapy has been associated with the emergence of resistance to drugs. The incorrect use of anti-TB drugs, either due to prescription errors, low patient compliance, or poor quality of drugs, led to the widespread emergence of Mycobacterium tuberculosis strains with an expanding spectrum of resistance. The spread of multidrug-resistant (MDR) strains (ie, strains resistant to both isoniazid and rifampicin) has represented a major threat to TB control since the 1990s. In 2006, the first cases of MDR strains with further resistance to fluoroquinolone and injectable drugs were described and named extensively drug-resistant TB (XDR-TB). The emergence of XDR-TB strains is a result of mismanagement of MDR cases, and treatment relies on drugs that are less potent and more toxic than those used to treat drug-susceptible or MDR strains. Furthermore, treatment success is lower and mortality higher than achieved in MDR-TB cases, and the number of drugs necessary in the intensive phase of treatment may be higher than the four drugs recommended for MDR-TB. Linezolid may represent a valuable drug to treat cases of XDR-TB. Delamanid, bedaquiline, and PA-824 are new anti-TB agents in the development pipeline that have the potential to enhance the cure rate of XDR-TB. The best measures to prevent new cases of XDR-TB are the correct management of MDR-TB patients, early detection, and proper treatment of existing patients with XDR-TB. PMID:24729727

Matteelli, Alberto; Roggi, Alberto; Carvalho, Anna CC

2014-01-01

192

Drug resistance and biochemical characteristics of Salmonella from turkeys.  

PubMed Central

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

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

1995-01-01

193

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

PubMed Central

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

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

2012-01-01

194

Old drugs, new purpose: retooling existing drugs for optimized treatment of resistant tuberculosis.  

PubMed

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

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

2012-08-01

195

Tetracycline Resistance Gene Maintenance under Varying Bacterial Growth Rate, Substrate and Oxygen Availability, and Tetracycline  

E-print Network

at lower levels, with ratios of resistance to 16S rDNA genes decreasing by about 2- fold). A higher rateTetracycline Resistance Gene Maintenance under Varying Bacterial Growth Rate, Substrate and Oxygen. J. Alvarez*, GSI Environmental Inc., 2211 Norfolk, Suite 1000, Houston, Texas 77098, United States

Alvarez, Pedro J.

196

Phenotypic Resistance and the Dynamics of Bacterial Escape from Phage Control  

PubMed Central

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

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

2014-01-01

197

Worldwide Emergence of Extensively Drug-resistant Tuberculosis  

PubMed Central

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. tuberculosis isolates that were resistant to second-line anti-TB drugs during 20002004. We defined extensively drug-resistant TB (XDR-TB) as MDR-TB with further resistance to ?3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14 (61%) contributed data on 17,690 isolates, which reflected drug susceptibility results from 48 countries. Of 3,520 (19.9%) MDR-TB isolates, 347 (9.9%) met criteria for XDR-TB. Further investigation of population-based trends and expanded efforts to prevent drug resistance and effectively treat patients with MDR-TB are crucial for protection of public health and control of TB. PMID:17552090

Wright, Abigail; Bai, Gill-Han; Barrera, Lucia; Boulahbal, Fadila; Martin-Casabona, Nuria; Drobniewski, Francis; Gilpin, Chris; Havelkova, Marta; Lepe, Rosario; Lumb, Richard; Metchock, Beverly; Portaels, Francoise; Rodrigues, Maria Filomena; Rusch-Gerdes, Sabine; Van Deun, Armand; Vincent, Veronique; Laserson, Kayla; Wells, Charles; Cegielski, J. Peter

2007-01-01

198

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

199

Evolution of Drug Resistance in Experimental Populations of Candida albicans  

PubMed Central

Adaptation to inhibitory concentrations of the antifungal agent fluconazole was monitored in replicated experimental populations founded from a single, drug-sensitive cell of the yeast Candida albicans and reared over 330 generations. The concentration of fluconazole was maintained at twice the MIC in six populations; no fluconazole was added to another six populations. All six replicate populations grown with fluconazole adapted to the presence of drug as indicated by an increase in MIC; none of the six populations grown without fluconazole showed any change in MIC. In all populations evolved with drug, increased fluconazole resistance was accompanied by increased resistance to ketoconazole and itraconazole; these populations contained ergosterol in their cell membranes and were amphotericin sensitive. The increase in fluconazole MIC in the six populations evolved with drug followed different trajectories, and these populations achieved different levels of resistance, with distinct overexpression patterns of four genes involved in azole resistance: the ATP-binding cassette transporter genes, CDR1 and CDR2; the gene encoding the target enzyme of the azoles in the ergosterol biosynthetic pathway, ERG11; and the major facilitator gene, MDR1. Selective sweeps in these populations were accompanied by additional genomic changes with no known relationship to drug resistance: loss of heterozygosity in two of the five marker genes assayed and alterations in DNA fingerprints and electrophoretic karyotypes. These results show that chance, in the form of mutations that confer an adaptive advantage, is a determinant in the evolution of azole drug resistance in experimental populations of C. albicans. PMID:10692355

Cowen, Leah E.; Sanglard, Dominique; Calabrese, David; Sirjusingh, Caroline; Anderson, James B.; Kohn, Linda M.

2000-01-01

200

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

201

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

PubMed Central

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

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

1971-01-01

202

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

203

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-directed search through mutation sequence space identi es nearby drug resistant mutant strains that might arise it is estimated to infect 3 5 million persons, is the leading cause of death in adults from age 14 to 35

Pazzani, Michael J.

204

Glutathione-associated Enzymes in Anticancer Drug Resistance1  

Microsoft Academic Search

The importance of thiol-mediated detoxification of anticancer drugs that produce toxic electrophiles has been of considerable interest to many investigators. Glutathione and glutathione S-transferases (GST) are the focus of much attention in characterizing drug resistant cells. However, ambiguous and sometimes conflicting data have complicated the field. This article attempts to clarify some of the confusion. The following observations are well

Kenneth D. Tew

1994-01-01

205

Emergence of Increased Resistance and Extensively Drug-Resistant Tuberculosis Despite Treatment Adherence, South Africa  

PubMed Central

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 2003November 2005, a total of 77 had multidrug-resistant (MDR) TB, 26 had preextensively 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.

2010-01-01

206

Drug interactions modulate the potential for evolution of resistance  

E-print Network

) Antimicrobial treatments increasingly rely on multidrug combina- tions, in part because of the emergence and spread of antibiotic resistance. The continued effectiveness of combination treatments depends crucially a window of drug concentrations high enough to inhibit wild-type growth but low enough for some resistant

Kishony, Roy

207

Duke researchers describe how breast cancer cells acquire drug resistance  

Cancer.gov

A seven-year quest to understand how breast cancer cells resist treatment with the targeted therapy lapatinib has revealed a previously unknown molecular network that regulates cell death. The discovery provides new avenues to overcome drug resistance, according to researchers at Duke Cancer Institute.

208

Aneuploidy and Isochromosome Formation in Drug-Resistant Candida albicans  

Microsoft Academic Search

Resistance to the limited number of available antifungal drugs is a serious problem in the treatment of Candida albicans. We found that aneuploidy in general and a specific segmental aneuploidy, consisting of an isochromosome composed of the two left arms of chromosome 5, were associated with azole resistance. The isochromosome forms around a single centromere flanked by an inverted repeat

Anna Selmecki; Anja Forche; Judith Berman

2006-01-01

209

Drug-Resistant Tuberculosis in High-Risk Groups, Zimbabwe  

PubMed Central

To estimate prevalence of multidrug-resistant tuberculosis (MDR TB) in Harare, Zimbabwe, in 2012, we performed microbiologic testing on acid-fast bacilli smear-positive sputum samples from patients previously treated for TB. Twenty (24%) of 84 specimens were consistent with MDR TB. A national drug-resistance survey is needed to determine MDR TB prevalence in Zimbabwe. PMID:24377879

Makumbirofa, Salome; Makamure, Beauty; Sandy, Charles; Bara, Wilbert; Mungofa, Stanley; Hopewell, Philip C.; Mason, Peter

2014-01-01

210

Drug resistant rhinoviruses from the nose of experimentally treated volunteers  

Microsoft Academic Search

Summary Viruses were isolated from nasal washings of volunteers receiving experimental therapy for rhinovirus type 9 infection with intranasal sprays of a new synthetic antiviral R61837. On a screening test nine subjects yielded drug sensitive virus and four resistant virus. In four others the virus was sensitive at first but became resistant later, while in one the reverse occurred. Evidence

C. Dearden; W. Al-Nakib; K. Andries; R. Woestenborghs; D. A. J. Tyrrell

1989-01-01

211

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

212

Molecular characterisation of drug-resistant Plasmodium falciparum from Thailand  

Microsoft Academic Search

BACKGROUND: The increasing levels of Plasmodium falciparum resistance to chloroquine (CQ) in Thailand have led to the use of alternative antimalarials, which are at present also becoming ineffective. In this context, any strategies that help improve the surveillance of drug resistance, become crucial in overcoming the problem. METHODS: In the present study, we have established the in vitro sensitivity to

Dinora Lopes; Kanchana Rungsihirunrat; Ftima Nogueira; Aree Seugorn; Jos Pedro Gil; Virgilio E do Rosrio; Pedro Cravo

2002-01-01

213

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

214

Demonstration of Plasmid-Mediated Drug Resistance in Mycobacterium abscessus  

PubMed Central

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

Matsumoto, Cristianne Kayoko; Bispo, Paulo Jos Martins; Santin, Katiane; Nogueira, Christiane Loureno

2014-01-01

215

Acquisition of Drug Resistance and Dependence by Prions  

PubMed Central

We have reported that properties of prion strains may change when propagated in different environments. For example, when swainsonine-sensitive 22L prions were propagated in PK1 cells in the presence of swainsonine, drug-resistant variants emerged. We proposed that prions constitute quasi- populations comprising a range of variants with different properties, from which the fittest are selected in a particular environment. Prion populations developed heterogeneity even after biological cloning, indicating that during propagation mutation-like processes occur at the conformational level. Because brain-derived 22L prions are naturally swainsonine resistant, it was not too surprising that prions which had become swa sensitive after propagation in cells could revert to drug resistance. Because RML prions, both after propagation in brain or in PK1 cells, are swainsonine sensitive, we investigated whether it was nonetheless possible to select swainsonine-resistant variants by propagation in the presence of the drug. Interestingly, this was not possible with the standard line of PK1 cells, but in certain PK1 sublines not only swainsonine-resistant, but even swainsonine-dependent populations (i.e. that propagated more rapidly in the presence of the drug) could be isolated. Once established, they could be passaged indefinitely in PK1 cells, even in the absence of the drug, without losing swainsonine dependence. The misfolded prion protein (PrPSc) associated with a swainsonine-dependent variant was less rapidly cleared in PK1 cells than that associated with its drug-sensitive counterpart, indicating that likely structural differences of the misfolded PrP underlie the properties of the prions. In summary, propagation of prions in the presence of an inhibitory drug may not only cause the selection of drug-resistant prions but even of stable variants that propagate more efficiently in the presence of the drug. These adaptations are most likely due to conformational changes of the abnormal prion protein. PMID:23408888

Oelschlegel, Anja M.; Weissmann, Charles

2013-01-01

216

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 invivo 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; Frstner, Konrad U; Wermser, Charlotte; Stengel, Stephanie T; Modamio, Jennifer; Ohlsen, Knut; Foster, Kevin R; Lopez, Daniel

2014-08-28

217

Bacterial flora and antimicrobial resistance in raw frozen cultured seafood imported to Denmark.  

PubMed

Intensified aquaculture includes the use of antimicrobials for disease control. In contrast to the situation in livestock, Escherichia coli and enterococci are not part of the normal gastrointestinal flora of fish and shrimp and therefore not suitable indicators of antimicrobial resistance in seafood. In this study, the diversity and phenotypic characteristics of the bacterial flora in raw frozen cultured and wild-caught shrimp and fish were evaluated to identify potential indicators of antimicrobial resistance. The bacterial flora cultured on various agar media at different temperatures yielded total viable counts of 4.0 10(4) to 3.0 10(5) CFU g(-1). Bacterial diversity was indicated by 16S rRNA sequence analysis of 84 isolates representing different colony types; 24 genera and 51 species were identified. Pseudomonas spp. (23% of isolates), Psychrobacter spp. (17%), Serratia spp. (13%), Exiguobacterium spp. (7%), Staphylococcus spp. (6%), and Micrococcus spp. (6%) dominated. Disk susceptibility testing of 39 bacterial isolates to 11 antimicrobials revealed resistance to ampicillin, amoxicillin-clavulanic acid, erythromycin, and third generation cephalosporins. Resistance to third generation cephalosporins was found in Pseudomonas, a genus naturally resistant to most ?-lactam antibiotics, and in Staphylococcus hominis. Half of the isolates were susceptible to all antimicrobials tested. Results indicate that identification of a single bacterial resistance indicator naturally present in seafood at point of harvest is unlikely. The bacterial flora found likely represents a processing rather than a raw fish flora because of repeated exposure of raw material to water during processing. Methods and appropriate indicators, such as quantitative PCR of resistance genes, are needed to determine how antimicrobials used in aquaculture affect resistance of bacteria in retailed products. PMID:23462087

Noor Uddin, Gazi M; Larsen, Marianne Halberg; Guardabassi, Luca; Dalsgaard, Anders

2013-03-01

218

Introduction Treatment resistance in antidepressant drug therapy  

E-print Network

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

219

Resistance to echinocandin-class antifungal drugs  

Microsoft Academic Search

Invasive fungal infections cause morbidity and mortality in severely ill patients, and limited drug classes restrict treatment choices. The echinocandin drugs are the first new class of antifungal compounds that target the fungal cell wall by blocking ?-1,3-d-glucan synthase. Elevated MIC values with occasional treatment failure have been reported for strains of Candida. Yet, an uncertain correlation exists between clinical

David S. Perlin

2007-01-01

220

Indoleamides are active against drug-resistant Mycobacterium tuberculosis.  

PubMed

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 antimycobacterial 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

2013-01-01

221

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

222

Isoniazid Resistance and the Future of Drug-Resistant Tuberculosis  

E-print Network

by mycobacterial catalase-peroxidase to exert its antibacterial activity. Most INH resistance in clinical isolates mycobacterial catalase-peroxidase activity.25 Loss of catalase- Address reprint requests to: Dr. Megan Murray

Cohen, Ted

223

Anti Tuberculosis Drug Resistance in West of Iran  

PubMed Central

Background and Objective: Mycobacterium tuberculosis has developed resistance to antituberculosis drugs and becoming a major and alarming public health problem in worldwide. This study was aimed to determine antituberculosis drug resistance rate and to identify multidrug resistant tuberculosis (MDR-TB) in West of Iran. Materials and Methods: Of 130 samples were included between December 2011 and July 2012 in the study from that 112 cases were M. tuberculosis. The proportional method was carried out according to the Clinical and Laboratory Standards Institute on Lowenstein-Jensen against isoniazid, rifampicin, streptomycin, ethambutol, pyrazinamide, para aminosalicylic acid, ethionamide, cycloserine (CYC). The microdilution method was carried out using 7H9 broth with 96 well-plates. Results: From 112 isolates, resistance was observed to isoniazid 18 (16.07%), rifampicin 16 (14.28%), streptomycin 25 (22.32%), ethambutol 15 (13.39%), pyrazinamide 27 (24.10%), para aminosalicylic acid 19 (16.96%), CYC 4 (3.57%), and ethionamide 14 (12.5%) cases. 16 isolates were MDR. Conclusion: The high prevalence of MDR-TB in our study is assumed to be due to recent transmission of drug-resistant strains. Overall, the rate of drug resistance in our study was high, which is in line with findings of some high-burden countries. Hence that early case detection, rapid drug susceptibility testing, and effective anti-TB treatment is necessary.

Mohajeri, Parviz; Norozi, Baharak; Atashi, Sara; Farahani, Abbas

2014-01-01

224

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

225

Update on the management of Helicobacter pylori infection, including drug-resistant organisms.  

PubMed

Helicobacter pylori infection has many different clinical outcomes. Not all infected persons need to be treated. Therefore, indications for treatment have to be clear, and several consensus guidelines have been formulated to aid the medical practitioner in this decision-making process. Triple therapy with a proton pump inhibitor (PPI), in combination with amoxicillin and clarithromycin is the established treatment of choice. For patients with penicillin hypersensitivity, metronidazole can be substituted for amoxicillin. Bacterial resistance to antibiotics is a major factor adversely affecting treatment success. Resistance to metronidazole has been reported in up to 80%, and resistance to clarithromycin in 2-10% of strains cultured. Resistance to either one of the antibiotics has been reported to result in a drop in efficacy of up to 50%. Emergence of resistance to both metronidazole and clarithromycin following failed therapy is a cause for concern; this underlines the need to use the best available first-line therapy. To avoid the emergence of resistance to both key antibiotics, the combination of metronidazole and clarithromycin should be avoided where possible. For failed treatment, several strategies can be employed. These include ensuring better compliance with repeat therapy, and maximizing the efficacy of repeat treatment by increasing dosage and duration of treatment, as well as altering the choice of drugs. Quadruple therapy incorporating a bismuth compound with a PPI, tetracycline and metronidazole has been a popular choice as a "rescue" therapy. Ranitidine bismuth citrate has been shown to be able to overcome metronidazole and clarithromycin resistance; it may be a useful compound drug to use in place of a PPI in "rescue" therapies. In the case of persistent treatment failures, it is useful to consider repeating gastroscopy and obtaining tissue for culture, and then prescribe antibiotics according to bacterial susceptibility patterns. It is also important in refractory cases to review the original indication for treatment and determine the importance of the indication. PMID:11982731

Goh, K L

2002-04-01

226

Antifungal drug resistance evoked via RNAi-dependent epimutations.  

PubMed

Microorganisms evolve via a range of mechanisms that may include or involve sexual/parasexual reproduction, mutators, aneuploidy, Hsp90 and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show that 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 peptidylprolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild-type phenotype when grown without exposure to the drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNAs and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves the generation of a double-stranded RNA trigger intermediate using the fkbA mature mRNA as a template 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; Nicols, Francisco E; Granek, Joshua A; Mieczkowski, Piotr; Torres-Martnez, Santiago; Ruiz-Vzquez, Rosa M; Cardenas, Maria E; Heitman, Joseph

2014-09-25

227

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

228

Resistance of bacterial biofilms to disinfectants: a review  

Microsoft Academic Search

A biofilm can be defined as a community of microorganisms adhering to a surface and surrounded by a complex matrix of extrapolymeric substances. It is now generally accepted that the biofilm growth mode induces microbial resistance to disinfection that can lead to substantial economic and health concerns. Although the precise origin of such resistance remains unclear, different studies have shown

A. Bridier; R. Briandet; V. Thomas; F. Dubois-Brissonnet

2011-01-01

229

Bacterial gene amplification: implications for the evolution of antibiotic resistance  

Microsoft Academic Search

Recent data suggest that, in response to the presence of antibiotics, gene duplication and amplification (GDA) constitutes an important adaptive mechanism in bacteria. For example, resistance to sulphonamide, trimethoprim and ?-lactams can be conferred by increased gene dosage through GDA of antibiotic hydrolytic enzymes, target enzymes or efflux pumps. Furthermore, most types of antibiotic resistance mechanism are deleterious in the

Linus Sandegren; Dan I. Andersson

2009-01-01

230

Assembly and Channel Opening in a Bacterial Drug Efflux Machine  

PubMed Central

Summary Drugs and certain proteins are transported across the membranes of Gram-negative bacteria by energy-activated pumps. The outer membrane component of these pumps is a channel that opens from a sealed resting state during the transport process. We describe two crystal structures of the Escherichia coli outer membrane protein TolC in its partially open state. Opening is accompanied by the exposure of three shallow intraprotomer grooves in the TolC trimer, where our mutagenesis data identify a contact point with the periplasmic component of a drug effluxpump, AcrA. We suggest that the assemblyof multidrug efflux pumps is accompanied by induced fit of TolC driven mainly by accommodation of the periplasmic component. PMID:18406332

Bavro, Vassiliy N.; Pietras, Zbigniew; Furnham, Nicholas; Perez-Cano, Laura; Fernandez-Recio, Juan; Pei, Xue Yuan; Misra, Rajeev; Luisi, Ben

2008-01-01

231

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

232

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

PubMed

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

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

2013-10-01

233

Nanomechanics of drug-target interactions and antibacterial resistance detection.  

