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

PubMed Central

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

Zhang, Quan-Guo



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

PubMed Central

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

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



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


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



Drug Resistance  


... day and exactly as prescribed. What is drug resistance? Once a person becomes infected with HIV, the virus begins to multiply (make copies of itself) in the body. As HIV multiplies, it sometimes mutates (changes form) and produces variations of itself. Variations of ...


Dendrimer-based multivalent vancomycin nanoplatform for targeting the drug-resistant bacterial surface.  


Vancomycin represents the preferred ligand for bacteria-targeting nanosystems. However, it is inefficient for emerging vancomycin-resistant species because of its poor affinity to the reprogrammed cell wall structure. This study demonstrates the use of a multivalent strategy as an effective way for overcoming such an affinity limitation in bacteria targeting. We designed a series of fifth generation (G5) poly(amidoamine) (PAMAM) dendrimers tethered with vancomycin at the C-terminus at different valencies. We performed surface plasmon resonance (SPR) studies to determine their binding avidity to two cell wall models, each made with either a vancomycin-susceptible (D)-Ala-(D)-Ala or vancomycin-resistant (D)-Ala-(D)-Lac cell wall precursor. These conjugates showed remarkable enhancement in avidity in the cell wall models tested, including the vancomycin-resistant model, which had an increase in avidity of four to five orders of magnitude greater than free vancomycin. The tight adsorption of the conjugate to the model surface corresponded with its ability to bind vancomycin-susceptible Staphylococcus aureus bacterial cells in vitro as imaged by confocal fluorescent microscopy. This vancomycin platform was then used to fabricate the surface of iron oxide nanoparticles by coating them with the dendrimer conjugates, and the resulting dendrimer-covered magnetic nanoparticles were demonstrated to rapidly sequester bacterial cells. In summary, this article investigates the biophysical basis of the tight, multivalent association of dendrimer-based vancomycin conjugates to the bacterial cell wall, and proposes a potential new use of this nanoplatform in targeting Gram-positive bacteria. PMID:23259666

Choi, Seok Ki; Myc, Andrzej; Silpe, Justin Ezekiel; Sumit, Madhuresh; Wong, Pamela Tinmoi; McCarthy, Kelly; Desai, Ankur M; Thomas, Thommey P; Kotlyar, Alina; Holl, Mark M Banaszak; Orr, Bradford G; Baker, James R



[Resistance to antituberculous drugs].  


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

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



Novel Bacterial Metabolite Merochlorin A Demonstrates in vitro Activity against Multi-Drug Resistant Methicillin-Resistant Staphylococcus aureus  

PubMed Central

Background We evaluated the in vitro activity of a merochlorin A, a novel compound with a unique carbon skeleton, against a spectrum of clinically relevant bacterial pathogens and against previously characterized clinical and laboratory Staphylococcus aureus isolates with resistance to numerous antibiotics. Methods Merochlorin A was isolated and purified from a marine-derived actinomycete strain CNH189. Susceptibility testing for merochlorin A was performed against previously characterized human pathogens using broth microdilution and agar dilution methods. Cytotoxicity was assayed in tissue culture assays at 24 and 72 hours against human HeLa and mouse sarcoma L929 cell lines. Results The structure of as new antibiotic, merochlorin A, was assigned by comprehensive spectroscopic analysis. Merochlorin A demonstrated in vitro activity against Gram-positive bacteria, including Clostridium dificile, but not against Gram negative bacteria. In S. aureus, susceptibility was not affected by ribosomal mutations conferring linezolid resistance, mutations in dlt or mprF conferring resistance to daptomycin, accessory gene regulator knockout mutations, or the development of the vancomycin-intermediate resistant phenotype. Merochlorin A demonstrated rapid bactericidal activity against MRSA. Activity was lost in the presence of 20% serum. Conclusions The unique meroterpenoid, merochlorin A demonstrated excellent in vitro activity against S. aureus and C. dificile and did not show cross-resistance to contemporary antibiotics against Gram positive organisms. The activity was, however, markedly reduced in 20% human serum. Future directions for this compound may include evaluation for topical use, coating biomedical devices, or the pursuit of chemically modified derivatives of this compound that retain activity in the presence of serum. PMID:22279537

Sakoulas, George; Nam, Sang-Jip; Loesgen, Sandra; Fenical, William; Jensen, Paul R.; Nizet, Victor; Hensler, Mary



Bacterial Resistance in Acne  

Microsoft Academic Search

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

E. A. Eady




Microsoft Academic Search

ABSTRACTThis paper reviews the dynamics behind, and ethical issues associated with, the phenomenon of drug resistance. Drug resistance is an important ethical issue partly because of the severe consequences likely to result from the increase in drug resistant pathogens if more is not done to control them. Drug resistance is also an ethical issue because, rather than being a mere




Boosting bacterial metabolism to combat antibiotic resistance.  