PubMed

The cantilever sensor, which acts as a transducer of reactions between model bacterial cell wall matrix immobilized on its surface and antibiotic drugs in solution, has shown considerable potential in biochemical sensing applications with unprecedented sensitivity and specificity. The drug-target interactions generate surface stress, causing the cantilever to bend, and the signal can be analyzed optically when it is illuminated by a laser. The change in surface stress measured with nano-scale precision allows disruptions of the biomechanics of model bacterial cell wall targets to be tracked in real time. Despite offering considerable advantages, multiple cantilever sensor arrays have never been applied in quantifying drug-target binding interactions. Here, we report on the use of silicon multiple cantilever arrays coated with alkanethiol self-assembled monolayers mimicking bacterial cell wall matrix to quantitatively study antibiotic binding interactions. To understand the impact of vancomycin on the mechanics of bacterial cell wall structures. We developed a new model(1) which proposes that cantilever bending can be described by two independent factors; i) namely a chemical factor, which is given by a classical Langmuir adsorption isotherm, from which we calculate the thermodynamic equilibrium dissociation constant (Kd) and ii) a geometrical factor, essentially a measure of how bacterial peptide receptors are distributed on the cantilever surface. The surface distribution of peptide receptors (p) is used to investigate the dependence of geometry and ligand loading. It is shown that a threshold value of p ~10% is critical to sensing applications. Below which there is no detectable bending signal while above this value, the bending signal increases almost linearly, revealing that stress is a product of a local chemical binding factor and a geometrical factor combined by the mechanical connectivity of reacted regions and provides a new paradigm for design of powerful agents to combat superbug infections. PMID:24192763

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

2013-01-01

234

The global spread of drug-resistant influenza  

PubMed Central

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

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

2012-01-01

235

Neighborhood Drug Markets: A risk environment for bacterial sexually transmitted infections among urban youth  

PubMed Central

We hypothesized that neighborhoods with drug markets, as compared to those without, have a greater concentration of infected sex partners, i.e. core transmitters, and that in these areas, there is an increased risk environment for STIs. This study determined if neighborhood drug markets were associated with a high-risk sex partnership and, separately, with a current bacterial STI (chlamydia and/or gonorrhea) after controlling for individual demographic and sexual risk factors among a household sample of young people in Baltimore City, MD. Analyses also tested whether links were independent of neighborhood socioeconomic status. Data for this study were collected from a household study, systematic social observations and police arrest, public health STI surveillance and U.S. census data. Nonlinear multilevel models showed that living in neighborhoods with household survey-reported drug markets increased the likelihood of having a high-risk sex partnership after controlling for individual level demographic factors and illicit drug use and neighborhood socioeconomic status. Further, living in neighborhoods with survey-reported drug markets increased the likelihood of having a current bacterial STI after controlling for individual level demographic and sexual risk factors and neighborhood socioeconomic status. The results suggest that local conditions in neighborhoods with drug markets may play an important role in setting-up risk environments for high-risk sex partnerships and bacterial STIs. Patterns observed appeared dependent on the type of drug market indicator used. Future studies should explore how conditions in areas with local drug markets may alter sexual networks structures and whether specific types of drug markets are particularly important in determining STI risk. PMID:22386616

Jennings, Jacky M.; Taylor, Ralph B.; Salhi, Rama A.; Furr-Holden, C.Debra M.; Ellen, Jonathan M.

2012-01-01

236

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

237

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 (M), 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

238

Drug resistance to targeted therapies: dj 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, Ren

2014-09-12

239

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 200C or 550C retained bactericidal activity, while cation-exchanged CsAg02 and CsAg02 heated to 900C 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

240

In vitro efficacy of cefquinome (INN) and other anti-infective drugs against bovine bacterial isolates from Belgium, France, Germany, The Netherlands, and the United Kingdom.  

PubMed

The in vitro antibacterial activity of cefquinome (INN), an aminothiazolyl-cephalosporin of the fourth generation of cephalosporins, was investigated by determining the minimal inhibitory concentration (MIC, microgram/ml) for 714 bacterial isolates of bovine origin and comparing it with those of amoxicillin, amoxicillin and clavulanic acid, ceftiofur, cephapirin, enrofloxacin, gentamicin, kanamycin and oxytetracycline. Drug resistance was determined by using break-points, which consider the dosage regimen and pharmacokinetics of the veterinary antimicrobials investigated. Cefquinome demonstrated a very high in vitro activity against bacterial isolates of Pasteurella spp., Escherichia coli and Salmonella spp. Overall, the level of resistance against the different anti-infectives tested was lowest for cefquinome. For the remaining substances examined, in vitro activity and the level of resistance showed considerable differences. The chemical and pharmaceutical features of cefquinome are discussed. PMID:8578918

Bttner, A; Schmid, P; Humke, R

1995-08-01

241

[Outcomes of treatment of chemotherapy drugs different manufacturers tuberculosis patients with multiple drug resistance].  

PubMed

The article is devoted to studying the effectiveness of treatment of tuberculosis (TB) patients with multidrug-resistant TB drugs 2 number of different manufacturers. To assess the effectiveness of treatment of second-line drugs were taken to study two groups of patients: Group 1 - 164 patients who received anti-TB drugs from the Global Fund and Group 2 174 patients who received anti-TB drugs for the national program. Comparative evaluation showed high efficiency second-line drugs from the Global Fund, as evidenced by the high level of 95,8 % abacillation in a short time in this patient group. PMID:25341241

Tabriz, N; Ospanova, B; Nurtazina, J; Mutayhan, J; Tabriz, K

2014-09-01

242

The Role of Transport Mechanisms in Mycobacterium Tuberculosis Drug Resistance and Tolerance  

PubMed Central

In the fight against tuberculosis, cell wall permeation of chemotherapeutic agents remains a critical but largely unsolved question. Here we review the major mechanisms of small molecule penetration into and efflux from Mycobacterium tuberculosis and other mycobacteria, and outline how these mechanisms may contribute to the development of phenotypic drug tolerance and induction of drug resistance. M. tuberculosis is intrinsically recalcitrant to small molecule permeation thanks to its thick lipid-rich cell wall. Passive diffusion appears to account for only a fraction of total drug permeation. As in other bacterial species, influx of hydrophilic compounds is facilitated by water-filled open channels, or porins, spanning the cell wall. However, the diversity and density of M. tuberculosis porins appears lower than in enterobacteria. Besides, physiological adaptations brought about by unfavorable conditions are thought to reduce the efficacy of porins. While intracellular accumulation of selected drug classes supports the existence of hypothesized active drug influx transporters, efflux pumps contribute to the drug resistant phenotype through their natural abundance and diversity, as well as their highly inducible expression. Modulation of efflux transporter expression has been observed in phagocytosed, non-replicating persistent and multi-drug resistant bacilli. Altogether, M. tuberculosis has evolved both intrinsic properties and acquired mechanisms to increase its level of tolerance towards xenobiotic substances, by preventing or minimizing their entry. Understanding these adaptation mechanisms is critical to counteract the natural mechanisms of defense against toxic compounds and develop new classes of chemotherapeutic agents that positively exploit the influx and efflux pathways of mycobacteria. PMID:24281307

Sarathy, Jansy Passiflora; Dartois, Veronique; Lee, Edmund Jon Deoon

2012-01-01

243

Antimicrobial Resistance Pattern in Enterococcus faecalis Strains Isolated From Expressed Prostatic Secretions of Patients With Chronic Bacterial Prostatitis  

PubMed Central

Purpose Enterococcus faecalis is one of the most common pathogens linked to chronic bacterial prostatitis (CBP). Owing to a limited number of previous studies addressing this topic, we aimed to determine the drug resistance patterns of E. faecalis strains isolated from CBP patients. Materials and Methods One thousand twenty-one patients visited a single hospital owing to chronic prostatitis for 5 years. Culture specimens were obtained by use of a modified Meares-Stamey method. The minimal inhibitory concentrations of the antimicrobials were assessed by use of the Vitek II microbial identification system as suggested by the Clinical and Laboratory Standards Institute. Results Forty-one samples from 41 patients who had significant E. faecalis loads for defining CBP were included in this study. The E. faecalis strains in our study were resistant to penicillin (9.7%), ampicillin (0%), ampicillin/sulbactam (0%), nitrofurantoin (0%), imipenem (0%), vancomycin (0%), teicoplanin (0%), quinupristin/dalfopristin (100%), ciprofloxacin (9.7%), levofloxacin (4.8%), norfloxacin (26.8%), erythromycin (95%), gentamicin (46.3%), tetracycline (97.5%), and trimethoprim/sulfamethoxazole (31.5%), respectively. Conclusions Fluoroquinolones have been the preferred antibiotics for treating CBP. Because of their low rate of drug resistance, fluoroquinolones are suitable therapeutic agents for E. faecalis strains causing CBP in Korea. Even though tetracycline, erythromycin, and trimethoprim/sulfamethoxazole have been prescribed as an empirical antimicrobial therapy for chronic prostatitis, we cannot recommend these drugs for treatment of E. faecalis isolates because of the high rates of drug resistance. PMID:23878692

Seo, Yumi

2013-01-01

244

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

245

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; Tomas, Maria

2013-01-01

246

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

247

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

248

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

249

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

250

[Antibacterial drug resistance in Latin America: consequences for infectious disease control].  

PubMed

Antibacterial drug resistance is a particularly significant issue in Latin America. This article explores antimicrobial resistance in three classes of clinically important bacteria: gram-positive bacteria, enterobacteria, and nonfermenting gram-negative bacilli. The gram-positive bacteria frequently responsible for infections in humans are for the most part cocci: staphylococci, streptococci (including pneumococci), and enterococci, in both community and hospital settings. This situation is no different in the Region of the Americas. Among the gram-positive bacteria, the causative agents of bacteremia are most commonly strains of coagulase-negative Staphylococcus, followed by enterococci. This report explores the resistance of these species to different antimicrobial drugs, resistance mechanisms in community and hospital strains, and new drugs for treating infections caused by these bacteria. In Latin America, antimicrobial resistance in Enterococcus strains is still a minor problem compared to the situation in the United States. The strains of the genus Streptococcus isolated from respiratory infections are still sensitive to penicillin. Furthermore, the resistance of enterobacteria is extremely important in the Region, particularly because of the broad dissemination of CTX-M extended-spectrum beta-lactamases (ESBL), some of which originated in Latin America. This article analyzes the resistance of Streptococcus pneumoniae, beta-hemolytic streptococci, and viridans group streptococci. Among the nonfermenting gram-negative bacilli, while Pseudomonas aeruginosa strains remain the leading cause of bacteremia, infections caused by strains of Acinetobacter spp. have proliferated extensively in some areas. With regard to antibiotics, several options are available for treating gram-positive bacterial infections. The same cannot be said for infections caused by enterobacteria and nonfermenting gram-negative bacilli, where options for the effective treatment of patients are still insufficient. PMID:22358396

Casellas, Jos Mara

2011-12-01

251

The prevalence of multidrug-resistant bacterial strains has substantially  

E-print Network

of these three compounds to CrtM. Next, the authors assessed the antimicrobial potential of one activity. J. Exp. Med. 202, 209­215 (2005) ANTIMICROBIALS Cholesterol-biosynthesis inhibitor stops infection RESEARCH HIGHLIGHTS Nature Reviews Drug Discovery | AOP, published online 14 March 2008

Nizet, Victor

252

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

253

Multiantibiotic resistance caused by active drug extrusion in hospital pathogens  

Microsoft Academic Search

All living organisms from bacteria to mammals extrude noxious compounds to the external medium. When exposed to antibiotics,\\u000a bacteria actively extrude intracellular antibiotic and develop resistance to the drug. NosocomialStaphylococcus aureaus, Pseudomonas aeruginosa and other bacteria are resistant to a broad range of antibiotics and to structurally and functionally diverse chemotherapeutic\\u000a agents and disinfectants. For this reason nosocomial infections are

Taiji Nakae; Eisaku Yoshihara; Hiroshi Yoneyama

1997-01-01

254

Increasing Bacterial Resistance in Pediatric Acute Conjunctivitis (1997-1998)  

Microsoft Academic Search

We sought to determine the current level of resistance in Haemophilus influenzae and Streptococcus pneu- moniae, the primary pathogens of pediatric conjunctivitis. Between January 1997 and March 1998, we pro- spectively cultured acute conjunctivitis in 250 ambulatory pediatric patients from rural Kentucky whose average age was 24.3 months. In those 250 cases, 106 H. influenzae (42% of the total) and

STAN L. BLOCK; JAMES HEDRICK; RON TYLER; ALAN SMITH; REBECCA FINDLAY; EILEEN KEEGAN; DAVE W. STROMAN

2000-01-01

255

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

256

Characteristics of patients with drug resistant and drug sensitive tuberculosis in East London between 1984 and 1992.  

PubMed Central

BACKGROUND--The aim of this study was to investigate retrospectively factors associated with drug resistant tuberculosis at the London Chest Hospital. METHODS--The microbiology results for patients with tuberculosis at the hospital for the period 1984-92 were reviewed, together with case notes and chest radiographs of all patients with drug resistant tuberculosis and of 101 patients with drug sensitive tuberculosis notified during the same period as a control group. RESULTS--Culture positive pulmonary tuberculosis occurred in 292 patients. Drug resistant strains were isolated from 20 patients (6.8%). Ten of the 292 (3.4%) had strains resistant to a single drug and nine (3.1%) had resistance to more than one first line drug. One patient had strains resistant to isoniazid and capreomycin. Strains resistant to more than one drug were all resistant to isoniazid and rifampicin. In five patients these strains were also resistant to pyrazinamide and in two they were resistant to streptomycin. Single drug resistant strains were resistant to isoniazid (nine patients) or streptomycin (one patient). Among the risk factors studied previous treatment for tuberculosis was the most significant association with drug resistant tuberculosis (7/9) for patients with resistance to more than one drug; 5/11 for single drug resistance compared with 6/101 patients in the drug sensitive group (odds ratio 22.8). Other risk factors were bilateral disease at presentation (odds ratio 8.5), and disease at a young age (odds ratio 1.03). CONCLUSIONS--Previous treatment for tuberculosis and bilateral disease at presentation were found to be more commonly associated with cases of drug resistant than with drug sensitive tuberculosis. PMID:8091328

al Jarad, N.; Parastatides, S.; Paul, E. A.; Sheldon, C. D.; Gaya, H.; Rudd, R. M.; Empey, D. W.

1994-01-01

257

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

PubMed

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

Zuniga, Ramiro; Nguyen, Tam

2013-04-01

258

Exploring N-acylhydrazone derivatives against clinical resistant bacterial strains.  

PubMed

Bacterial multiresistance is a health problem worldwide that demands new antimicrobials for treating bacterial-related infections. In this study, we evaluated the antimicrobial activity and the theoretical toxicology profile of N-substituted-phenylamino-5-methyl-1H-1,2,3-triazole-4-carbohydrazide derivatives against gram-positive and gram-negative bacteria clinical strains. On that purpose we determined the minimum inhibitory (MIC) and bactericidal (MBC) concentrations, the in vitro cytotoxicity, and in silico risk profiles, also comparing with antimicrobial agents of clinical use. Among the 16 derivatives analyzed, four nitrofurans (N-H-FUR-NO(2), N-Br-FUR-NO(2), N-F-FUR-NO(2), N-Cl-FUR-NO(2)) showed promising MIC and MBC values (MIC = MBC = 1-16 ?g/mL). The experimental data revealed the potential of these derivatives, which were comparable to the current antimicrobials with similar bactericidal and bacteriostatic profiles. Therefore, these molecules may be feasible options to be explored for treating infections caused by multiresistant strains. Our in vitro and in silico toxicity reinforced these results as these derivatives presented low cytotoxicity against human macrophages and low theoretical risk profile for irritant and reproductive effects compared to the current antimicrobials (e.g., vancomycin and ciprofloxacin). The molecular modeling analysis also revealed positive values for their theoretical druglikeness and drugscore. The presence of a 5-nitro-2-furfur-2-yl group seems to be essential for the antimicrobial activity, which pointed these acylhydrazone derivatives as promising for designing more potent and safer compounds. PMID:24807624

Lannes, Andressa C; Leal, Bruno; Novais, Juliana S; Lione, Viviane; Monteiro, Georgia C T S; Loureno, Andr L; Sathler, Plnio C; Jordo, Alessandro K; Rodrigues, Carlos R; Cabral, Lcio M; Cunha, Anna Claudia; Campos, Vinicius; Ferreira, Vtor F; de Souza, Maria Ceclia B V; Santos, Dilvani O; Castro, Helena C

2014-09-01

259

Rational Drug Redesign to Overcome Drug Resistance in Cancer Therapy: Imatinib Moving Target  

PubMed Central

Protein kinases are central targets for drug-based cancer treatment. To avoid functional impairment, the cell develops mechanisms of drug resistance, primarily based on adaptive mutations. Redesigning a drug to target a drug-resistant mutant kinase constitutes a therapeutic challenge. We approach the problem by redesigning the anticancer drug imatinib guided by local changes in interfacial de-wetting propensities of the C-Kit kinase target introduced by an imatinib-resistant mutation. The ligand is redesigned by sculpting the shifting hydration patterns of the target. The association with the modified ligand overcomes the mutation-driven destabilization of the induced fit. Consequently, the redesigned drug inhibits both mutant and wild-type kinase. The modeling effort is validated through molecular dynamics, test tube kinetic assays of downstream phosphorylation activity, high-throughput bacteriophage-display kinase screening, cellular proliferation assays, and cellular immunoblots. The inhibitor redesign reported delineates a molecular engineering paradigm to impair routes for drug resistance. PMID:17483313

Fernandez, Ariel; Sanguino, Angela; Peng, Zhenghong; Crespo, Alejandro; Ozturk, Eylem; Zhang, Xi; Wang, Shimei; Bornmann, William; Lopez-Berestein, Gabriel

2007-01-01

260

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

261

Neonatal Sepsis: High Antibiotic Resistance of the Bacterial Pathogens in a Neonatal Intensive Care Unit of a Tertiary Care Hospital  

PubMed Central

Objective: To study the bacterial pathogens causing neonatal sepsis and their sensitivity pattern so that guidelines can be prepared for empirical antibiotic therapy. Materials and Methods: We conducted a prospective analysis of all the cases admitted to the neonatal intensive care unit (NICU) of a tertiary care hospital and studied the culture and sensitivity pattern of organisms isolated. The neonates who presented with signs and symptoms of septicemia, with/without pneumonia and/or meningitis were studied and a detailed record of the maturity, age at onset, sex, birth weight (weight on admission for home deliveries), symptoms and signs along with the maternal risk factors was made. The cases with suspect sepsis were screened using various screening markers. Blood culture was done in all the cases, while cerebrospinal fluid was analysed only in those indicated. Sensitivity of the isolated organism was tested by Kirby Bauer disc diffusion techniques and various drug resistance mechanisms were studied. Result: Out of the 190 neonates (M:F=1.22:1) admitted to the NICU, 60 (31.57%) shows blood culture positive. Ninety-five percent cases were due to early onset septicemia. Thirty one neonates had Gram negative, twenty seven had Gram positive septicemia and two had candidial infection. Seventy percent Gram-positive isolates were resistant to penicillin. Ninety percent Gram negative isolates were resistant to gentamycin and ampicillin. Carbapenem resistance mechanisms such as ESBL. Conclusion: There is an increasing trend of antibiotic resistance to the commonly used and available drugs. Continuous surveillance for antibiotic susceptibility should be done to look for resistance pattern. PMID:24027694

Shah, Arpita Jigar; Mulla, Summaiya A.; Revdiwala, Sangita B.

2012-01-01

262

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides*  

E-print Network

, promoting GAS resistance to the antimicrobial peptide. Conclusion: Ska contributes to GAS innate immune to subvert peptide-based innate immune defense. The bacterial pathogen Group A Streptococcus (GAS) colo- nizes epithelial and mucosal surfaces and can cause a broad spectrum of human disease. Through

Nizet, Victor

263

Mosquitocidal bacterial toxins: diversity, mode of action and resistance phenomena.  