The metabolic state of a bacterial cell influences its susceptibility to antibiotics. In this issue, Peng et al. (2015) show that resistant bacteria can be sensitized to antibiotic treatment through the addition of exogenous metabolites that stimulate central metabolic pathways and increase drug uptake. PMID:25651168

Bhargava, Prerna; Collins, James J



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


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



Targeting Bacterial Central Metabolism for Drug Development.  


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

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



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



Bacterial resistance to aminoglycoside antibiotics.  


The aminoglycoside antibiotics are broad-spectrum antibacterial compounds that are used extensively for the treatment of many bacterial infections. In view of the current concerns over the global rise in antibiotic-resistant microorganisms, there has been renewed interest in the mechanisms of resistance to the aminoglycosides, including the superfamily of aminoglycoside-modifying enzymes. PMID:9211644

Davies, J; Wright, G D



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?5–10?2 copy/16S) but not sul3. Among the natural bacterial assemblage, all sul1, sul2, and sul3 were detected (10?5–10?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.



A case report of a multi-drug resistant bacterial infection in a diabetic patient treated in northeast Brazil.  


Diabetes mellitus is one of the most critical health conditions around the world, not only in terms of the number of affected people, disability, and premature mortality, but also in regards to the health care costs involved in controlling and treating its complications. Among the most constant ailments the diabetic patient suffers is the diabetic foot, defined as any infection, ulceration, and/or necrosis of deep tissues associated with neurological abnormalities and various degrees of peripheral vascular disease of the lower limbs. Diabetic foot ulcerations have become a major and increasing public health concern and its associated morbidities, impairment of the patients' quality of life, and the implied costs for management have attracted the attention of numerous health care providers. In this case report, the authors review a unique presentation of a polymicrobial infection of a multi-drug resistant character species formed by oxacillin-resistant Staphylococcus aureus, Acinetobacter baumannii and Acinetobacter lwoffii. PMID:22745851

Neto, Renato Motta; Ansaldi, Miguel Angel; da Costa, Maria Eduarda S M; da Silva, Samuel Oliveira; Luz, Victor Hugo F



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.



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



Antimicrobial use and bacterial resistance  

Microsoft Academic Search

The current epidemic of bacterial resistance is attributed, in part, to the overuse of antibiotics. Recent studies have documented increases in resistance with over-use of particular antibiotics and improvements in susceptibility when antibiotic use is controlled. The most effective means of improving use of antibiotics is unknown. Comprehensive management programs directed by multi-disciplinary teams, computer-assisted decision-making, and antibiotic cycling have

Sara Monroe; Ronald Polk



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 ...

Mrs. Koyle



Strategies for reversing drug resistance  

Microsoft Academic Search

Drug resistance, intrinsic or acquired, is a problem for all chemotherapeutic agents. In this review, we examine numerous strategies that have been tested or proposed to reverse drug resistance. Included among these strategies are approaches targeting the apoptosis pathway. Although the process of apoptosis is complex, it provides several potential sites for therapeutic intervention. A variety of targets and approaches

Tito Fojo; Susan Bates



Bacteriophage host range and bacterial resistance.  


Host range describes the breadth of organisms a parasite is capable of infecting, with limits on host range stemming from parasite, host, or environmental characteristics. Parasites can adapt to overcome host or environmental limitations, while hosts can adapt to control the negative impact of parasites. We consider these adaptations as they occur among bacteriophages (phages) and their bacterial hosts, since they are significant to phage use as antibacterials (phage therapy) or to protection of industrial ferments from phage attack. Initially, we address how phage host range can (and should) be defined plus summarize claims of host ranges spanning multiple bacterial genera. Subsequently, we review bacterial mechanisms of phage resistance. These include adsorption resistance, which results in reduced interaction between phage and bacterium; what we describe as "restriction," where bacteria live but phages die; and abortive infections, where both phage and bacterium die. Adsorption resistance includes loss of phage receptor molecules on hosts as well as physical barriers hiding receptor molecules (e.g., capsules). Restriction mechanisms include phage-genome uptake blocks, superinfection immunity, restriction modification, and CRISPR, all of which function postphage adsorption but prior to terminal phage takeover of host metabolism. Standard laboratory selection methods, involving exposure of planktonic bacteria to high phage densities, tend to directly select for these prehost-takeover resistance mechanisms. Alternatively, resistance mechanisms that do not prevent bacterium death are less readily artificially selected. Contrasting especially bacteria mutation to adsorption resistance, these latter mechanisms likely are an underappreciated avenue of bacterial resistance to phage attack. PMID:20359459

Hyman, Paul; Abedon, Stephen T



Antibacterial Mechanisms of Polymyxin and Bacterial Resistance  

PubMed Central

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

Qin, Wangrong; Fang, Shisong; Qiu, Juanping



Selection and evolution of resistance to antimicrobial drugs.  


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. PMID:24933583

Hughes, Diarmaid



Antiviral Drug Resistance: Mechanisms and Clinical Implications  

PubMed Central

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

Chou, Sunwen



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



Trichomonads, hydrogenosomes and drug resistance.  


Trichomonas vaginalis and Tritrichomonas foetus are sexually transmitted pathogens of the genito-urinary tract of humans and cattle, respectively. These organisms are amitochondrial anaerobes possessing hydrogenosomes, double membrane-bound organelles involved in catabolic processes extending glycolysis. The oxidative decarboxylation of pyruvate in hydrogenosomes is coupled to ATP synthesis and linked to ferredoxin-mediated electron transport. This pathway is responsible for metabolic activation of 5-nitroimidazole drugs, such as metronidazole, used in chemotherapy of trichomoniasis. Prolonged cultivation of trichomonads under sublethal pressure of metronidazole results in development of drug resistance. In both pathogenic species the resistance develops in a multistep process involving a sequence of stages that differ in drug susceptibility and metabolic activities. Aerobic resistance, similar to that occurring in clinical isolates of T. vaginalis from treatment-refractory patients, appears as the earliest stage. The terminal stage is characterised by stable anaerobic resistance at which the parasites show very high levels of minimal lethal concentration for metronidazole under anaerobic conditions (approximately 1000 microg ml(-1)). The key event in the development of resistance is progressive decrease and eventual loss of the pyruvate:ferredoxin oxidoreductase so that the drug-activating process is averted. In T. vaginalis at least, the development of resistance is also accompanied by decreased expression of ferredoxin. The pyruvate:ferredoxin oxidoreductase deficiency completely precludes metronidazole activation in T. foetus, while T. vaginalis possesses an additional drug-activating system which must be eliminated before the full resistance is acquired. This alternative pathway involves the hydrogenosomal malic enzyme and NAD:ferredoxin oxidoreductase. Metronidazole-resistant trichomonads compensate for the hydrogenosomal deficiency by an increased rate of glycolysis and by changes in their cytosolic pathways. Trichomonas vaginalis enhances lactate fermentation while T. foetus activates pyruvate conversion to ethanol. Drug-resistant T. foetus also increases activity of the cytosolic NADP-dependent malic enzyme, to enhance the pyruvate producing bypass and provide NADPH required by alcohol dehydrogenase. Production of succinate by this species is abolished. Metabolic changes accompanying in-vitro development of metronidazole resistance demonstrate the versatility of trichomonad metabolism and provide an interesting example of how unicellular eukaryotes can adjust their metabolism in response to the pressure of an unfavorable environment. PMID:10221623

Kulda, J



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.



Drug resistance in epilepsy: expression of drug resistance proteins in common causes of refractory epilepsy  

Microsoft Academic Search

Summary Epilepsy is resistant to drug treatment in about one- third of cases, but the mechanisms underlying this drug resistance are not understood. In cancer, drug resist- ance has been studied extensively. Amongst the various resistance mechanisms, overexpression of drug resist- ance proteins, such as multi-drug resistance gene-1 P- glycoprotein (MDR1) and multidrug resistance-associ- ated protein 1 (MRP1), has been

S. M. Sisodiya; W.-R. Lin; B. N. Harding; M. V. Squier; M. Thom



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



Multidrug resistant to extensively drug resistant tuberculosis: What is next?  