PubMed

Bacteria active against dipteran larvae (mosquitoes and black flies) include a wide variety of Bacillus thuringiensis and B. sphaericus strains, as well as isolates of Brevibacillus laterosporus and Clostridium bifermentans. All display different spectra and levels of activity correlated with the nature of the toxins, mainly produced during the sporulation process. This paper describes the structure and mode of action of the main mosquitocidal toxins, in relationship with their potential use in mosquito and/or black fly larvae control. Investigations with laboratory and field colonies of mosquitoes that have become highly resistant to the B. sphaericus Bin toxin have shown that several mechanisms of resistance are involved, some affecting the toxin/receptor binding step, others unknown. PMID:11142715

Charles, J F; Nielsen-LeRoux, C

2000-01-01

264

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

265

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

266

PHARMACOLOGY RESEARCH, SAFETY TESTING AND REGULATION SERIES ANTIBIOTIC RESISTANCE  

E-print Network

Substances S. B. Zotov and O. I. Tuzhikov ISBN: 978-1-60741-973-0 Antibiotic Resistance: Causes and Risk. Bonilla, Adriel R. II. Muniz, Kaden P. [DNLM: 1. Drug Resistance, Bacterial. 2. Anti-Bacterial Agents

Hemminga, Marcus A.

267

Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa  

PubMed Central

The anaerobic protozoa Giardia duodenalis, Trichomonas vaginalis, and Entamoeba histolytica infect up to a billion people each year. G. duodenalis and E. histolytica are primarily pathogens of the intestinal tract, although E. histolytica can form abscesses and invade other organs, where it can be fatal if left untreated. T. vaginalis infection is a sexually transmitted infection causing vaginitis and acute inflammatory disease of the genital mucosa. T. vaginalis has also been reported in the urinary tract, fallopian tubes, and pelvis and can cause pneumonia, bronchitis, and oral lesions. Respiratory infections can be acquired perinatally. T. vaginalis infections have been associated with preterm delivery, low birth weight, and increased mortality as well as predisposing to human immunodeficiency virus infection, AIDS, and cervical cancer. All three organisms lack mitochondria and are susceptible to the nitroimidazole metronidazole because of similar low-redox-potential anaerobic metabolic pathways. Resistance to metronidazole and other drugs has been observed clinically and in the laboratory. Laboratory studies have identified the enzyme that activates metronidazole, pyruvate:ferredoxin oxidoreductase, to its nitroso form and distinct mechanisms of decreasing drug susceptibility that are induced in each organism. Although the nitroimidazoles have been the drug family of choice for treating the anaerobic protozoa, G. duodenalis is less susceptible to other antiparasitic drugs, such as furazolidone, albendazole, and quinacrine. Resistance has been demonstrated for each agent, and the mechanism of resistance has been investigated. Metronidazole resistance in T. vaginalis is well documented, and the principal mechanisms have been defined. Bypass metabolism, such as alternative oxidoreductases, have been discovered in both organisms. Aerobic versus anaerobic resistance in T. vaginalis is discussed. Mechanisms of metronidazole resistance in E. histolytica have recently been investigated using laboratory-induced resistant isolates. Instead of downregulation of the pyruvate:ferredoxin oxidoreductase and ferredoxin pathway as seen in G. duodenalis and T. vaginalis, E. histolytica induces oxidative stress mechanisms, including superoxide dismutase and peroxiredoxin. The review examines the value of investigating both clinical and laboratory-induced syngeneic drug-resistant isolates and dissection of the complementary data obtained. Comparison of resistance mechanisms in anaerobic bacteria and the parasitic protozoa is discussed as well as the value of studies of the epidemiology of resistance. PMID:11148007

Upcroft, Peter; Upcroft, Jacqueline A.

2001-01-01

268

Environment-mediated drug resistance: a major contributor to minimal residual disease  

Microsoft Academic Search

Environment-mediated drug resistance is a form of de novo drug resistance that protects tumour cells from the initial effects of diverse therapies. Surviving foci of residual disease can then develop complex and permanent acquired resistance in response to the selective pressure of therapy. Recent evidence indicates that environment-mediated drug resistance arises from an adaptive, reciprocal signalling dialogue between tumour cells

Mark B. Meads; Robert A. Gatenby; William S. Dalton

2009-01-01

269

Sequence Note Low Prevalence of Drug Resistance Transmitted Virus  

E-print Network

of people living with HIV=AIDS as well as prevention of horizontal and vertical transmission. However=HIVCP_KHM.pdf). The same year, the National Center for HIV=AIDS, Dermatology and STD (NCHADS) reported that CambodiaSequence Note Low Prevalence of Drug Resistance Transmitted Virus in HIV Type 1-Infected ARV

Paris-Sud XI, Université de

270

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. A rule­directed search through mutation sequence space identifies nearby drug resistant mutant strains, is the leading cause of death in adults from age 14 to 35, and is the nation's leading cause of productive years

Pazzani, Michael J.

271

"Applied" Aspects of the Drug Resistance Strategies Project  

ERIC Educational Resources Information Center

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

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

2010-01-01

272

Population genomics of drug resistance in Candida albicans  

E-print Network

Population genomics of drug resistance in Candida albicans Leah E. Cowen* , Andre´ Nantel , Malcolm in gene expression occurred in four replicate populations of the pathogenic fungus Candida albicans during mutation is limited. Initially isogenic experimental populations of the diploid patho- genic yeast Candida

Kohn, Linda M.

273

P-Glycoprotein and Drug Resistance in Systemic Autoimmune Diseases  

PubMed Central

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

Picchianti-Diamanti, Andrea; Rosado, Maria Manuela; Scarsella, Marco; Lagana, Bruno; D'Amelio, Raffaele

2014-01-01

274

Bacterial resistance evolution by recruitment of super-integron gene cassettes.  

PubMed

The capture and spread of antibiotic resistance determinants by integrons underlies the rapid evolution of multiple antibiotic resistance among diverse Gram-negative clinical isolates. The association of multiple resistance integrons (MRIs) with mobile DNA elements facilitates their transit across phylogenetic boundaries and augments the potential impact of integrons on bacterial evolution. Recently, ancestral chromosomal versions, the super-integrons (SIs), were found to be genuine components of the genomes of diverse bacterial species. SIs possess evolutionary characteristics and stockpiles of adaptive functions, including cassettes related to antibiotic resistance determinants previously characterized in clinical isolates, which suggest that MRIs and their resistance genes were originally recruited from SIs and their pool of amassed genes. However, the recombination activity of integrons has never been demonstrated in a bacterium other than Escherichia coli. We introduced a naturally occurring MRI (TpR, SulR) on a conjugative plasmid into Vibrio cholerae, a species known to harbour a SI. We show that MRIs can randomly recruit genes directly from the cache of SI cassettes. By applying a selective constraint for the development of antibiotic resistance, we demonstrate bacterial resistance evolution through the recruitment a novel, but phenotypically silent, chloramphenicol acetyltransferase gene from the V. cholerae SI and its precise insertion into the MRI. The resulting resistance profile (CmR, TpR, SulR) could then be disseminated by conjugation to other clinically relevant pathogens at high frequency. These results demonstrate that otherwise phenotypically sensitive strains may still be a genetic source for the evolution of resistance to clinically relevant antibiotics through integron-mediated recombination events. PMID:11952913

Rowe-Magnus, Dean A; Guerout, Anne-Marie; Mazel, Didier

2002-03-01

275

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

PubMed Central

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

Shenoi, Sheela; Friedland, Gerald

2009-01-01

276

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

277

Microbial development of drug resistance: mechanisms and clinical significance.  

PubMed

Bacteria have demonstrated a disconcerting ability to develop resistance to antimicrobial agents nearly as quickly as new compounds become available. During the past two decades the molecular bases of several types of resistance have been elucidated. Mechanisms of resistance include the transference of genetic material either through conjugation (involving direct contact between microorganisms), or indirectly through transduction (involving bacteriophages). In addition to this "infectious" drug resistance, genetic mutations which permit the utilization of new metabolic pathways, and the production of enzymes which can inactivate the antimicrobic have been described. One particularly complex problem has been the ability of many Enterobacteriaceae to develop resistance to multiple antimicrobials simultaneously. The possible effect of such an occurrence is illustrated by the recent epidemic of multiply resistant Salmonella typhi in Mexico. Because the typhoid bacilli shared an identical resistance pattern to an epidemic Shigella dysenteriae type 1 the in vivo interspecies transmission of resistance has been postulated. Understanding the various mechanisms of resistance development should allow more rational use of antimicrobial agents. PMID:806419

Lawrence, R M; Hoeprich, P D

1975-03-01

278

Nanomechanical detection of antibiotic-mucopeptide binding in a model for superbug drug resistance.  

PubMed

The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements have quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions activated by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also have an impact on our understanding of antibiotic drug action in bacteria. PMID:18989336

Ndieyira, Joseph Wafula; Watari, Moyu; Barrera, Alejandra Donoso; Zhou, Dejian; Vgtli, Manuel; Batchelor, Matthew; Cooper, Matthew A; Strunz, Torsten; Horton, Mike A; Abell, Chris; Rayment, Trevor; Aeppli, Gabriel; McKendry, Rachel A

2008-11-01

279

Nanomechanical detection of antibiotic-mucopeptide binding in a model for superbug drug resistance  

NASA Astrophysics Data System (ADS)

The alarming growth of the antibiotic-resistant superbugs methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE) is driving the development of new technologies to investigate antibiotics and their modes of action. We report the label-free detection of vancomycin binding to bacterial cell wall precursor analogues (mucopeptides) on cantilever arrays, with 10 nM sensitivity and at clinically relevant concentrations in blood serum. Differential measurements have quantified binding constants for vancomycin-sensitive and vancomycin-resistant mucopeptide analogues. Moreover, by systematically modifying the mucopeptide density we gain new insights into the origin of surface stress. We propose that stress is a product of a local chemical binding factor and a geometrical factor describing the mechanical connectivity of regions activated by local binding in terms of a percolation process. Our findings place BioMEMS devices in a new class of percolative systems. The percolation concept will underpin the design of devices and coatings to significantly lower the drug detection limit and may also have an impact on our understanding of antibiotic drug action in bacteria.

Ndieyira, Joseph Wafula; Watari, Moyu; Barrera, Alejandra Donoso; Zhou, Dejian; Vgtli, Manuel; Batchelor, Matthew; Cooper, Matthew A.; Strunz, Torsten; Horton, Mike A.; Abell, Chris; Rayment, Trevor; Aeppli, Gabriel; McKendry, Rachel A.

2008-11-01

280

Multi-resistant bacteria in spontaneous bacterial peritonitis: A new step in management?  

PubMed Central

Spontaneous bacterial peritonitis (SBP) is the most typical infection observed in cirrhosis patients. SBP is responsible for an in-hospital mortality rate of approximately 32%. Recently, pattern changes in the bacterial flora of cirrhosis patients have been observed, and an increase in the prevalence of infections caused by multi-resistant bacteria has been noted. The wide-scale use of quinolones in the prophylaxis of SBP has promoted flora modifications and resulted in the development of bacterial resistance. The efficacy of traditionally recommended therapy has been low in nosocomial infections (up to 40%), and multi-resistance has been observed in up to 22% of isolated germs in nosocomial SBP. For this reason, the use of a broad empirical spectrum antibiotic has been suggested in these situations. The distinction between community-acquired infectious episodes, healthcare-associated infections, or nosocomial infections, and the identification of risk factors for multi-resistant germs can aid in the decision-making process regarding the empirical choice of antibiotic therapy. Broad-spectrum antimicrobial agents, such as carbapenems with or without glycopeptides or piperacillin-tazobactam, should be considered for the initial treatment not only of nosocomial infections but also of healthcare-associated infections when the risk factors or severity signs for multi-resistant bacteria are apparent. The use of cephalosporins should be restricted to community-acquired infections. PMID:25339797

de Mattos, Angelo Alves; Costabeber, Ane Micheli; Lionco, Livia Caprara; Tovo, Cristiane Valle

2014-01-01

281

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

282

Troglitazone reverses the multiple drug resistance phenotype in cancer cells  

PubMed Central

A major problem in treating cancer is the development of drug resistance. We previously demonstrated doxorubicin (DOX) resistance in K562 human leukemia cells that was associated with upregulation of glyoxalase 1 (GLO-1) and histone H3 expression. The thiazolidinedione troglitazone (TRG) downregulated GLO-1 expression and further upregulated histone H3 expression and post-translational modifications in these cells, leading to a regained sensitivity to DOX. Given the pleiotropic effects of epigenetic changes in cancer development, we hypothesized that TRG may downregulate the multiple drug resistance (MDR) phenotype in a variety of cancer cells. To test this, MCF7 human breast cancer cells and K562 cells were cultured in the presence of low-dose DOX to establish DOX-resistant cell lines (K562/DOX and MCF7/DOX). The MDR phenotype was confirmed by Western blot analysis of the 170 kDa P-glycoprotein (Pgp) drug efflux pump multiple drug resistance protein 1 (MDR-1), and the breast cancer resistance protein (BCRP). TRG markedly decreased expression of both MDR-1 and BCRP in these cells, resulting in sensitivity to DOX. Silencing of MDR-1 expression also sensitized MCF7/DOX cells to DOX. Use of the specific and irreversible peroxisome proliferator-activated receptor gamma (PPAR?) inhibitor GW9662 in the nanomolar range not only demonstrated that the action of TRG on MCF/DOX was PPAR?-independent, but indicated that PPAR? may play a role in the MDR phenotype, which is antagonized by TRG. We conclude that TRG is potentially a useful adjunct therapy in chemoresistant cancers. PMID:19920924

Davies, Gerald F; Juurlink, Bernhard HJ; Harkness, Troy AA

2009-01-01

283

The Bacterial Defensin Resistance Protein MprF Consists of Separable Domains for Lipid Lysinylation and Antimicrobial Peptide Repulsion  

PubMed Central

Many bacterial pathogens achieve resistance to defensin-like cationic antimicrobial peptides (CAMPs) by the multiple peptide resistance factor (MprF) protein. MprF plays a crucial role in Staphylococcus aureus virulence and it is involved in resistance to the CAMP-like antibiotic daptomycin. MprF is a large membrane protein that modifies the anionic phospholipid phosphatidylglycerol with l-lysine, thereby diminishing the bacterial affinity for CAMPs. Its widespread occurrence recommends MprF as a target for novel antimicrobials, although the mode of action of MprF has remained incompletely understood. We demonstrate that the hydrophilic C-terminal domain and six of the fourteen proposed trans-membrane segments of MprF are sufficient for full-level lysyl-phosphatidylglycerol (Lys-PG) production and that several conserved amino acid positions in MprF are indispensable for Lys-PG production. Notably, Lys-PG production did not lead to efficient CAMP resistance and most of the Lys-PG remained in the inner leaflet of the cytoplasmic membrane when the large N-terminal hydrophobic domain of MprF was absent, indicating a crucial role of this protein part. The N-terminal domain alone did not confer CAMP resistance or repulsion of the cationic test protein cytochrome c. However, when the N-terminal domain was coexpressed with the Lys-PG synthase domain either in one protein or as two separate proteins, full-level CAMP resistance was achieved. Moreover, only coexpression of the two domains led to efficient Lys-PG translocation to the outer leaflet of the membrane and to full-level cytochrome c repulsion, indicating that the N-terminal domain facilitates the flipping of Lys-PG. Thus, MprF represents a new class of lipid-biosynthetic enzymes with two separable functional domains that synthesize Lys-PG and facilitate Lys-PG translocation. Our study unravels crucial details on the molecular basis of an important bacterial immune evasion mechanism and it may help to employ MprF as a target for new anti-virulence drugs. PMID:19915718

Ernst, Christoph M.; Staubitz, Petra; Mishra, Nagendra N.; Yang, Soo-Jin; Hornig, Gabriele; Kalbacher, Hubert; Bayer, Arnold S.; Kraus, Dirk; Peschel, Andreas

2009-01-01

284

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

285

Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase  

E-print Network

of Research, Emerging Infectious Diseases Research Unit, Silver Spring, Maryland, United States of America identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs

286

Cultivable bacterial microbiota of northern bobwhite (Colinus virginianus): a new reservoir of antimicrobial resistance?  

PubMed

The northern bobwhite (Colinus virginianus) is an ecologically and economically important avian species. At the present time, little is known about the microbial communities associated with these birds. As the first step to create a quail microbiology knowledge base, the current study conducted an inventory of cultivable quail tracheal, crop, cecal, and cloacal microbiota and associated antimicrobial resistance using a combined bacteriology and DNA sequencing approach. A total of 414 morphologically unique bacterial colonies were selected from nonselective aerobic and anaerobic cultures, as well as selective and enrichment cultures. Analysis of the first 500-bp 16S rRNA gene sequences in conjunction with biochemical identifications revealed 190 non-redundant species-level taxonomic units, representing 160 known bacterial species and 30 novel species. The bacterial species were classified into 4 phyla, 14 orders, 37 families, and 59 or more genera. Firmicutes was the most commonly encountered phylum (57%) followed by Actinobacteria (24%), Proteobacteria (17%) and Bacteroidetes (0.02%). Extensive diversity in the species composition of quail microbiota was observed among individual birds and anatomical locations. Quail microbiota harbored several opportunistic pathogens, such as E. coli and Ps. aeruginosa, as well as human commensal organisms, including Neisseria species. Phenotypic characterization of selected bacterial species demonstrated a high prevalence of resistance to the following classes of antimicrobials: phenicol, macrolide, lincosamide, quinolone, and sulphate. Data from the current investigation warrant further investigation on the source, transmission, pathology, and control of antimicrobial resistance in wild quail populations. PMID:24937705

Su, Hongwen; McKelvey, Jessica; Rollins, Dale; Zhang, Michael; Brightsmith, Donald J; Derr, James; Zhang, Shuping

2014-01-01

287

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, Nicols; Mencacci, Nicols; Picca, Pablo; Toum, Laila; Lentz, Ezequiel; Bravo-Almonacid, Fernando; Mentaberry, Alejandro

2012-01-20

288

Antibiotic resistance among cultured bacterial isolates from bioethanol fermentation facilities across the United States.  

PubMed

Bacterial contamination of fuel ethanol fermentations by lactic acid bacteria (LAB) can have crippling effects on bioethanol production. Producers have had success controlling bacterial growth through prophylactic addition of antibiotics to fermentors, yet concerns have arisen about antibiotic resistance among the LAB. Here, we report on mechanisms used by 32 LAB isolates from eight different US bioethanol facilities to persist under conditions of antibiotic stress. Minimum inhibitory concentration assays with penicillin, erythromycin, and virginiamycin revealed broad resistance to each of the antibiotics as well as high levels of resistance to individual antibiotics. Phenotypic assays revealed that antibiotic inactivation mechanisms contributed to the high levels of individual resistances among the isolates, especially to erythromycin and virginiamycin, yet none of the isolates appeared to use a ?-lactamase. Biofilm formation was noted among the majority of the isolates and may contribute to persistence under low levels of antibiotics. Nearly all of the isolates carried at least one canonical antibiotic resistance gene and many carried more than one. The erythromycin ribosomal methyltransferase (erm) gene class was found in 19 of 32 isolates, yet a number of these isolates exhibit little to no resistance to erythromycin. The erm genes were present in 15 isolates that encoded more than one antibiotic resistance mechanism, suggestive of potential genetic linkages. PMID:24748439

Murphree, Colin A; Heist, E Patrick; Moe, Luke A

2014-09-01

289

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

290

Discussion on research methods of bacterial resistant mutation mechanisms under selective culture--uncertainty analysis of data from the Luria-Delbrck fluctuation experiment.  

PubMed

Whether bacterial drug-resistance is drug-induced or results from rapid propagation of random spontaneous mutations in the flora prior to exposure, remains a long-term key issue concerned and debated in both genetics and medicinal fields. In a pioneering study, Luria and Delbrck exposed E. coli to T1 phage, to investigate whether the number of resistant colonies followed the Poisson distribution. They deduced that the development of resistant colonies is independent of phage presence. Similar results have since been obtained on solid medium containing antibacterial agents. Luria and Delbrck's conclusions were long considered a gold standard for analyzing drug resistance mutations. More recently, the concept of adaptive mutation has triggered controversy over this approach. Microbiological observation shows that, following exposure to drugs of various concentrations, drug-resistant cells emerge and multiply depending on the time course, and show a process function, inconsistent with the definition of Poisson distribution (which assumes not only that resistance is independent of drug quantity but follows no specific time course). At the same time, since cells tend to aggregate after division rather than separating, colonies growing on drug plates arise from the multiplication of resistant bacteria cells of various initial population sizes. Thus, statistical analysis based on equivalence of initial populations will yield erroneous results. In this paper, 310 data from the Luria-Delbrck fluctuation experiment were reanalyzed from this perspective. In most cases, a high-end abnormal value, resulting from the non-synchronous variation of the two above-mentioned time variables, was observed. Therefore, the mean value cannot be regarded as an unbiased expectation estimate. The ratio between mean value and variance was similarly incomparable, because two different sampling methods were used. In fact, the Luria-Delbrck data appear to follow an aggregated, rather than Poisson distribution. In summary, the statistical analysis of Luria and Delbrck is insufficient to describe rules of resistant mutant development and multiplication. Correction of this historical misunderstanding will enable new insight into bacterial resistance mechanisms. PMID:23160830

Jin, Jianling; Wei, Gang; Yang, Weiqiang; Zhang, Huaiqiang; Gao, Peiji

2012-11-01

291

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

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

2013-02-01

292

Bottlenecks in the Transferability of Antibiotic Resistance from Natural Ecosystems to Human Bacterial Pathogens  

PubMed Central

It is generally accepted that resistance genes acquired by human pathogens through horizontal gene transfer originated in environmental, non-pathogenic bacteria. As a consequence, there is increasing concern on the roles that natural, non-clinical ecosystems, may play in the evolution of resistance. Recent studies have shown that the variability of determinants that can provide antibiotic resistance on their expression in a heterologous host is much larger than what is actually found in human pathogens, which implies the existence of bottlenecks modulating the transfer, spread, and stability of antibiotic resistance genes. In this review, the role that different factors such as founder effects, ecological connectivity, fitness costs, or second-order selection may have on the establishment of a specific resistance determinant in a population of bacterial pathogens is analyzed. PMID:22319513

Martnez, Jos L.

2011-01-01

293

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

294

Emergence and natural selection of drug-resistant prions  

PubMed Central

Drug resistance is a refractory barrier in the battle against many fatal diseases caused by rapidly evolving agents, including HIV, apicomplexans and specific cancers. Emerging evidence suggests that drug resistance might extend to lethal prion disorders and related neurodegenerative amyloidoses. Prions are self-replicating protein conformers, usually cross-? amyloid polymers, which are naturally transmitted between individuals and promote phenotypic change. Prion conformers are catalytic templates that specifically convert other copies of the same protein to the prion form. Once in motion, this chain reaction of conformational replication can deplete all non-prion copies of a protein. Typically, prions exist as ensembles of multiple structurally distinct, self-replicating forms or strains. Each strain confers a distinct phenotype and replicates at different rates depending on the environment. As replicators, prions are units of selection. Thus, natural selection inescapably enriches or depletes various prion strains from populations depending on their conformational fitness (ability to self-replicate) in the prevailing environment. The most successful prions confer advantages to their host as with numerous yeast prions. Here, I review recent evidence that drug-like small molecules can antagonize some prion strains but simultaneously select for drug-resistant prions composed of mammalian PrP or the yeast prion protein, Sup35. For Sup35, the drug-resistant strain configures original intermolecular amyloid contacts that are not ordinarily detected. Importantly, a synergistic small-molecule cocktail counters prion diversity by eliminating multiple Sup35 prion strains. Collectively, these advances illuminate the plasticity of prionogenesis and suggest that synergistic combinatorial therapies might circumvent this pathological vicissitude. PMID:20422111

2010-01-01

295

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

296

Survival of multi-drug resistant enteropathogenic Escherichia coli and Salmonella paratyphi in Vembanadu  

E-print Network

Survival of multi-drug resistant enteropathogenic Escherichia coli and Salmonella paratyphi the survival response of multi-drug resistant enteropathogenic Escherichia coli and Salmonella paratyphi- otypes of Escherichia coli, Salmonella enterica typhi and paratyphi are highly endemic to India

Mazumder, Asit

297

Elaboration of a global strategy for containing microbial drug resistance.  

PubMed

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

Zabicki, W

2001-01-01

298

Combating bacteria and drug resistance by inhibiting mechanisms of persistence and adaptation  

Microsoft Academic Search

Antibiotics have revolutionized the treatment of infectious disease but have also rapidly selected for the emergence of resistant pathogens. Traditional methods of antibiotic discovery have failed to keep pace with the evolution of this resistance, which suggests that new strategies to combat bacterial infections may be required. An improved understanding of bacterial stress responses and evolution suggests that in some

Peter A Smith; Floyd E Romesberg

2007-01-01

299

Convergent Evolutionary Analysis Identifies Significant Mutations in Drug Resistance Targets of Mycobacterium tuberculosis  

Microsoft Academic Search

Mycobacterium tuberculosis adapts to the environment by selecting for advantageous single-nucleotide poly- morphisms (SNPs). We studied whether advantageous SNPs could be distinguished from neutral mutations within genes associated with drug resistance. A total of 1,003 clinical isolates of M. tuberculosis were related phylogenetically and tested for the distribution of SNPs in putative drug resistance genes. Drug resistance- associated versus non-drug-resistance-associated

Manzour Hernando Hazbon; Alifiya S. Motiwala; Magali Cavatore; Michael Brimacombe; Thomas S. Whittam; David Alland

2008-01-01

300

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; Mentre, France

2014-01-01

301

Inheritance of resistance to bacterial blight in 21 cultivars of rice.  

PubMed

ABSTRACT Genetic analysis for resistance to bacterial blight (Xanthomonas oryzae pv. oryzae) of 21 rice (Oryza sativa L.) cultivars was carried out. These cultivars were divided into two groups based on their reactions to Philippine races of bacterial blight. Cultivars of group 1 were resistant to race 1 and those of group 2 were susceptible to race 1 but resistant to race 2. All the cultivars were crossed with TN1, which is susceptible to all the Philippine races of X. oryzae pv. oryzae. F(1) and F(2) populations of hybrids of group 1 cultivars were evaluated using race 1 and F(1) and F(2) populations of hybrids of group 2 cultivars were evaluated using race 2. All the cultivars showed monogenic inheritance of resistance. Allelic relationships of the genes were investigated by crossing these cultivars with different testers having single genes for resistance. Three cultivars have Xa4, another three have xa5, one has xa8, two have Xa3, eight have Xa10, and one has Xa4 as well as Xa10. Three cultivars have new, as yet undescribed, genes. Nep Bha Bong To has a new recessive gene for moderate resistance to races 1, 2, and 3 and resistance to race 5. This gene is designated xa26(t). Arai Raj has a dominant gene for resistance to race 2 which segregates independently of Xa10. This gene is designated as Xa27(t). Lota Sail has a recessive gene for resistance to race 2 which segregates independently of Xa10. This gene is designated as xa28(t). PMID:18943128

Lee, K S; Rasabandith, S; Angeles, E R; Khush, G S

2003-02-01

302

Resistance and Susceptibility of Arabidopsis thaliana to Bacterial Wilt Caused by Ralstonia solanacearum.  

PubMed

ABSTRACT Tomato bacterial wilt caused by Ralstonia solanacearum is a model system for studying plant-bacterial interactions, because it is genetically one of the best characterized plant diseases. We demonstrate here that four different strains of R. solanacearum, two from radishes (Rd4 and Rd15) and two from tomato (Ps21 and Ps95), can infect 27 different ecotypes of Arabidopsis thaliana, causing different responses. All ecotypes tested were highly susceptible to strain Rd15, which caused symptoms similar to those observed in tomato plants. For example, leaf drooping and discoloration developed just 3 days after inoculation, and plants completely wilted within 1 week. Strains Rd4 and Ps95 were less infectious than Rd15. With these two strains, a variety of disease responses were observed among different ecotypes at 2 weeks after inoculation; both susceptible and resistant ecotypes of A. thaliana were identified. Ps21 was the least infectious of the four strains and caused almost no symptoms in any of the ecotypes of Arabidopsis tested. Direct bacterial isolation and plant skeleton hybridization analysis from infected plants indicated that bacterial colonization was correlated with the severity of symptoms. Growth of bacteria was limited to the infection site in resistant plants, whereas the bacteria spread throughout susceptible plants by 1 week after inoculation. PMID:18944956

Yang, C H; Ho, G D

1998-04-01

303

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

304

Antimalarial Drug Resistance in Africa: Strategies for Monitoring and Deterrence  

Microsoft Academic Search

Despite the initiation in 1998 by the World Health Organization of a campaign to Roll Back Malaria, the rates of disease\\u000a and death caused by Plasmodium falciparum malaria in sub-Saharan Africa are growing. Drug resistance has been implicated as one of the main factors in this disturbing\\u000a trend. The efforts of international agencies, governments, public health officials, advocacy groups and

C. V. Plowe

305

Drug-Resistant Tuberculosis in Sub-Saharan Africa  

Microsoft Academic Search

Drug-resistant tuberculosis (DRTB) is an emerging infectious disease threat to sub-Saharan Africa (SSA), particularly in the\\u000a regions hit hardest by the HIV epidemic. Numerous challenges face clinicians and public health officials tasked with combating\\u000a DRTB in SSA. These include difficulties providing effective diagnosis, treatment, and prevention of this illness. Furthermore,\\u000a combating DRTB requires addressing various legal and ethical complexities. A

Jeffrey Hafkin; Victoria M. Gammino; Joseph J. Amon

2010-01-01

306

Arsenite Resistance in Leishmania and Possible Drug Targets  

Microsoft Academic Search

Parasitic infections are of enormous public health importance. Leishmaniasis is currently regarded as the second-most dreaded\\u000a parasitic disease after malaria (WHO). Visceral leishmaniasis or kala-azar, caused by Leishmania donovani, is the most fatal\\u000a form of leishmaniasis afflicting millions of people worldwide. No vaccination is available against leishmaniasis and fast\\u000a spreading drug resistance in these parasitic organisms is posing a major

Gaganmeet Singh; K. G. Jayanarayan; Chinmoy S. Dey

307

Proteasome Inhibition Circumvents Solid Tumor Resistance to Topoisomerase II-directed Drugs1  

Microsoft Academic Search

Physiological cell conditions, such as glucose deprivation and hypoxia, play a role in developing drug resistance in solid tumors. These tumor- specific conditions cause decreased expression of DNA topoisomerase IIa (topo IIa), rendering cells resistant to topo II-targeted drugs, such as etoposide and doxorubicin. We show here that inhibition of proteasome attenuated drug resistance by inhibiting topo IIa depletion induced

Yasunari Ogiso; Akihiro Tomida; Shuhong Lei; Takashi Tsuruo

2000-01-01

308

Tumour heterogeneity and drug resistance: Personalising cancer medicine through functional genomics  

Microsoft Academic Search

Intrinsic and acquired drug resistance leads to the eventual failure of cancer treatment regimens in the majority of advanced solid tumours. Understanding drug resistance mechanisms will prove vital in the future development of personalised therapeutic approaches. Functional genomics technologies may permit the discovery of predictive biomarkers by unravelling pathways involved in drug resistance and allow the systematic identification of novel

Alvin J.X. Lee; Charles Swanton

2012-01-01

309

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

310

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

311

Chromosomal alterations cause the high rates and wide ranges of drug resistance in cancer cells  

E-print Network

Chromosomal alterations cause the high rates and wide ranges of drug resistance in cancer cells, aneuploidy is the primary cause of the high rates and wide ranges of drug resistance in cancer cells. ? 2005 to answer four critical sets of questions about drug resistance in cancer cells. First: How do cancer cells

Duesberg, Peter

312

FINITE DIMENSIONAL MODELS OF DRUG RESISTANT AND PHASE SPECIFIC CANCER CHEMOTHERAPY  

E-print Network

FINITE DIMENSIONAL MODELS OF DRUG RESISTANT AND PHASE SPECIFIC CANCER CHEMOTHERAPY Urszula, 2004 Abstract We consider the problem of modeling drug resistance and phase specificity of cancer. MATHEMATICAL MODELS FOR CANCER CHEMOTHERAPY WITH A SINGLE KILLING AGENT UNDER EVOLVING DRUG RESISTANCE We

Ledzewicz, Urszula

313

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

314

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

315

Transcriptional Responses of Resistant and Susceptible Fish Clones to the Bacterial Pathogen Flavobacterium psychrophilum  

PubMed Central

Flavobacterium psychrophilum is a bacterial species that represents one of the most important pathogens for aquaculture worldwide, especially for salmonids. To gain insights into the genetic basis of the natural resistance to F. psychrophilum, we selected homozygous clones of rainbow trout with contrasted susceptibility to the infection. We compared the transcriptional response to the bacteria in the pronephros of a susceptible and a resistant line by micro-array analysis five days after infection. While the basal transcriptome of healthy fish was significantly different in the resistant and susceptible lines, the transcriptome modifications induced by the bacteria involved essentially the same genes and pathways. The response to F. psychrophilum involved antimicrobial peptides, complement, and a number of enzymes and chemokines. The matrix metalloproteases mmp9 and mmp13 were among the most highly induced genes in both genetic backgrounds. Key genes of both pro- and anti-inflammatory response such as IL1 and IL10, were up-regulated with a greater magnitude in susceptible animals where the bacterial load was also much higher. While higher resistance to F. psychrophilum does not seem to be based on extensive differences in the orientation of the immune response, several genes including complement C3 showed stronger induction in the resistant fish. They may be important for the variation of susceptibility to the infection. PMID:22720048

Martin, Samuel A. M.; Jouneau, Luc; Bernardet, Jean-Francois; Houel, Armel; Lunazzi, Aurelie; Duchaud, Eric; Michel, Christian; Quillet, Edwige; Boudinot, Pierre

2012-01-01

316

Ethanol-resistant polymeric film coatings for controlled drug delivery.  

PubMed

The sensitivity of controlled release dosage forms to the presence of ethanol in the gastro intestinal tract is critical, if the incorporated drug is potent and exhibits severe side effects. This is for instance the case for most opioid drugs. The co-ingestion of alcoholic beverages can lead to dose dumping and potentially fatal consequences. For these reasons the marketing of hydromorphone HCl extended release capsules (Palladone) was suspended. The aim of this study was to develop a novel type of controlled release film coatings, which are ethanol-resistant: even the presence of high ethanol concentrations in the surrounding bulk fluid (e.g., up to 40%) should not affect the resulting drug release kinetics. Interestingly, blends of ethylcellulose and medium or high viscosity guar gums provide such ethanol resistance. Theophylline release from pellets coated with the aqueous ethylcellulose dispersion Aquacoat ECD 30 containing 10 or 15% medium and high viscosity guar gum was virtually unaffected by the addition of 40% ethanol to the release medium. Furthermore, drug release was shown to be long term stable from this type of dosage forms under ambient and stress conditions (without packaging material), upon appropriate curing. PMID:23570984

Rosiaux, Y; Muschert, S; Chokshi, R; Leclercq, B; Siepmann, F; Siepmann, J

2013-07-10

317

Drug Resistance Mechanisms of Mycoplasma pneumoniae to Macrolide Antibiotics  

PubMed Central

Throat swabs from children with suspected Mycoplasma pneumoniae (M. pneumoniae) infection were cultured for the presence of M. pneumoniae and its species specificity using the 16S rRNA gene. Seventy-six M. pneumoniae strains isolated from 580 swabs showed that 70 were erythromycin resistant with minimum inhibitory concentrations (MIC) around 32512?mg/L. Fifty M. pneumoniae strains (46 resistant, 4 sensitive) were tested for sensitivity to tetracycline, ciprofloxacin, and gentamicin. Tetracycline and ciprofloxacin had some effect, and gentamicin had an effect on the majority of M. pneumoniae strains. Domains II and V of the 23S rRNA gene and the ribosomal protein L4 and L22 genes, both of which are considered to be associated with macrolide resistance, were sequenced and the sequences were compared with the corresponding sequences in M129 registered with NCBI and the FH strain. The 70 resistant strains all showed a 2063 or 2064 site mutation in domain V of the 23S rRNA but no mutations in domain II. Site mutations of L4 or L22 can be observed in either resistant or sensitive strains, although it is not known whether this is associated with drug resistance. PMID:24592385

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

2014-01-01

318

[Drug resistance in nosocomial strains of staphylococci to methicillin].  

PubMed

The aim of the present study was the analysis of drug susceptibility of MRSA and MRCNS strains isolated from patients hospitalized in 14 wards of the State Clinical Hospital No 1 in Warsaw. The strains were identified (ID 32 STAPH), and their susceptibility to antimicrobial agents (ATB STAPH) was determined in ATB system (bioMrieux, France). Four methods were applied to confirm the resistance to methicillin: ATB-plus system, disc-diffusion method (Oxa 1 microgram, Oxoid, U.K.), Crystal MRSA ID (Becton Dickinson-BBL, USA) and agar screen test in TSA medium (Difco, USA) with methicillin (25 mg/l, Sigma, USA). 108 Staphylococcus spp. strains were found in 300 clinical specimens. 56 strains were methicillin-resistant (52%). Among methicillin-resistant strains 13 MRSA, 28 MRSE and 15 of other species were found. All MRSA strains were susceptible to vancomycin, teicoplanin and fusidic acid. MRCNS were susceptible first of all to vancomycin (43/43), minocycline (42/43) and pristinamycin (42/43). On the basis of the obtained results it can be stated that methicillin-resistant staphylococci occur in hospital wards. The greatest number of methicillin-resistant strains was cultured from patients hospitalized in surgery wards (32), methicillin-resistant strains much more frequently occur among coagulase-negative staphylococci, especially in Staphylococcus epidermis. Glycopeptide antibiotics are most active against isolated MRSA strains. The most active therapeutic agent against MRCNS is vancomycin. PMID:9857608

Sawicka-Grzelak, A; Rokosz, A; Meisel-Miko?ajczyk, F

1998-01-01

319

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-nave 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

320

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

321

A conservative region of the mercuric reductase gene (mera) as a molecular marker of bacterial mercury resistance  

PubMed Central

The most common bacterial mercury resistance mechanism is based on the reduction of Hg(II) to Hg0, which is dependent of the mercuric reductase enzyme (MerA) activity. The use of a 431 bp fragment of a conservative region of the mercuric reductase (merA) gene was applied as a molecular marker of this mechanism, allowing the identification of mercury resistant bacterial strains. PMID:24031221

Sotero-Martins, Adriana; de Jesus, Michele Silva; Lacerda, Michele; Moreira, Josino Costa; Filgueiras, Ana Luzia Lauria; Barrocas, Paulo Rubens Guimaraes

2008-01-01

322

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

PubMed Central

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

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

2013-01-01

323

Human health consequences of antimicrobial drug-resistant Salmonella and other foodborne pathogens.  

PubMed

There are several clinical and public health consequences associated with antimicrobial drug resistance in non-Typhi Salmonella species and other foodborne pathogens. If bacteria acquire resistance to clinically important antimicrobial drugs, early empirical treatment may fail, and there will be limitations in the choices of treatment after the establishment of microbial diagnosis. Drug-resistant gastrointestinal pathogens preferentially cause illness in persons receiving antimicrobial drugs for any medical condition. Consequently, emerging resistance in foodborne pathogens may result in increased burdens of illness and outbreaks in settings where patients are treated with antimicrobial drugs. Finally, resistance may be associated with increased virulence, and several epidemiological studies have demonstrated that infections with drug-resistant non-Typhi Salmonella serotypes and Campylobacter species are associated with excess mortality and morbidity. Mitigation of drug resistance in foodborne bacteria is likely to be of benefit for human health. PMID:16267734

Mlbak, Kre

2005-12-01

324

Mechanisms of antifungal drug resistance in Candida dubliniensis.  

PubMed

Candida dubliniensis was first described in 1995 and is the most closely related species to the predominant human fungal pathogen Candida albicans. C. dubliniensis is significantly less prevalent and less pathogenic than C. albicans and is primarily associated with infections in HIV-infected individuals and other immunocompromised cohorts. The population structure of C. dubliniensis consists of three well-defined major clades and is significantly less diverse than C. albicans. The majority of C. dubliniensis isolates are susceptible to antifungal drugs commonly used to treat Candida infections. To date only two major patterns of antifungal drug resistance have been identified and the molecular mechanisms of these are very similar to the resistance mechanisms that have been described previously in C. albicans. However, significant differences are evident in the predominant antifungal drug mechanisms employed by C. dubliniensis, differences that reflect its more clonal nature, its lower prevalence and characteristics of its genome, the complete sequence of which has only recently been determined. PMID:20521937

Coleman, David C; Moran, Gary P; McManus, Brenda A; Sullivan, Derek J

2010-06-01

325

Rifampin Drug Resistance Tests for Tuberculosis: Challenging the Gold Standard  

PubMed Central

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 Lwenstein-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

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.

2013-01-01

326

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 Lwenstein-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

327

MULTI-FUNCTIONAL NANOCARRIERS TO OVERCOME TUMOR DRUG RESISTANCE  

PubMed Central

The development of resistance to variety of chemotherapeutic agents is one of the major challenges in effective cancer treatment. Tumor cells are able to generate a multi-drug resistance (MDR) phenotype due to microenvironmental selection pressures. This review addresses the use of nanotechnology-based delivery systems to overcome MDR in solid tumors. Our own work along with evidence from the literature illustrates the development of various types of engineered nanocarriers specifically designed to enhance tumor-targeted delivery through passive and active targeting strategies. Additionally, multi-functional nanocarriers are developed to enhance drug delivery and overcome MDR by either simultaneous or sequential delivery of resistance modulators (e.g., with P-glycoprotein substrates), agents that regulate intracellular pH, agents that lower the apoptotic threshold (e.g., with ceramide), or in combination with energy delivery (e.g., sound, heat, and light) to enhance the effectiveness of anticancer agents in refractory tumors. In preclinical studies, the use of multi-functional nanocarriers has shown significant promise in enhancing cancer therapy, especially against MDR tumors. PMID:18538481

Jabr-Milane, Lara S.; van Vlerken, Lilian E.; Yadav, Sunita; Amiji, Mansoor M.

2008-01-01

328

Pipecolic acid enhances resistance to bacterial infection and primes salicylic acid and nicotine accumulation in tobacco  

PubMed Central

Distinct amino acid metabolic pathways constitute integral parts of the plant immune system. We have recently identified pipecolic acid (Pip), a lysine-derived non-protein amino acid, as a critical regulator of systemic acquired resistance (SAR) and basal immunity to bacterial infection in Arabidopsis thaliana. In Arabidopsis, Pip acts as an endogenous mediator of defense amplification and priming. For instance, Pip conditions plants for effective biosynthesis of the phenolic defense signal salicylic acid (SA), accumulation of the phytoalexin camalexin, and expression of defense-related genes. Here, we show that tobacco plants respond to leaf infection by the compatible bacterial pathogen Pseudomonas syringae pv tabaci (Pstb) with a significant accumulation of several amino acids, including Lys, branched-chain, aromatic, and amide group amino acids. Moreover, Pstb strongly triggers, alongside the biosynthesis of SA and increases in the defensive alkaloid nicotine, the production of the Lys catabolites Pip and ?-aminoadipic acid. Exogenous application of Pip to tobacco plants provides significant protection to infection by adapted Pstb or by non-adapted, hypersensitive cell death-inducing P. syringae pv maculicola. Pip thereby primes tobacco for rapid and strong accumulation of SA and nicotine following bacterial infection. Thus, our study indicates that the role of Pip as an amplifier of immune responses is conserved between members of the rosid and asterid groups of eudicot plants and suggests a broad practical applicability for Pip as a natural enhancer of plant disease resistance. PMID:24025239

Vogel-Adghough, Drissia; Stahl, Elia; Navarova, Hana; Zeier, Jurgen

2013-01-01

329

CHEMICAL COMPOSITION AND HEAT RESISTANCE OF SOME AEROBIC BACTERIAL SPORES1  

PubMed Central

Walker, Homer W. (Iowa State University of Science and Technology, Ames), Jack R. Matches, and John C. Ayres. Chemical composition and heat resistance of some aerobic bacterial spores. J. Bacteriol. 82:960966. 1961.Analyses of spores of Bacillus species for nitrogen, carbohydrate, dipicolinic acid, and phosphorus showed little correlation with heat resistance. However, as the molar concentration of magnesium increased in relation to dipicolinic acid and calcium concentrations, heat resistance generally decreased. Analyses of several batches of spores indicated that this relationship between calcium, magnesium, and dipicolinic acid did not always hold true. Therefore, while these materials apparently play an important role, other factors need to be included before a full explanation of thermal stability of spores can be made. PMID:14004586

Walker, Homer W.; Matches, Jack R.; Ayres, John C.

1961-01-01

330

Numerical modeling of the transmission dynamics of drug-sensitive and drug-resistant HSV-2  

NASA Astrophysics Data System (ADS)

A competitive finite-difference method will be constructed and used to solve a modified deterministic model for the spread of herpes simplex virus type-2 (HSV-2) within a given population. The model monitors the transmission dynamics and control of drug-sensitive and drug-resistant HSV-2. Unlike the fourth-order Runge-Kutta method (RK4), which fails when the discretization parameters exceed certain values, the novel numerical method to be developed in this paper gives convergent results for all parameter values.

Gumel, A. B.

2001-03-01

331

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

332

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 hosts 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

333

Mechanisms of drug resistance in Mycobacterium tuberculosis and current status of rapid molecular diagnostic testing.  

PubMed

Drug-resistant tuberculosis has become a global problem and a major public health concern. While mechanisms of resistance are fairly well characterized for most agents, particularly the first line agents, our knowledge of drug resistance is by no means exhaustive, and strains continue to emerge that carry novel resistance-related mutations. The purpose of this review is to summarize our current understanding of the genetic basis of drug resistance in Mycobacterium tuberculosis, highlighting emerging areas of research. The development of rapid detection methods has been a major breakthrough in the fight against drug-resistant tuberculosis. Rapid detection methods are available for both rifampin- and isoniazid-resistant tuberculosis, but have yet to be developed for other first line agents. Rapid detection methods will become increasingly important as multi-drug resistant strains of M. tuberculosis become more prevalent, even for detecting tuberculosis that is resistant to second line agents. PMID:21515239

Laurenzo, David; Mousa, Shaker A

2011-07-01

334

Modulation of drug-metabolizing systems by bacterial endotoxin in carp liver and immune organs.  

PubMed

This report describes a study of the effects of bacterial endotoxin [lipopolysaccharide (LPS)] on cytochrome P450 levels and ethoxyresorufin O-deethylase (EROD) and glutathione S-transferase (GST) activities in liver and two main immune organs of carp: spleen and head kidney. Also studied was the paucity of the carp drug-metabolizing system in an environment subject to pollution by a polycyclic aromatic hydrocarbon, 3-methylcholanthrene (3MC), when fish respond to an immune activation by lipopolysaccharide (LPS). In the presence of bacterial endotoxin the basal cytochrome P450 levels were decreased in liver and spleen. EROD activity was increased in liver and basal GST activity was increased in spleen. When fish were treated concomitantly with 3MC and LPS, a suppression of cytochrome P450 induction in liver and head kidney was observed. EROD activity induced by 3MC was not modified by administration of LPS. GST activity was suppressed by treatment with LPS and inducing agent in liver and head kidney. In the present study it was found that endotoxin can have profound and differential effects on fish basal biotransformation of drugs in the liver and immune organs. Also, the induction of biotransformation enzymes by 3MC was modified when fish responded to an immune stimulation. PMID:9756707

Marionnet, D; Chambras, C; Taysse, L; Bosgireaud, C; Deschaux, P

1998-10-01

335

Biological and biochemical characterization of tunicamycin-resistant Leishmania mexicana: mechanism of drug resistance and virulence.  

PubMed Central

A parasitic protozoan, Leishmania mexicana amazonensis, was previously made resistant to tunicamycin (J.A. Kink and K.-P. Chang, Proc. Natl. Acad. Sci. USA 84:1253-1257, 1987). In the present study, six different tunicamycin-resistant variants were biologically and biochemically compared with their parental wild type to further delineate the mechanism of tunicamycin resistance and that of their virulence observed. In contrast to their parental wild type, all tunicamycin-resistant variants were found to grow and differentiate in tunicamycin-containing medium. The 50% lethal doses of tunicamycin for variants resistant to 10 or 80 micrograms of tunicamycin per ml were 20- and 100-fold higher, respectively, than that of the wild type. Specific activity of the microsomal N-acetylglucosamine-1-phosphate transferase was 4- to 12-fold higher in the tunicamycin-resistant cells than in their parental wild type and tunicamycin-sensitive revertants. The level of the enzyme activity is proportional to the degree of drug resistance. Inhibition kinetics studies showed that the enzyme from all groups was equally sensitive to the drug, with a 50% effective concentration of 1 to 1.3 micrograms of tunicamycin per ml. Thus, tunicamycin resistance of the variants is caused primarily by an increased level of their enzyme without alteration of its structure. Protein glycosylation determined by the incorporation of 2-D-[3H]mannose was about twofold higher in the tunicamycin-resistant variants than in their parental wild type. The increased glycosyltransferase activity in the latter apparently renders their protein glycosylation insensitive to the inhibition by tunicamycin. A major membrane glycoprotein of 63 kilodaltons (gp63) on the leishmania surface was found to be about threefold higher in the tunicamycin-resistant variants than in the wild type, as determined by immunoprecipitation with a monoclonal antibody specific for this antigen. Tunicamycin treatment of the wild type and tunicamycin-resistant variants caused changes in the electrophoretic mobility of this molecule, indicating a higher degree of its glycosylation in the latter cells. The tunicamycin-resistant variants parasitized macrophages in vitro more effectively than did the wild type, accounting for their virulence seen in mice. Thus, a high level of the glycosyltransferase enables the tunicamycin-resistant cells not only to overcome the inhibitory effect of tunicamycin on protein glycosylation but also to express their virulence, possibly by regulating N glycosylation of leishmanial proteins critical for leishmanias to establish intracellular parasitism. Images PMID:3036710

Kink, J A; Chang, K P

1987-01-01

336

Local anesthetic and antiepileptic drug access and binding to a bacterial voltage-gated sodium channel.  

PubMed

Voltage-gated sodium (Nav) channels are important targets in the treatment of a range of pathologies. Bacterial channels, for which crystal structures have been solved, exhibit modulation by local anesthetic and anti-epileptic agents, allowing molecular-level investigations into sodium channel-drug interactions. These structures reveal no basis for the "hinged lid"-based fast inactivation, seen in eukaryotic Nav channels. Thus, they enable examination of potential mechanisms of use- or state-dependent drug action based on activation gating, or slower pore-based inactivation processes. Multimicrosecond simulations of NavAb reveal high-affinity binding of benzocaine to F203 that is a surrogate for FS6, conserved in helix S6 of Domain IV of mammalian sodium channels, as well as low-affinity sites suggested to stabilize different states of the channel. Phenytoin exhibits a different binding distribution owing to preferential interactions at the membrane and water-protein interfaces. Two drug-access pathways into the pore are observed: via lateral fenestrations connecting to the membrane lipid phase, as well as via an aqueous pathway through the intracellular activation gate, despite being closed. These observations provide insight into drug modulation that will guide further developments of Nav inhibitors. PMID:25136136

Boiteux, Cline; Vorobyov, Igor; French, Robert J; French, Christopher; Yarov-Yarovoy, Vladimir; Allen, Toby W

2014-09-01

337

The Wag31 protein interacts with AccA3 and coordinates cell wall lipid permeability and lipophilic drug resistance in Mycobacterium smegmatis.  

PubMed

Mycobacterium tuberculosis, especially drug resistant tuberculosis, is a serious threat to global human health. Compared with other bacterial pathogens, M. tuberculosis gains stronger natural drug resistance from its unusually lipid-rich cell wall. As a DivIVA homolog, Wag31 has been demonstrated to be closely involved in peptidoglycan synthesis, cell growth and cell division. Previous research rarely investigated the role of Wag31 in drug resistance. In this study, we found Wag31 knock-down in Mycobacterium smegmatis resulted in a co-decrease of the resistance to four lipophilic drugs (rifampicin, novobiocin, erythromycin and clofazimine) and an increase in the cell permeability to lipophilic molecules. Six proteins (AccA3, AccD4 and AccD5, Fas, InhA and MmpL3) that are involved in fatty acid and mycolic acid synthesis were identified in the Wag31 interactome through Co-Immunoprecipitation. The Wag31-AccA3 interaction was confirmed by the pull-down assay. AccA3 overexpression resulted in a decrease in lipid permeability and an increase in the resistance of rifampicin and novobiocin. It confirmed the close relationship of lipophilic drug resistance, lipid permeability and the Wag31-AccA3 interaction. These results demonstrated that Wag31 maintained the resistance to lipophilic drugs and that Wag31 could play a role in controlling the lipid permeability of the cell wall through the Wag31-AccA3 interaction. PMID:24792177

Xu, Wen-xi; Zhang, Lu; Mai, Jun-tao; Peng, Ru-chao; Yang, En-zhuo; Peng, Chao; Wang, Hong-hai

2014-06-01

338

Comparative Resistance of AH26 and a New Sealer Prototype to a Bacterial Challenge  

PubMed Central

Objective. This study compared the leakage resistance of a New Sealer Prototype (NSP) with a traditional sealer (AH 26) in Resilon-filled roots subjected to a bacterial challenge. Study Design. 41 roots were instrumented to ISO size 50 apically. Group 1 (n = 20) contained Resilon and AH 26 sealer and roots in group 2 (n = 21) contained Resilon and NSP. Roots were embedded in a dual-chamber model with the upper chamber containing Streptococcus mutans inoculum. Evidence of bacterial penetration was observed for 1 month. Fisher's Test was used to analyze the data. Results. 8 of 20 roots (40%) in the AH 26 group demonstrated leakage whereas 3 of 21 roots (14%) in the NSP group leaked. The difference in leakage rates was not statistically significant (P = 0.053). Conclusion. The traditional sealer (AH 26) demonstrated increased leakage rates compared to the New Sealer Prototype (NSP), but the difference did not reach statistical significance in this study. PMID:22505898

Duggan, Derek; Zhong, Sheng; Rivera, Eric; Arnold, Roland; Simmons, Eric

2012-01-01

339

Plasmonic Nanobubbles Rapidly Detect and Destroy Drug-Resistant Tumors  

PubMed Central

The resistance of residual cancer cells after oncological resection to adjuvant chemoradiotherapies results in both high recurrence rates and high non-specific tissue toxicity, thus preventing the successful treatment of such cancers as head and neck squamous cell carcinoma (HNSCC). The patients' survival rate and quality of life therefore depend upon the efficacy, selectivity and low non-specific toxicity of the adjuvant treatment. We report a novel, theranostic in vivo technology that unites both the acoustic diagnostics and guided intracellular delivery of anti-tumor drug (liposome-encapsulated doxorubicin, Doxil) in one rapid process, namely a pulsed laser-activated plasmonic nanobubble (PNB). HNSCC-bearing mice were treated with gold nanoparticle conjugates, Doxil, and single near-infrared laser pulses of low energy. Tumor-specific clusters of gold nanoparticles (solid gold spheres) converted the optical pulses into localized PNBs. The acoustic signals of the PNB detected the tumor with high specificity and sensitivity. The mechanical impact of the PNB, co-localized with Doxil liposomes, selectively ejected the drug into the cytoplasm of cancer cells. Cancer cell-specific generation of PNBs and their intracellular co-localization with Doxil improved the in vivo therapeutic efficacy from 5-7% for administration of only Doxil or PNBs alone to 90% thus demonstrating the synergistic therapeutic effect of the PNB-based intracellular drug release. This mechanism also reduced the non-specific toxicity of Doxil below a detectable level and the treatment time to less than one minute. Thus PNBs combine highly sensitive diagnosis, overcome drug resistance and minimize non-specific toxicity in a single rapid theranostic procedure for intra-operative treatment. PMID:23139725

Lukianova-Hleb, Ekaterina Y.; Ren, Xiaoyang; Townley, Debra; Wu, Xiangwei; Kupferman, Michael E.; Lapotko, Dmitri O.

2012-01-01

340

Emergence of Extensively Drug-Resistant Haemophilus parainfluenzae in Switzerland  

PubMed Central

Two homosexual men were colonized in the urethra with Haemophilus parainfluenzae nonsusceptible to ampicillin (MIC, 8 ?g/ml), amoxicillin-clavulanate (MIC, 4 ?g/ml), cefotaxime (MIC, 1.5 ?g/ml), cefepime (MIC, 3 ?g/ml), meropenem (MIC, 0.5 ?g/ml), cefuroxime, azithromycin, ciprofloxacin, tetracycline, and chloramphenicol (all MICs, ?32 ?g/ml). Repetitive extragenic palindromic PCR (rep-PCR) showed that the strains were indistinguishable. The isolates had amino acid substitutions in PBP3, L4, GyrA, and ParC and possessed Mef(A), Tet(M), and CatS resistance mechanisms. This is the first report of extensively drug-resistant (XDR) H. parainfluenzae. PMID:23545526

Tinguely, Regula; Seiffert, Salome N.; Furrer, Hansjakob; Perreten, Vincent; Droz, Sara

2013-01-01

341

The effect of continuous drug exposure on the immune response of lambs challenged with drug-susceptible or drug-resistant nematode larvae  

Microsoft Academic Search

Groups of lambs either with or without controlled-release albendazole (ABZ) capsules (CRCs) were challenged twice weekly for 6 weeks with either drug-susceptible or drug-resistant Ostertagia circumcincta and Trichostrongylus colubriformis. Groups with and without CRCs remained unchallenged as controls. There was minimal establishment of drug-susceptible parasites of either species in those lambs with CRCs. However, drug-resistant parasites of both species established

I. A. Sutherland; D. M. Leathwick; R. S. Green; C. M. Miller; A. E. Brown

1998-01-01

342

Role of mTOR in anticancer drug resistance: Perspectives for improved drug treatment  

Microsoft Academic Search

The mammalian target of rapamycin (mTOR) pathway plays a central role in regulating protein synthesis, ribosomal protein translation, and cap-dependent translation. Deregulations in mTOR signaling are frequently associated with tumorigenesis, angiogenesis, tumor growth and metastasis. This review highlights the role of the mTOR in anticancer drug resistance. We discuss the network of signaling pathways in which the mTOR kinase is

Bing-Hua Jiang; Ling-Zhi Liu

2008-01-01

343

Deciphering an Outbreak of Drug-Resistant Mycobacterium tuberculosis  

PubMed Central

There have been ample warnings that multidrug-resistant (MDR) tuberculosis (TB) will continue to emerge if countries do not strengthen their control of TB. In low-incidence European countries, however, these warnings have been substantiated mainly by outbreaks in association with human immunodeficiency virus (HIV)-positive patients. The aim of this study was to investigate an outbreak of infection with MDR and drug-resistant Mycobacterium tuberculosis that was diagnosed among 20 HIV-negative patients living in Norway. Of these, 19 were immigrants from East Africa and one was an ethnic Norwegian. We wanted to find out if transmission had taken place in Norway or abroad and to identify the genetic basis of drug resistance. The strains were analyzed by IS6110 restriction fragment length polymorphism, antibiotic susceptibility tests, spoligotyping, reverse hybridization to regions of the rpoB gene, and sequencing of the katG gene. Epidemiological links between the patients were mapped, and the strains were compared to those isolated in 36 other countries and regions. All strains were resistant to isoniazid and carried Ala234Gly, Ser315Thr, and Arg463Leu substitutions in the katG gene. Eleven strains were MDR and carried a Ser531Leu substitution in the rpoB gene. MDR was acquired in the index patient after arrival in Norway. Links were found among 14 patients. The strain was imported from Somalia but acquired MDR and was transmitted in Norway. This demonstrated that MDR strains are not necessarily imported from high-incidence countries and can be highly communicable. The outbreak underscores a deficiency in the TB control measures employed in many countries and challenges the adequacy of the policy of screening immigrants for TB only on arrival. PMID:12517827

Dahle, Ulf R.; Sandven, Per; Heldal, Einar; Mannsaaker, Turid; Caugant, Dominique A.

2003-01-01

344

New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance.  

E-print Network

of drug resistance. These include simplified nucleic aciddrug resistance. Diagnostics for active tuberculosis Nucleic aciddrug resistance. For diagnosis, new tools include newer versions of nucleic acid

Pai, Madhukar; Kalantri, Shriprakash; Dheda, Keertan

2006-01-01

345

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

346

In vitro evaluation of the risk of inducing bacterial resistance to disinfection treatment with photolysis of hydrogen peroxide.  

PubMed

The purpose of the present study was to evaluate the risk of inducing bacterial resistance to disinfection treatment with photolysis of H2O2 and comparing this with existing antibacterial agents. We tested seven antibacterial agents, including amoxicillin, cefepime hydrochloride, erythromycin, ofloxacin, clindamycin hydrochloride, ciprofloxacin hydrochloride, and minocycline hydrochloride, as positive controls for validation of the assay protocol. For all of the agents tested, at least one of the four bacterial species (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Streptococcus salivarius) was resistant to these agents by repeated exposure to subinhibitory concentrations of the agents up to 10 times. In contrast, antibacterial activity against any of the bacterial species tested (S. aureus, E. faecalis, E. coli, S. salivarius, Pseudomonas aeruginosa, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans) was not affected by repeated exposure to the disinfection treatment up to 40 times. This finding suggested that the risk of inducing bacterial resistance by disinfection treatment was low. The active ingredient of this disinfection treatment is hydroxyl radicals generated by photolysis of H2O2. Therefore, hydroxyl radicals interact with several cell structures and different metabolic pathways in microbial cells, probably resulting in a lack of development of bacterial resistance. In conclusion, disinfection treatment with photolysis of H2O2 appears to be a potential alternative for existing antimicrobial agents in terms of a low risk of inducing bacterial resistance. PMID:24282582

Ikai, Hiroyo; Odashima, Yu; Kanno, Taro; Nakamura, Keisuke; Shirato, Midori; Sasaki, Keiichi; Niwano, Yoshimi

2013-01-01

347

In Vitro Evaluation of the Risk of Inducing Bacterial Resistance to Disinfection Treatment with Photolysis of Hydrogen Peroxide  

PubMed Central

The purpose of the present study was to evaluate the risk of inducing bacterial resistance to disinfection treatment with photolysis of H2O2 and comparing this with existing antibacterial agents. We tested seven antibacterial agents, including amoxicillin, cefepime hydrochloride, erythromycin, ofloxacin, clindamycin hydrochloride, ciprofloxacin hydrochloride, and minocycline hydrochloride, as positive controls for validation of the assay protocol. For all of the agents tested, at least one of the four bacterial species (Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, and Streptococcus salivarius) was resistant to these agents by repeated exposure to subinhibitory concentrations of the agents up to 10 times. In contrast, antibacterial activity against any of the bacterial species tested (S. aureus, E. faecalis, E. coli, S. salivarius, Pseudomonas aeruginosa, Streptococcus mutans, and Aggregatibacter actinomycetemcomitans) was not affected by repeated exposure to the disinfection treatment up to 40 times. This finding suggested that the risk of inducing bacterial resistance by disinfection treatment was low. The active ingredient of this disinfection treatment is hydroxyl radicals generated by photolysis of H2O2. Therefore, hydroxyl radicals interact with several cell structures and different metabolic pathways in microbial cells, probably resulting in a lack of development of bacterial resistance. In conclusion, disinfection treatment with photolysis of H2O2 appears to be a potential alternative for existing antimicrobial agents in terms of a low risk of inducing bacterial resistance. PMID:24282582

Ikai, Hiroyo; Odashima, Yu; Kanno, Taro; Nakamura, Keisuke; Shirato, Midori; Sasaki, Keiichi; Niwano, Yoshimi

2013-01-01

348

Please cite this article in press as: Duesberg, P. et al., Cancer drug resistance: The central role of the karyotype, Drug Resist. Updat. (2007), doi:10.1016/j.drup.2007.02.003  

E-print Network

Please cite this article in press as: Duesberg, P. et al., Cancer drug resistance: The central role8 Drug Resistance Updates xxx (2007) xxx­xxx Cancer drug resistance: The central role 5 February 2007 Abstract Current genetic and epigenetic theories of cancer-specific drug resistance

Duesberg, Peter

349

Bacteriological profile and antimicrobial resistance patterns of clinical bacterial isolates in a University Hospital.  

PubMed

The objective of this study was to determine the patterns of bacterial isolates found in blood culture of patients with bactermia in King Abdul Aziz University Hospital in addition to determination of antibiotic resistance. A retrospective analysis of the 672 positive samples collected over the period of December 2006-December 2008. The observed mean age was 40 years with comparable distribution in both genders. 65.2% of the population were Non-Saudi. 65.5% of isolates were Gram positive, mainly Staphylococcus epidermidis, on the other hand Klebsiella was the common Gram negative bacteria. Diabetes has been observed in 38.5%. Mortality was 32.4 (P-value 0.001) in diabetic patients versus non-diabetics. Benzyl penicillin, clindamycin, erythromycin, tetracycline, ciprofloxacin, oxacillin caused resistance to more than 50% of Gram positive organisms whereas antimicrobial resistance to ampicillin, nitrofurantoin, levofloxacin, piperacillin, cefuroxime and cefuroxime was found in Gram negative isolates. To conclude vancomycin, teicoplanin, linizolid, and piperacillin/tazobactam, were effective antimicrobial agents against the majority of bacterial isolates. Gram positive organisms are the common cause of bactermia. The highest risk of mortality is associated with Streptococcus pyogenes. PMID:19717107

Ahmed, Maimoonaa Mushtaq; Bahlas, Sami

2009-07-01

350

PHACOS, a functionalized bacterial polyester with bactericidal activity against methicillin-resistant Staphylococcus aureus.  

PubMed

Biomaterial-associated infections represent a significant clinical problem, and treatment of these microbial infections is becoming troublesome due to the increasing number of antibiotic-resistant strains. Here, we report a naturally functionalized bacterial polyhydroxyalkanoate (PHACOS) with antibacterial properties. We demonstrate that PHACOS selectively and efficiently inhibits the growth of methicillin-resistant Staphylococcus aureus (MRSA) both in vitro and in vivo. This ability has been ascribed to the functionalized side chains containing thioester groups. Significantly less (3.2-fold) biofilm formation of S. aureus was detected on PHACOS compared to biofilms formed on control poly(3-hydroxyoctanoate-co-hydroxyhexanoate) and poly(ethylene terephthalate), but no differences were observed in bacterial adhesion among these polymers. PHACOS elicited minimal cytotoxic and inflammatory effects on murine macrophages and supported normal fibroblast adhesion. In vivo fluorescence imaging demonstrated minimal inflammation and excellent antibacterial activity for PHACOS compared to controls in an in vivo model of implant-associated infection. Additionally, reductions in neutrophils and macrophages in the vicinity of sterile PHACOS compared to sterile PHO implant were observed by immunohistochemistry. Moreover, a similar percentage of inflammatory cells was found in the tissue surrounding sterile PHACOS and S. aureus pre-colonized PHACOS implants, and these levels were significantly lower than S. aureus pre-colonized control polymers. These findings support a contact active surface mode of antibacterial action for PHACOS and establish this functionalized polyhydroxyalkanoate as an infection-resistant biomaterial. PMID:24094939

Dinjaski, Nina; Fernndez-Gutirrez, Mar; Selvam, Shivaram; Parra-Ruiz, Francisco J; Lehman, Susan M; San Romn, Julio; Garca, Ernesto; Garca, Jos L; Garca, Andrs J; Prieto, Mara Auxiliadora

2014-01-01

351

In vitro antimicrobial activity of Nigella sativa oil agains t multi-drug resistant bacteria  

Microsoft Academic Search

Abstract: An alarming increase in bacterial strains resistant to existing antimicrobial agents demands,a renewed effort to seek agents effective against pathogenic bacteria resistant to current antimicrobials. Nigella sativa L. essential oil was studied for antibacterial activity against various clinical isolates of bacteria resistant to a number of antibiotics, in varying concentrations by Disc Agar diffusion technique using impregnated filter paper

Mohd Tariq Salman; Rahat Ali Khan; Indu Shukla

352

Role of intratumoural heterogeneity in cancer drug resistance: molecular and clinical perspectives  

PubMed Central

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential. PMID:22733553

Saunders, Nicholas A; Simpson, Fiona; Thompson, Erik W; Hill, Michelle M; Endo-Munoz, Liliana; Leggatt, Graham; Minchin, Rodney F; Guminski, Alexander

2012-01-01

353

New insights in the bacterial spore resistance to extreme terrestrial and extraterrestrial factors  

NASA Astrophysics Data System (ADS)

Based on their unique resistance to various space parameters, Bacillus endospores are one of the model systems used for astrobiological studies. The extremely high resistance of bacterial endospores to environmental stress factors has intrigued researchers since long time and many characteristic spore features, especially those involved in the protection of spore DNA, have already been uncovered. The disclosure of the complete genomic sequence of Bacillus subtilis 168, one of the often used astrobiological model system, and the rapid development of tran-scriptional microarray techniques have opened new opportunities of gaining further insights in the enigma of spore resistance. Spores of B. subtilis were exposed to various extreme ter-restrial and extraterrestrial stressors to reach a better understanding of the DNA protection and repair strategies, which them to cope with the induced DNA damage. Following physical stress factors of environmental importance -either on Earth or in space -were selected for this thesis: (i) mono-and polychromatic UV radiation, (ii) ionizing radiation, (iii) exposure to ultrahigh vacuum; and (iv) high shock pressures simulating meteorite impacts. To reach a most comprehensive understanding of spore resistance to those harsh terrestrial or simulated extraterrestrial conditions, a standardized experimental protocol of the preparation and ana-lyzing methods was established including the determination of the following spore responses: (i) survival, (ii) induced mutations, (iii) DNA damage, (iv) role of different repair pathways by use of a set of repair deficient mutants, and (v) transcriptional responses during spore germi-nation by use of genome-wide transcriptome analyses and confirmation by RT-PCR. From this comprehensive set of data on spore resistance to a variety of environmental stress parameters a model of a "built-in" transcriptional program of bacterial spores in response to DNA damaging treatments to ensure DNA restoration during germination has been developed.

Moeller, Ralf; Horneck, Gerda; Reitz, Guenther

354

Predicting bacterial resistance using the time inside the mutant selection window: Possibilities and limitations.  

PubMed

The time inside the mutant selection window (TMSW) has been shown to be less predictive of selection of fluoroquinolone-resistant bacteria than the ratio of the area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC). To explore the different predictive powers of TMSW and AUC/MIC, enrichment of ciprofloxacin-resistant mutants of four Escherichia coli strains was studied in an in vitro dynamic model at widely ranging TMSW values. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Peak antibiotic concentrations were simulated to be close to the MIC, between the MIC and the mutant prevention concentration (MPC), and above the MPC, with TMSW varying from 0% to 100% of the dosing interval. Amplification of resistant mutants was monitored by plating on medium with 8 MIC of the antibiotic. For each organism, TMSW plots of the area under the bacterial mutant concentration-time curve (AUBCM) exhibited a hysteresis loop: at a given TMSW that corresponds to the points on the ascending portion of the bell-shaped AUBCM-AUC/MIC curve [when the time above the MPC (T>MPC) was zero], the AUBCM was greater than at the same TMSW related to the descending portion (T>MPC>0). A sigmoid function fits these separate data sets well for combined data with the four organisms (r(2)=0.81 and 0.92, respectively), in contrast to fitting the whole data pool while ignoring the AUC/MIC-resistance relationship (r(2)=0.61). These data allow the appropriate use of TMSW as a predictor of bacterial resistance. PMID:25218155

Firsov, Alexander A; Portnoy, Yury A; Strukova, Elena N; Shlykova, Darya S; Zinner, Stephen H

2014-10-01

355

Retrovirus-mediated transfer and expression of drug resistance genes in human haematopoietic progenitor cells.  

PubMed

Patients with certain genetic disorders can be cured by bone marrow transplantation. However, as prospective donors do not exist for most patients with potentially curable genetic abnormalities, an alternative treatment for such patients involves the transfer of cloned genes into the patient's haematopoietic stem cells followed by re-infusion of the treated cells. Retroviral vectors provide an efficient means for transferring genes into mammalian cells and have been used to transfer genes into mouse haematopoietic cells. We have now produced amphotropic retroviral vectors containing either the bacterial gene for neomycin resistance or a mutant dihydrofolate reductase gene that confers resistance to methotrexate and have used these vectors to infect and confer drug resistance to human haematopoietic progenitor cells in vitro. Transfer could be demonstrated in the absence of helper virus by using an amphotropic retrovirus packaging cell line, PA12 (ref. 9). These studies are an important step towards the eventual application of retrovirus-mediated gene transfer to human gene therapy and for molecular approaches to the study of human haematopoiesis. PMID:3960109

Hock, R A; Miller, A D

356

Standing Genetic Variation and the Evolution of Drug Resistance in HIV  

E-print Network

different situations in which HIV drug resistance may evolve: starting triple-drug therapy, treatment therapy, we find that drug resistance evolves from standing genetic variation in approximately 6 Pennings. This is an open-access article distributed under the terms of the Creative Commons Attribution

357

Extensively Drug-Resistant Streptococcus pneumoniae, South Korea, 20112012  

PubMed Central

To better understand extensively drug resistant Streptococcus pneumoniae, we assessed clinical and microbiological characteristics of 5 extensively drug-resistant pneumococcal isolates. We concluded that long-term care facility residents who had undergone tracheostomy might be reservoirs of these pneumococci; 13- and 23-valent pneumococcal vaccines should be considered for high-risk persons; and antimicrobial drugs should be used judiciously. PMID:24750694

Cho, Sun Young; Baek, Jin Yang; Kim, So Hyun; Ha, Young Eun; Chung, Doo Ryeon; Lee, Nam Yong; Peck, Kyong Ran; Song, Jae-Hoon

2014-01-01

358

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

359

Protein, cell and bacterial fouling resistance of polypeptoid-modified surfaces: effect of side-chain chemistry{  

E-print Network

on short-term and long-term protein, cell and bacterial fouling resistance. Introduction Biofouling of biofouling include accumulation of proteins and cells on biosensor surfaces,1 stents and cardiovascular and cells, long- term biofouling resistance remains a challenge. We recently reported the design

360

Genetic mapping reveals a single major QTL for bacterial wilt resistance in Italian ryegrass ( Lolium multiflorum Lam.)  

Microsoft Academic Search

Bacterial wilt caused by Xanthomonas translucens pv. graminis (Xtg) is a major disease of economically important forage crops such as ryegrasses and fescues. Targeted breeding based on seedling inoculation has resulted in cultivars with considerable levels of resistance. However, the mechanisms of inheritance of resistance are poorly understood and further breeding progress is difficult to obtain. This study aimed to

Bruno Studer; Beat Boller; Doris Herrmann; Eva Bauer; Ulrich K. Posselt; Franco Widmer; Roland Klliker

2006-01-01

361

Nosocomial Infections and Multidrug-Resistant Bacterial Organisms in the Pediatric Intensive Care Unit  

Microsoft Academic Search

Nosocomial infections in Pediatric Intensive Care Units (PICUs) caused by multidrug-resistant bacterial organisms are increasing.\\u000a This review attempts to report on significant findings in the current literature related to nosocomial infections in PICU\\u000a settings with an international perspective. The types of nosocomial infections are addressed, including catheter-related bloodstream\\u000a infections, ventilator-associated pneumonia, urinary tract infections, gastrointestinal infections and post-surgical wound\\u000a infections.

Eric J. McGrath; Basim I. Asmar

2011-01-01

362

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

PubMed Central

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 University 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, followed by Staphylococcus aureus and Pseudomonas aeruginosa. Candida species also increased in importance as bloodstream infection isolates, from 1.0% in 1981-1986 to 16.2% in 1999. The most frequent isolates from urinary tract infections were Candida species (23.6%), followed by Escherichia coli (18.6%) and P. aeruginosa (11.0%). P. aeruginosa remained the most frequent isolates for respiratory tract and surgical site infections in the past 13 years. A remarkable increase in incidence was found in methicillin-resistant S. aureus (from 4.3% in 1981-1986 to 58.9% in 1993-1998), cefotaxime-resistant E. coli (from 0% in 1981-1986 to 6.1% in 1993-1998), and cefotaxime-resistant Klebsiella pneumoniae (from 4.0% in 1981-1986 to 25.8% in 1993-1998). Etiologic shifts in nosocomial infections and an upsurge of antimicrobial resistance among these pathogens, particularly those isolated from intensive care units, are impressive and alarming. PMID:11749750

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

2002-01-01

363

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy  

E-print Network

The evolution of drug resistance and the curious orthodoxy of aggressive chemotherapy Andrew F. antibiotic resistance | evolutionary medicine | Plasmodium | patient treatment regimens | long-course chemotherapy The evolution of drug-resistant pathogens significantly affects human well-being and health

Read, Andrew

364

Drug Resistance Mechanisms in Entamoeba histolytica, Giardia lamblia, Trichomonas vaginalis , and Opportunistic Anaerobic Protozoa  

Microsoft Academic Search

Resistance of organisms to toxic agents is a survival mechanism fundamental for adaptation and evolution of life. As a counterpart,\\u000a drug resistance is a medical problem in cancer and infectious diseases, with not many alternatives available. Entamoeba histolytica, Giardia lamblia (syn. duodenalis or intestinalis), and Trichomonas vaginalis (Fig. 1) are anaerobic and microaerophilic pathogens capable of developing drug resistance. Over

Esther Orozco; Laurence A. Marchat; Consuelo Gmez; Csar Lpez-Camarillo; D. Guillermo Prez

365

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

E-print Network

and bactericidal activities against the important human pathogen methicillin-resis- tant Staphylococcus aureus, vancomycin-resistant Enterococcus faecalis (VRE), and two Gram-negative bacterial species. At least 20 in the preeminent Gram-positive bacterial pathogen Staphylococcus aureus, which is increasingly unresponsive

Nizet, Victor

366

Antimalarial drug resistance: a review of the biology and strategies to delay emergence and spread  

PubMed Central

The emergence of resistance to former first-line antimalarial drugs has been an unmitigated disaster. In recent years, artemisinin class drugs have become standard and they are considered an essential tool for helping to eradicate the disease. However, their ability to reduce morbidity and mortality and to slow transmission requires the maintenance of effectiveness. Recently, an artemisinin delayed-clearance phenotype was described. This is believed to be the precursor to resistance and threatens local elimination and global eradication plans. Understanding how resistance emerges and spreads is important for developing strategies to contain its spread. Resistance is the result of two processes: (i) drug selection of resistant parasites; and (ii) the spread of resistance. In this review, we examine the factors that lead to both drug selection and the spread of resistance. We then examine strategies for controlling the spread of resistance, pointing out the complexities and deficiencies in predicting how resistance will spread. PMID:23394809

Klein, E.Y.

2013-01-01

367

Active wound dressings based on bacterial nanocellulose as drug delivery system for octenidine.  

PubMed

Although bacterial nanocellulose (BNC) may serve as an ideal wound dressing, it exhibits no antibacterial properties by itself. Therefore, in the present study BNC was functionalized with the antiseptic drug octenidine. Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Octenidine release was based on diffusion and swelling according to the Ritger-Peppas equation and characterized by a time dependent biphasic release profile, with a rapid release in the first 8h, followed by a slower release rate up to 96 h. The comparison between lab-scale and up-scale BNC identified thickness, water content, and the surface area to volume ratio as parameters which have an impact on the control of the release characteristics. Compression and tensile strength remained unchanged upon incorporation of octenidine in BNC. In biological assays, drug-loaded BNC demonstrated high biocompatibility in human keratinocytes and antimicrobial activity against Staphylococcus aureus. In a long-term storage test, the octenidine loaded in BNC was found to be stable, releasable, and biologically active over a period of 6 months without changes. In conclusion, octenidine loaded BNC presents a ready-to-use wound dressing for the treatment of infected wounds that can be stored over 6 months without losing its antibacterial activity. PMID:24792978

Moritz, Sebastian; Wiegand, Cornelia; Wesarg, Falko; Hessler, Nadine; Mller, Frank A; Kralisch, Dana; Hipler, Uta-Christina; Fischer, Dagmar

2014-08-25

368

Prevalence of antibacterial resistant bacterial contaminants from mobile phones of hospital inpatients  

PubMed Central

Mobile phones contaminated with bacteria may act as fomites. Antibiotic resistant bacterial contamination of mobile phones of inpatients was studied. One hundred and six samples were collected from mobile phones of patients admitted in various hospitals in Jazan province of Saudi Arabia. Eighty-nine (83.9%) out of 106 mobile phones were found to be contaminated with bacteria. Fifty-two (49.0%) coagulase-negative Staphylococcus, 12 (11.3%) Staphylococcus aureus, 7 (6.6%) Enterobacter cloacae, 3 (2.83%) Pseudomonas stutzeri, 3 (2.83%) Sphingomonas paucimobilis, 2 (1.8%) Enterococcus faecalis and 10 (9.4%) aerobic spore bearers were isolated. All the isolated bacteria were found to be resistant to various antibiotics. Hence, regular disinfection of mobile phones of hospital inpatients is advised. PMID:25292217

Vinod Kumar, B.; Hobani, Yahya Hasan; Abdulhaq, Ahmed; Jerah, Ahmed Ali; Hakami, Othman M.; Eltigani, Magdeldin; Bidwai, Anil K.

2014-01-01

369

Prevalence of antibacterial resistant bacterial contaminants from mobile phones of hospital inpatients.  

PubMed

Mobile phones contaminated with bacteria may act as fomites. Antibiotic resistant bacterial contamination of mobile phones of inpatients was studied. One hundred and six samples were collected from mobile phones of patients admitted in various hospitals in Jazan province of Saudi Arabia. Eighty-nine (83.9%) out of 106 mobile phones were found to be contaminated with bacteria. Fifty-two (49.0%) coagulase-negative Staphylococcus, 12 (11.3%) Staphylococcus aureus, 7 (6.6%) Enterobacter cloacae, 3 (2.83%) Pseudomonas stutzeri, 3 (2.83%) Sphingomonas paucimobilis, 2 (1.8%) Enterococcus faecalis and 10 (9.4%) aerobic spore bearers were isolated. All the isolated bacteria were found to be resistant to various antibiotics. Hence, regular disinfection of mobile phones of hospital inpatients is advised. PMID:25292217

Vinod Kumar, B; Hobani, Yahya Hasan; Abdulhaq, Ahmed; Jerah, Ahmed Ali; Hakami, Othman M; Eltigani, Magdeldin; Bidwai, Anil K

2014-01-01

370

Triclosan Derivatives: Towards Potent Inhibitors of Drug-Sensitive and Drug-Resistant Mycobacterium tuberculosis  

SciTech Connect

Isoniazid (INH) is a frontline antitubercular drug that inhibits the enoyl acyl carrier protein reductase InhA. Novel inhibitors of InhA that are not cross-resistant to INH represent a significant goal in antitubercular chemotherapy. The design, synthesis, and biological activity of a series of triclosan-based inhibitors is reported, including their promising efficacy against INH-resistant strains of M. tuberculosis. Triclosan has been previously shown to inhibit InhA, an essential enoyl acyl carrier protein reductase involved in mycolic acid biosynthesis, the inhibition of which leads to the lysis of Mycobacterium tuberculosis. Using a structure-based drug design approach, a series of 5-substituted triclosan derivatives was developed. Two groups of derivatives with alkyl and aryl substituents, respectively, were identified with dramatically enhanced potency against purified InhA. The most efficacious inhibitor displayed an IC{sub 50} value of 21 nM, which was 50-fold more potent than triclosan. X-ray crystal structures of InhA in complex with four triclosan derivatives revealed the structural basis for the inhibitory activity. Six selected triclosan derivatives were tested against isoniazid-sensitive and resistant strains of M. tuberculosis. Among those, the best inhibitor had an MIC value of 4.7 {mu}g mL{sup -1} (13 {mu}M), which represents a tenfold improvement over the bacteriocidal activity of triclosan. A subset of these triclosan analogues was more potent than isoniazid against two isoniazid-resistant M. tuberculosis strains, demonstrating the significant potential for structure-based design in the development of next generation antitubercular drugs.

Freundlich, Joel S.; Wang, Feng; Vilchze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, Jr., William R.; Sacchettini, James C.; (Einstein); (TAM); (Jacobus)

2009-06-30

371

Role of Breast Cancer Resistance Protein (BCRP/ABCG2) in Cancer Drug Resistance  

PubMed Central

Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed side population cells, which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the side population phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured. PMID:22248732

Natarajan, Karthika; Xie, Yi; Baer, Maria R.; Ross, Douglas D.

2012-01-01

372

High catalytic efficiency and resistance to denaturing in bacterial Rho GTPase-activating proteins.  

PubMed

Several major bacterial pathogens use the type III secretion system (TTSS) to deliver virulence factors into host cells. Bacterial Rho GTPase activating proteins (RhoGAPs) comprise a remarkable family of type III secreted toxins that modulate cytoskeletal dynamics and manipulate cellular signaling pathways. We show that the RhoGAP activity of Salmonella SptP and Pseudomonas ExoS toxins is resistant to variations in the concentration of NaCl or MgCl(2), unlike the known salt dependant nature of the activity of some eukaryotic GAPs such as p190, RanGAP and p120GAP. Furthermore, SptP-GAP and ExoS-GAP display full activity after treatment at 80C or with 6 m urea, which suggests that these protein domains are capable of spontaneous folding into an active state following denaturing such as what might occur upon transit through the TTSS needle. We determined the catalytic activity of bacterial GAPs for Rac1, CDC42 and RhoA GTPases and found that ExoS, in addition to Yersinia YopE and Aeromonas AexT toxins, display higher catalytic efficiencies for Rac1 and CDC42 than the known eukaryotic GAPs, making them the most catalytically efficient RhoGAPs known. This study expands our knowledge of the mechanism of action of GAPs and of the ways bacteria mimic host activities and promote catalysis of eukaryotic signaling proteins. PMID:21534865

Litvak, Yael; Levin-Klein, Rena; Avner, Moti; Selinger, Zvi

2011-04-01

373

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

PubMed

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 aureus was then inoculated into the middle ears. An additional 8 guinea pigs were used as controls; the PE tubes were inserted without middle ear inoculation. All PE tubes were removed on day 10 and analyzed for bacterial contamination using culture, immunofluorescence, and scanning electron microscopy (SEM). All infected ears developed otitis media with otorrhea, but none of the animal control ears drained. Fluorescence imaging of the animal control tubes showed large cellular components consistent with inflammation. The infected tubes showed heavy DNA fluorescence consistent with bacteria and inflammatory cells. All animal control tubes except the ion-bombarded silicone tubes showed adherent inflammatory film on SEM. Also, all tubes placed in infected ears except the ion-bombarded silicone tubes showed adherent bacterial and inflammatory films on SEM. Nonadherent surface properties such as the ion-bombarded silicone may be helpful in preventing chronic PE tube contamination. PMID:10229584

Saidi, I S; Biedlingmaier, J F; Whelan, P

1999-05-01

374

Populational adaptive evolution, chemotherapeutic resistance and multiple anti-cancer therapies  

E-print Network

Populational adaptive evolution, chemotherapeutic resistance and multiple anti-cancer therapies resistant to the drug(s). This may occur either because of evolution independent of drug(s), or because agriculture pest resistance to toxic crops [31, 45], bacterial resistance to antibiotics [1], mosquito

375

QSAR Study of -Lactam Antibiotic Efflux by the Bacterial Multidrug Resistance Pump AcrB Mrcia Miguel Castro Ferreira (PQ) and Rudolf Kiralj (PQ)  

E-print Network

QSAR Study of -Lactam Antibiotic Efflux by the Bacterial Multidrug Resistance Pump AcrB Márcia antibiotics (penicillins and cephalosporins) as substrates of multidrug resistance efflux membrane pump Acr M. M. C., Kiralj R., "QSAR study of -lactam antibiotic efflux by the bacterial multidrug resistance

Ferreira, Márcia M. C.

376

Clonal Composition and Community Clustering of Drug-Susceptible and -Resistant Escherichia coli Isolates from Bloodstream Infections  

PubMed Central

Multidrug-resistant Escherichia coli strains belonging to a single lineage frequently account for a large proportion of extraintestinal E. coli infections in many parts of the world. However, limited information exists on the community prevalence and clonal composition of drug-susceptible E. coli strains. Between July 2007 and September 2010, we analyzed all consecutively collected Gram-negative bacterial isolates from patients with bloodstream infection (BSI) admitted to a public hospital in San Francisco for drug susceptibility and associated drug resistance genes. The E. coli isolates were genotyped for fimH single nucleotide polymorphisms (SNPs) and multilocus sequence types (MLSTs). Among 539 isolates, E. coli accounted for 249 (46%); 74 (30%) of them were susceptible to all tested drugs, and 129 (52%) were multidrug resistant (MDR). Only five MLST genotypes accounted for two-thirds of the E. coli isolates; the most common were ST131 (23%) and ST95 (18%). Forty-seven (92%) of 51 ST131 isolates, as opposed to only 8 (20%) of 40 ST95 isolates, were MDR (P < 0.0001). The Simpson's diversity index for drug-susceptible ST genotypes was 87%, while the index for MDR ST genotypes was 81%. ST95 strains were comprised of four fimH types, and one of these (f-6) accounted for 67% of the 21 susceptible isolates (P < 0.003). A large proportion (>70%) of both MDR and susceptible E. coli BSI isolates represented community-onset infections. These observations show that factors other than the selective pressures of antimicrobial agents used in hospitals contribute to community-onset extraintestinal infections caused by clonal groups of E. coli regardless of their drug resistance. PMID:23147723

Adams-Sapper, Sheila; Diep, Binh An; Perdreau-Remington, Francoise

2013-01-01

377

Mycobacterium tuberculosis complex drug resistance pattern and identification of species causing tuberculosis in the West and Centre regions of Cameroon  

PubMed Central

Background Data on the levels of resistance of Mycobacterium tuberculosis complex (MTBC) strains to first line anti-tuberculosis drugs in Cameroon, and on the species of MTBC circulating in the country are obsolete. The picture about 10 years after the last studies, and 6 years after the re-organisation of the National Tuberculosis (TB) Control Programme (NTBCP) is not known. Methods The study was conducted from February to July 2009 in the West and Centre regions of Cameroon. A total of 756 suspected patients were studied. MTBC species were detected by the standard Ziehl-Neelsen staining method. Bacterial susceptibility to the first line drugs [isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (SM)] were performed on cultures using the indirect proportion method. MTBC species were identified by standard biochemical and culture methods. Results Of the 756 suspected patients, 154 (20.37%) were positive by smear microscopy. Of these, 20.77% were HIV patients. The growth of Mycobacterium was observed with the sputa from 149 (96.75%) subjects. All the isolates were identified as either M. tuberculosis or M. africanum. Among these, 16 (10.73%) were resistant to at least one drug (13.3% for the West region and 8.1% for the Centre). The initial resistance rates were 7.35% for the Centre region and 11.29% for the West region, while the acquired resistance rates were 16.66% (1/6) for the Centre region and 23.07% (3/13) for the West. Within the two regions, the highest total resistance to one drug was obtained with INH and SM (2.68% each). Multidrug-resistance (MDR) was observed only in the West region at a rate of 6.67%. No resistance was recorded for EMB. Conclusions M. tuberculosis and M. africanum remain the MTBC species causing pulmonary TB in the West and Centre regions of Cameroon. Following the re-organisation of the NTBCP, resistance to all first line anti-TB drugs has declined significantly (p < 0.05 for West; and p < 0.01 for Centre) in comparison to previous studies. However, the general rates of anti-TB drug resistance remain high in the country, underscoring the need for greater enforcement of control strategies. PMID:21496268

2011-01-01

378

Drug-resistant tuberculosis in subjects included in the Second National Survey on Antituberculosis Drug Resistance in Porto Alegre, Brazil*, **  

PubMed Central

OBJECTIVE: To describe the prevalence of multidrug-resistant tuberculosis (MDR-TB) among tuberculosis patients in a major Brazilian city, evaluated via the Second National Survey on Antituberculosis Drug Resistance, as well as the social, demographic, and clinical characteristics of those patients. METHODS: Clinical samples were collected from tuberculosis patients seen between 2006 to 2007 at three hospitals and five primary health care clinics participating in the survey in the city of Porto Alegre, Brazil. The samples were subjected to drug susceptibility testing. The species of mycobacteria was confirmed using biochemical methods. RESULTS: Of the 299 patients included, 221 (73.9%) were men and 77 (27.3%) had a history of tuberculosis. The mean age was 36 years. Of the 252 patients who underwent HIV testing, 66 (26.2%) tested positive. The prevalence of MDR-TB in the sample as a whole was 4.7% (95% CI: 2.3-7.1), whereas it was 2.2% (95% CI: 0.3-4.2) among the new cases of tuberculosis and 12.0% (95% CI: 4.5-19.5) among the patients with a history of tuberculosis treatment. The multivariate analysis showed that a history of tuberculosis and a longer time to diagnosis were both associated with MDR-TB. CONCLUSIONS: If our results are corroborated by other studies conducted in Brazil, a history of tuberculosis treatment and a longer time to diagnosis could be used as predictors of MDR-TB. PMID:24831400

Micheletti, Vania Celina Dezoti; Moreira, Jos da Silva; Ribeiro, Marta Osrio; Kritski, Afranio Lineu; Braga, Jos Ueleres

2014-01-01

379

Structure-Based Drug Design and Optimization of Mannoside Bacterial FimH Antagonists  

PubMed Central

FimH-mediated cellular adhesion to mannosylated proteins is critical in the ability of uropathogenic E. coli (UPEC) to colonize and invade the bladder epithelium during urinary tract infection. We describe the discovery and optimization of potent small-molecule FimH bacterial adhesion antagonists based on ?-D-mannose 1-position anomeric glycosides using X-ray structure-guided drug design. Optimized biaryl mannosides display low nanomolar binding affinity for FimH in a fluorescence polarization assay and sub micromolar cellular activity in a hemagglutination (HA) functional cell assay of bacterial adhesion. X-ray crystallography demonstrates that the biphenyl moiety makes several key interactions with the outer surface of FimH including ?-? interactions with Tyr-48 and an H-bonding electrostatic interaction with the Arg-98/Glu-50 salt-bridge. Dimeric analogs linked through the biaryl ring show an impressive 8-fold increase in potency relative to monomeric matched pairs and represent the most potent FimH antagonists identified to date. The FimH antagonists described herein hold great potential for development as novel therapeutics for the effective treatment of urinary tract infections. PMID:20507142

Han, Zhenfu; Pinkner, Jerome S.; Ford, Bradley; Obermann, Robert; Nolan, William; Wildman, Scott A.; Hobbs, Doug; Ellenberger, Tom; Cusumano, Corinne K.; Hultgren, Scott J.; Janetka, James W.

2010-01-01

380

Drug Resistance Profiles of Mycobacterium tuberculosis Complex and Factors Associated with Drug Resistance in the Northwest and Southwest Regions of Cameroon  

PubMed Central

Background Anti-tuberculosis drug resistance continues to be a major obstacle to tuberculosis (TB) control programmes with HIV being a major risk factor in developing TB. We investigated anti-TB drug resistance profiles and the impact of socioeconomic as well as behavioural factors on the prevalence of TB and drug resistance in two regions of Cameroon with such data paucity. Methods This was a hospital-based study in which 1706 participants, comprising 1133 females and 573 males consecutively enrolled from selected TB and HIV treatment centres of the Northwest and Southwest regions. Demographic, clinical and self-reported risk behaviours and socioeconomic data were obtained with the consent of participants using questionnaires. Culture and drug resistance testing were performed according to standard procedures. Results The prevalence of resistance to at least one anti-TB drug was 27.7% and multi-drug resistance was 5.9%. Smoking, concurrent alcohol consumption and smoking, being on antiretroviral therapy for ? 12 months and previous household contact with TB patient were independently associated with tuberculosis prevalence, while only previous tuberculosis infection was associated with drug resistance in a univariate analysis. Conclusion The study showed a high prevalence of drug resistance TB in the study population with only previous TB infection associated with drug resistance in a univariate analysis. It also provides evidence in our context, of the role of alcohol and smoking in increasing the risk of developing TB, which is more likely in people living with HIV/AIDS. Therefore, it is important for public health authorities to integrate and intensify alcohol/smoking abstention interventions in TB and HIV control programs in Cameroon. PMID:24146991

Meriki, Henry D.; Tufon, Kukwah A.; Atanga, Pascal N.; Ane-Anyangwe, Irene N.; Anong, Damian N.; Cho-Ngwa, Fidelis; Nkuo-Akenji, Theresa

2013-01-01

381

Extracellular Bacterial Pathogen Induces Host Cell Surface Reorganization to Resist Shear Stress  

PubMed Central

Bacterial infections targeting the bloodstream lead to a wide array of devastating diseases such as septic shock and meningitis. To study this crucial type of infection, its specific environment needs to be taken into account, in particular the mechanical forces generated by the blood flow. In a previous study using Neisseria meningitidis as a model, we observed that bacterial microcolonies forming on the endothelial cell surface in the vessel lumen are remarkably resistant to mechanical stress. The present study aims to identify the molecular basis of this resistance. N. meningitidis forms aggregates independently of host cells, yet we demonstrate here that cohesive forces involved in these bacterial aggregates are not sufficient to explain the stability of colonies on cell surfaces. Results imply that host cell attributes enhance microcolony cohesion. Microcolonies on the cell surface induce a cellular response consisting of numerous cellular protrusions similar to filopodia that come in close contact with all the bacteria in the microcolony. Consistent with a role of this cellular response, host cell lipid microdomain disruption simultaneously inhibited this response and rendered microcolonies sensitive to blood flowgenerated drag forces. We then identified, by a genetic approach, the type IV pili component PilV as a triggering factor of plasma membrane reorganization, and consistently found that microcolonies formed by a pilV mutant are highly sensitive to shear stress. Our study shows that bacteria manipulate host cell functions to reorganize the host cell surface to form filopodia-like structures that enhance the cohesion of the microcolonies and therefore blood vessel colonization under the harsh conditions of the bloodstream. PMID:19247442

Mikaty, Guillain; Soyer, Magali; Mairey, Emilie; Henry, Nelly; Dyer, Dave; Forest, Katrina T.; Morand, Philippe; Guadagnini, Stephanie; Prevost, Marie Christine; Nassif, Xavier; Dumenil, Guillaume

2009-01-01

382

Gene silencing using the recessive rice bacterial blight resistance gene xa13 as a new paradigm in plant breeding.  

PubMed

Resistant germplasm resources are valuable for developing resistant varieties in agricultural production. However, recessive resistance genes are usually overlooked in hybrid breeding. Compared with dominant traits, however, they may confer resistance to different pathogenic races or pest biotypes with different mechanisms of action. The recessive rice bacterial blight resistance gene xa13, also involved in pollen development, has been cloned and its resistance mechanism has been recently characterized. This report describes the conversion of bacterial blight resistance mediated by the recessive xa13 gene into a dominant trait to facilitate its use in a breeding program. This was achieved by knockdown of the corresponding dominant allele Xa13 in transgenic rice using recently developed artificial microRNA technology. Tissue-specific promoters were used to exclude most of the expression of artificial microRNA in the anther to ensure that Xa13 functioned normally during pollen development. A battery of highly bacterial blight resistant transgenic plants with normal seed setting rates were acquired, indicating that highly specific gene silencing had been achieved. Our success with xa13 provides a paradigm that can be adapted to other recessive resistance genes. PMID:22218673

Li, Changyan; Wei, Jing; Lin, Yongjun; Chen, Hao

2012-05-01

383

Plasmodium berghei:Identification of an mdr-like Gene Associated with Drug Resistance  

Microsoft Academic Search

Gervais, G. W., Trujillo, K., Robinson, B. L., Peters, W., and Serrano, A. E. 1999.Plasmodium berghei:Identification of anmdr-like gene associated with drug resistance.Experimental Parasitology91,8692. Amplification, mutations, or overexpression of thepfmdr1gene have been associated with multiple drug resistance in some strains ofPlasmodium falciparum.In order to better understand this potential mechanism of drug resistance, we are currently investigating putativemdrhomologuesin vivoin the rodent

Gary W Gervais; Kathy Trujillo; Brian L Robinson; Wallace Peters; Adelfa E Serrano

1999-01-01

384

Linezolid for Treatment of Chronic Extensively Drug-Resistant Tuberculosis  

PubMed Central

BACKGROUND Linezolid has antimycobacterial activity in vitro and is increasingly used for patients with highly drug-resistant tuberculosis. METHODS We enrolled 41 patients who had sputum-culturepositive extensively drug-resistant (XDR) tuberculosis and who did not have a response to any available chemotherapeutic option during the previous 6 months. Patients were randomly assigned to linezolid therapy that started immediately or after 2 months, at a dose of 600 mg per day, without a change in their background regimen. The primary end point was the time to sputum-culture conversion on solid medium, with data censored 4 months after study entry. After confirmed sputum-smear conversion or 4 months (whichever came first), patients underwent a second randomization to continued linezolid therapy at a dose of 600 mg per day or 300 mg per day for at least an additional 18 months, with careful toxicity monitoring. RESULTS By 4 months, 15 of the 19 patients (79%) in the immediate-start group and 7 of the 20 (35%) in the delayed-start group had culture conversion (P = 0.001). Most patients (34 of 39 [87%]) had a negative sputum culture within 6 months after linezolid had been added to their drug regimen. Of the 38 patients with exposure to linezolid, 31 (82%) had clinically significant adverse events that were possibly or probably related to linezolid, including 3 patients who discontinued therapy. Patients who received 300 mg per day after the second randomization had fewer adverse events than those who continued taking 600 mg per day. Thirteen patients completed therapy and have not had a relapse. Four cases of acquired resistance to linezolid have been observed. CONCLUSIONS Linezolid is effective at achieving culture conversion among patients with treatment-refractory XDR pulmonary tuberculosis, but patients must be monitored carefully for adverse events. (Funded by the National Institute of Allergy and Infectious Diseases and the Ministry of Health and Welfare, South Korea; ClinicalTrials.gov number, NCT00727844.) PMID:23075177

Lee, Myungsun; Lee, Jongseok; Carroll, Matthew W.; Choi, Hongjo; Min, Seonyeong; Song, Taeksun; Via, Laura E.; Goldfeder, Lisa C.; Kang, Eunhwa; Jin, Boyoung; Park, Hyeeun; Kwak, Hyunkyung; Kim, Hyunchul; Jeon, Han-Seung; Jeong, Ina; Joh, Joon Sung; Chen, Ray Y.; Olivier, Kenneth N.; Shaw, Pamela A.; Follmann, Dean; Song, Sun Dae; Lee, Jong-Koo; Lee, Dukhyoung; Kim, Cheon Tae; Dartois, Veronique; Park, Seung-Kyu; Cho, Sang-Nae; Barry, Clifton E.

2013-01-01

385

Transgenic Resistance Confers Effective Field Level Control of Bacterial Spot Disease in Tomato  

PubMed Central

We investigated whether lines of transgenic tomato (Solanum lycopersicum) expressing the Bs2 resistance gene from pepper, a close relative of tomato, demonstrate improved resistance to bacterial spot disease caused by Xanthomonas species in replicated multi-year field trials under commercial type growing conditions. We report that the presence of the Bs2 gene in the highly susceptible VF 36 background reduced disease to extremely low levels, and VF 36-Bs2 plants displayed the lowest disease severity amongst all tomato varieties tested, including commercial and breeding lines with host resistance. Yields of marketable fruit from transgenic lines were typically 2.5 times that of the non-transformed parent line, but varied between 1.5 and 11.5 fold depending on weather conditions and disease pressure. Trials were conducted without application of any copper-based bactericides, presently in wide use despite negative impacts on the environment. This is the first demonstration of effective field resistance in a transgenic genotype based on a plant R gene and provides an opportunity for control of a devastating pathogen while eliminating ineffective copper pesticides. PMID:22870280

Horvath, Diana M.; Stall, Robert E.; Jones, Jeffrey B.; Pauly, Michael H.; Vallad, Gary E.; Dahlbeck, Doug; Staskawicz, Brian J.; Scott, John W.

2012-01-01

386

Synthesis and evaluation of hetero- and homo-dimers of ribosome-targeting antibiotics: Antimicrobial activity, in vitro inhibition of translation, and drug resistance  

PubMed Central

In this study, we describe the synthesis of a full set of homo- and hetero-dimers of three intact structures of different ribosome-targeting antibiotics: tobramycin, clindamycin, and chloramphenicol. Several aspects of the biological activity of the dimeric structures were evaluated including antimicrobial activity, inhibition of in vitro bacterial protein translation, and the effect of dimerization on the action of several bacterial resistance mechanisms that deactivate tobramycin and chloramphenicol. This study demonstrates that covalently linking two identical or different ribosome-targeting antibiotics may lead to (i) a broader spectrum of antimicrobial activity, (ii) improved inhibition of bacterial translation properties compared to that of the parent antibiotics, and (iii) reduction in the efficacy of some drug-modifying enzymes that confer high levels of resistance to the parent antibiotics from which the dimers were derived. PMID:23786357

Berkov-Zrihen, Yifat; Green, Keith D.; Labby, Kristin J.; Feldman, Mark; Garneau-Tsodikova, Sylvie; Fridman, Micha

2013-01-01

387

Detached leaf inoculation of germplasm for rapid screening of resistance to citrus canker and citrus bacterial spot  

Microsoft Academic Search

A detached leaf protocol for rapid screening of germplasm for resistance to citrus canker (Xanthomonas citri subsp. citri, Xcc) and citrus bacterial spot (Xanthomonas alfalfae subsp. citrumelonis, Xac) was developed to evaluate limited quantities of leaf material. Bacterial inocula of Xcc or Xac at 104, 105, or 108cfuml?1 were injection-infiltrated into the abaxial surface of disinfested, immature leaves of susceptible

Marta I. Francis; Alma Pea; James H. Graham

2010-01-01

388

Non-Pathogenic Bacterial Flora May Inhibit Colonization by Methicillin-Resistant Staphylococcus aureus in Extremely Low Birth Weight Infants  

Microsoft Academic Search

Objectives: To evaluate our hypothesis that non-pathogenic bacterial flora inhibit later colonization with methicillin-resistant Staphylococcus aureus (MRSA) in extremely low birth weight (ELBW) infants, we performed a retrospective investigation of the association between non-pathogenic bacterial flora and later inhibition of colonization by MRSA in ELBW infants. Methods: A total of 110 preterm infants with birth weight <1,000 g admitted to

Akiko Shimizu; Kenji Shimizu; Tomohiko Nakamura

2008-01-01

389

Natural solution to antibiotic resistance: bacteriophages 'The Living Drugs'.  

PubMed

Antibiotics have been a panacea in animal husbandry as well as in human therapy for decades. The huge amount of antibiotics used to induce the growth and protect the health of farm animals has lead to the evolution of bacteria that are resistant to the drug's effects. Today, many researchers are working with bacteriophages (phages) as an alternative to antibiotics in the control of pathogens for human therapy as well as prevention, biocontrol, and therapy in animal agriculture. Phage therapy and biocontrol have yet to fulfill their promise or potential, largely due to several key obstacles to their performance. Several suggestions are shared in order to point a direction for overcoming common obstacles in applied phage technology. The key to successful use of phages in modern scientific, farm, food processing and clinical applications is to understand the common obstacles as well as best practices and to develop answers that work in harmony with nature. PMID:24781265

Jassim, Sabah A A; Limoges, Richard G

2014-08-01

390

Extensively drug-resistant tuberculosis in India: A review  

PubMed Central

Background & objectives: Extensively drug resistant tuberculosis (XDR-TB) has become a new threat for the control of TB in many countries including India. Its prevalence is not known in India as there is no nation-wide surveillance. However, there have been some reports from various hospitals in the country. Methods: We have reviewed the studies/information available in the public domain and found data from 10 tertiary care centres in 9 cities in India. Results: A total of 598 isolates of XDR Mycobacterium tuberculosis have been reported in the studies included. However, the reliability of microbiological methods used in these studies was not checked and thus the XDR-TB data remained invalidated in reference laboratories. Interpretation & conclusions: Systematic surveillance and containment interventions are urgently needed. PMID:23168700

Michael, Joy Sarojini; John, T. Jacob

2012-01-01

391

New developments in the treatment of severe drug resistant hypertension.  

PubMed

The purpose of this paper is to review the state-of-the-art of renal denervation system technology for treatment of drug resistant hypertension. We describe an investigational device that is currently tested in an on-going clinical trial. The denervation device uses the RF thermal ablation catheter attached to the RF generator. The RF catheter is inserted into the renal artery and positioned in the vicinity of the efferent and afferent parasympathetic innervations. Renal denervation is a minimally invasive, localized procedure and the procedural and recovery times are very short. The entire procedure lasts about 40 min. In early clinical trials, the systolic blood pressure in 87% of patients who underwent the denervation procedure resulted in an average blood pressure drop of greater than 10 mm Hg. The procedure has no systematic side effects, and appears to be beneficial in the management of hypertension in patients refractory to pharmacological therapy. PMID:22113765

Lobodzinski, S Suave

2011-01-01

392

Complete Genome Analysis of Three Acinetobacter baumannii Clinical Isolates in China for Insight into the Diversification of Drug Resistance Elements  

PubMed Central

Background The emergence and rapid spreading of multidrug-resistant Acinetobacter baumannii strains has become a major health threat worldwide. To better understand the genetic recombination related with the acquisition of drug-resistant elements during bacterial infection, we performed complete genome analysis on three newly isolated multidrug-resistant A. baumannii strains from Beijing using next-generation sequencing technology. Methodologies/Principal Findings Whole genome comparison revealed that all 3 strains share some common drug resistant elements including carbapenem-resistant blaOXA-23 and tetracycline (tet) resistance islands, but the genome structures are diversified among strains. Various genomic islands intersperse on the genome with transposons and insertions, reflecting the recombination flexibility during the acquisition of the resistant elements. The blood-isolated BJAB07104 and ascites-isolated BJAB0868 exhibit high similarity on their genome structure with most of the global clone II strains, suggesting these two strains belong to the dominant outbreak strains prevalent worldwide. A large resistance island (RI) of about 121-kb, carrying a cluster of resistance-related genes, was inserted into the ATPase gene on BJAB07104 and BJAB0868 genomes. A 78-kb insertion element carrying tra-locus and blaOXA-23 island, can be either inserted into one of the tniB gene in the 121-kb RI on the chromosome, or transformed to conjugative plasmid in the two BJAB strains. The third strains of this study, BJAB0715, which was isolated from spinal fluid, exhibit much more divergence compared with above two strains. It harbors multiple drug-resistance elements including a truncated AbaR-22-like RI on its genome. One of the unique features of this strain is that it carries both blaOXA-23 and blaOXA-58 genes on its genome. Besides, an Acinetobacter lwoffii adeABC efflux element was found inserted into the ATPase position in BJAB0715. Conclusions Our comparative analysis on currently completed Acinetobacter baumannii genomes revealed extensive and dynamic genome organizations, which may facilitate the bacteria to acquire drug-resistance elements into their genomes. PMID:23826102

Zhang, Zhaojun; Zhou, Qiming; Zhou, Jinchun; Wakeland, Edward K.; Fang, Xiangdong; Xuan, Zhenyu; Shen, Dingxia; Li, Quan-Zhen

2013-01-01

393

Molecular graphics approach to bacterial AcrB proteinb-lactam antibiotic molecular recognition in drug efflux mechanism  

E-print Network

compounds after prolonged anticancer or antimicrobial therapy [10­13]. Overuses and misuses of antimicrobials [9,12,14­17] also provoke MDR, resulting in mortality and therapy costs increase, infections the bacterial natural environment and drugs www.elsevi

Ferreira, Márcia M. C.

394

THE USE OF NANOPARTICLE-MEDIATED TARGETED GENE SILENCING AND DRUG DELIVERY TO OVERCOME TUMOR DRUG RESISTANCE  

PubMed Central

Overexpression of drug efflux transporters such as P-glycoprotein (P-gp) enables cancer cells to develop resistance to multiple anticancer drugs. Functional inhibitors of P-gp have shown promising efficacy in early clinical trials, but their long-term safety is yet to be established. A novel approach to overcome drug resistance is to use siRNA-mediated RNA interference to silence the expression of the efflux transporter. Because P-gp plays an important role in the physiological regulation of endogenous and xenobiotic compounds in the body, it is important to deliver P-gp targeted siRNA and anticancer drug specifically to tumor cells. Further, for optimal synergy, both the drug and siRNA may need to be temporally colocalized in the tumor cells. In the current study, we investigated the effectiveness of simultaneous and targeted delivery of anticancer drug, paclitaxel, along with P-gp targeted siRNA, using poly(D,L-lactide-co-glycolide) nanoparticles to overcome tumor drug resistance. Nanoparticles were surface functionalized with biotin for active tumor targeting. Dual agent nanoparticles encapsulating the combination of paclitaxel and P-gp targeted siRNA showed significantly higher cytotoxicity in vitro than nanoparticles loaded with paclitaxel alone. Enhanced therapeutic efficacy of dual agent nanoparticles could be correlated with effective silencing of the MDR1 gene that encodes for P-gp and with increased accumulation of paclitaxel in drug-resistant tumor cells. In vivo studies in a mouse model of drug-resistant tumor demonstrated significantly greater inhibition of tumor growth following treatment with biotin-functionalized nanoparticles encapsulating both paclitaxel and P-gp targeted siRNA at a paclitaxel dose that was ineffective in the absence of gene silencing. These results suggest that that the combination of P-gp gene silencing and cytotoxic drug delivery using targeted nanoparticles can overcome tumor drug resistance. PMID:19800114

Patil, Yogesh; Swaminathan, Suresh; Sadhukha, Tanmoy; Ma, Linan; Panyam, Jayanth

2009-01-01

395

Building in efficacy: developing solutions to combat drug-resistant S. pneumoniae.  

PubMed

The development of our understanding of the pharmacokinetic (PK) and pharmacodynamic (PD) principles that determine antimicrobial efficacy has advanced substantially over the last 10 years. We are now in a position to use PK/PD principles to set targets for antimicrobial design and optimisation so that we can predict eradication of specific pathogens or resistant variants when agents are used clinically. Optimisation of PK/PD parameters to enable the treatment of resistant pathogens with oral agents may not be possible with many current agents, such as some cephalosporins, macrolides and fluoroquinolones. Aminopenicillins, however, such as amoxicillin, have linear PK and have a good safety profile even at high doses. The new pharmacokinetically enhanced oral formulation of amoxicillin/clavulanate, 2000/125 mg twice daily, was designed using PK/PD principles to be able to eradicate Streptococcus pneumoniae with amoxicillin MICs of up to and including 4 mg/L, which includes most penicillin-resistant isolates. For amoxicillin and amoxicillin/clavulanate, a time above MIC (T > MIC) of 35-40% of the dosing interval (based on blood levels) is predictive of high bacteriological efficacy. This target was met by the design of a unique bilayer tablet incorporating 437.5 mg of sustained-release sodium amoxicillin in one layer plus 562.5 mg of immediate-release amoxicillin trihydrate and 62.5 mg of clavulanate potassium in the second layer, with two tablets administered for each dose. This unique design extends the bacterial killing time by increasing the T > MIC to 49% of the dosing interval against pathogens with MICs of 4 mg/L, and 60% of the dosing interval against pathogens with MICs of 2 mg/L. Based on these results, this new amoxicillin/clavulanate formulation should be highly effective in treating respiratory tract infections due to drug-resistant S. pneumoniae as well as beta-lactamase-producing pathogens, such as Haemophilus influenzae and Moraxella catarrhalis. PMID:14759230

Jacobs, M R

2004-04-01

396

"Applied" Aspects of the Drug Resistance Strategies Project  

PubMed Central

This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of applied from the traditional notion of utilizing theory, which we call applied.1, in order to consider theory-grounded, theory testing and theory developing applied research. We label this new definition applied.2 research. We then explain that our descriptive work describing the social processes of adolescent substance use, identity and use, and drug norms, as well as the subsequent development and dissemination of our keepin it REAL middle school substance use curriculum are examples of applied.1 work. In the applied.2 realm, we include our theory testing (e.g., tests of multiculturalism, narrative and performance theories, the Focus Theory of Norms) and theory-developing (e.g., parent-child communication, cultural grounding) research as well our new directions in theory development (e.g., adaptation processes). We conclude with a call for space in the discipline for applied.2 work that builds and tests theory through application to significant social issues that contribute to our communities. We note obstacles in departmental and scholarly norms but express optimism about the prospects for applied.2 research in the future of communication research. PMID:20711485

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

2010-01-01

397

Aurora Kinases as Targets in Drug-Resistant Neuroblastoma Cells  

PubMed Central

Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases. PMID:25268132

Rothweiler, Florian; Loschmann, Nadine; Nusse, Benedikt; Dirks, Wilhelm G.; Zehner, Richard; Cinatl, Jindrich

2014-01-01

398

Aurora kinases as targets in drug-resistant neuroblastoma cells.  

PubMed

Aurora kinase inhibitors displayed activity in pre-clinical neuroblastoma models. Here, we studied the effects of the pan-aurora kinase inhibitor tozasertib (VX680, MK-0457) and the aurora kinase inhibitor alisertib (MLN8237) that shows some specificity for aurora kinase A over aurora kinase B in a panel of neuroblastoma cell lines with acquired drug resistance. Both compounds displayed anti-neuroblastoma activity in the nanomolar range. The anti-neuroblastoma mechanism included inhibition of aurora kinase signalling as indicated by decreased phosphorylation of the aurora kinase substrate histone H3, cell cycle inhibition in G2/M phase, and induction of apoptosis. The activity of alisertib but not of tozasertib was affected by ABCB1 expression. Aurora kinase inhibitors induced a p53 response and their activity was enhanced in combination with the MDM2 inhibitor and p53 activator nutlin-3 in p53 wild-type cells. In conclusion, aurora kinases are potential drug targets in therapy-refractory neuroblastoma, in particular for the vast majority of p53 wild-type cases. PMID:25268132

Michaelis, Martin; Selt, Florian; Rothweiler, Florian; Lschmann, Nadine; Nsse, Benedikt; Dirks, Wilhelm G; Zehner, Richard; Cinatl, Jindrich

2014-01-01

399

"Applied" Aspects of the Drug Resistance Strategies Project.  

PubMed

This paper discusses the applied aspects of our Drug Resistance Strategies Project. We argue that a new definitional distinction is needed to expand the notion of "applied" from the traditional notion of utilizing theory, which we call "applied.1", in order to consider theory-grounded, theory testing and theory developing applied research. We label this new definition "applied.2" research. We then explain that our descriptive work describing the social processes of adolescent substance use, identity and use, and drug norms, as well as the subsequent development and dissemination of our keepin' it REAL middle school substance use curriculum are examples of "applied.1" work. In the "applied.2" realm, we include our theory testing (e.g., tests of multiculturalism, narrative and performance theories, the Focus Theory of Norms) and theory-developing (e.g., parent-child communication, cultural grounding) research as well our new directions in theory development (e.g., adaptation processes). We conclude with a call for space in the discipline for "applied.2" work that builds and tests theory through application to significant social issues that contribute to our communities. We note obstacles in departmental and scholarly norms but express optimism about the prospects for "applied.2" research in the future of communication research. PMID:20711485

Hecht, Michael L; Miller-Day, Michelle A

2010-08-01

400

Averting epidemics of extensively drug-resistant tuberculosis  

PubMed Central

Extensively drug-resistant tuberculosis (XDR TB) has been detected in most provinces of South Africa, particularly in the KwaZulu-Natal province where several hundred cases have been reported since 2004. We analyzed the transmission dynamics of XDR TB in the region using mathematical models, and observed that nosocomial transmission clusters of XDR TB may emerge into community-based epidemics under the public health conditions of many South African communities. The effective reproductive number of XDR TB in KwaZulu-Natal may be around 2. Intensified community-based case finding and therapy appears critical to curtailing transmission. In the setting of delayed disease presentation and high system demand, improved diagnostic approaches may need to be employed in community-based programs rather than exclusively at tertiary hospitals. Using branching process mathematics, we observed that early, community-based drug-susceptibility testing and effective XDR therapy could help curtail ongoing transmission and reduce the probability of XDR TB epidemics in neighboring territories. PMID:19365076

Basu, Sanjay; Friedland, Gerald H.; Medlock, Jan; Andrews, Jason R.; Shah, N. Sarita; Gandhi, Neel R.; Moll, Anthony; Moodley, Prashini; Sturm, A. Willem; Galvani, Alison P.

2009-01-01