Microsoft Academic Search

Drug resistant tuberculosis is a man made problem. While tuberculosis is hundred percent curable, multidrug resistant tuberculosis\\u000a (MDR-TB) is difficult to treat. Inadequate and incomplete treatment and poor treatment adherence has led to a newer form of\\u000a drug resistance known as extensively drug resistant tuberculosis (XDR-TB). XDR-TB is defined as tuberculosis caused by Mycobacterium tuberculosis strain, which is resistant to

Amita Jain; Pratima Dixit



Bacterial resistance to disinfectants: present knowledge and future problems  

Microsoft Academic Search

Bacterial resistance to antibiotics is a long-established, widely-studied problem. Increasingly, attention is being directed to the responses of various types of microbes to biocides (antiseptics, disinfectants and preservatives). Different groups of bacteria vary in their susceptibility to biocides, with bacterial spores being the most resistant, followed by mycobacteria, then Gramnegative organisms, with cocci generally being the most sensitive. There are

A. D. Russell



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



Leishmania donovani Develops Resistance to Drug Combinations  

PubMed Central

Drug combinations for the treatment of leishmaniasis represent a promising and challenging chemotherapeutic strategy that has recently been implemented in different endemic areas. However, the vast majority of studies undertaken to date have ignored the potential risk that Leishmania parasites could develop resistance to the different drugs used in such combinations. As a result, this study was designed to elucidate the ability of Leishmania donovani to develop experimental resistance to anti-leishmanial drug combinations. The induction of resistance to amphotericin B/miltefosine, amphotericin B/paromomycin, amphotericin B/SbIII, miltefosine/paromomycin, and SbIII/paromomycin was determined using a step-wise adaptation process to increasing drug concentrations. Intracellular amastigotes resistant to these drug combinations were obtained from resistant L. donovani promastigote forms, and the thiol and ATP levels and the mitochondrial membrane potential of the resistant lines were analysed. Resistance to drug combinations was obtained after 10 weeks and remained in the intracellular amastigotes. Additionally, this resistance proved to be unstable. More importantly, we observed that promastigotes/amastigotes resistant to one drug combination showed a marked cross-resistant profile to other anti-leishmanial drugs. Additionally, the thiol levels increased in resistant lines that remained protected against the drug-induced loss of ATP and mitochondrial membrane potential. We have therefore demonstrated that different resistance patterns can be obtained in L. donovani depending upon the drug combinations used. Resistance to the combinations miltefosine/paromomycin and SbIII/paromomycin is easily obtained experimentally. These results have been validated in intracellular amastigotes, and have important relevance for ensuring the long-term efficacy of drug combinations. PMID:23285310

García-Hernández, Raquel; Manzano, José Ignacio



Bacterial host resistance models in the evaluation of immunotoxicity.  


To assess potential immunomodulatory effects of a drug, pollutant, or natural product, an analysis of an exposed host's ability to resist challenge with a viable bacteria is one of the best gauges. Many factors govern whether a host exposed to a test agent and then infected becomes ill or dies at rates greater than infected control counterparts. Beyond the status of the host's immunocompetence, a bacterium's route of entry into the host and its inherent virulence are important variables determining how (and rate at which) an infection resolves. A pre-determination of endpoint(s) to be defined is critical during planning of resistance assays. If a study is to determine overall changes in immunocompetence due to exposure (regardless of regimen or dosage of test agent), then assessing shifts in morbidity/mortality at a defined lethal dose [LD(x)] value for the chosen route of infection would suffice. However, if a study is to define extent of immunomodulation in a particular body organ/cavity--or specific alterations in particular aspects of the humoral or cell-mediated immune responses--then careful selection of the pathogen, dose of the inoculum, means of infection of target site, and extent of the post-infection period to be examined, need to be made prior to host exposure to the test toxicant. This review will provide the Reader with background information about bacterial infections and how endpoint selection could be approached when designing resistance assays. An overview of protocols involved in the assays (e.g., bacterial preparation, host infection, post-infection endpoint analyses) and information about three bacteria that are among the most commonly employed in resistance assays is provided as well. PMID:17161299

Cohen, Mitchell D



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



Management of multidrug resistant bacterial endemic.  


The fight against multi-drug resistant Gram-negative bacilli (MDRGNB), especially extended-spectrum ?-lactamase producing Enterobacteriaceae, is about to be lost in our country. The emergence of new resistance mechanisms to carbapenems in these Enterobacteriaceae exposes patients to a risk of treatment failure without any other therapeutic options. This dramatic situation is paradoxical because we are well aware of the 2 major factors responsible for this situation: 1) MDRO cross-transmission, associated with a low compliance to standard precautions, especially hand hygiene, and 2) overexposure of patients to antibiotics. The implementation of a "search and isolate" policy, which was justified to control the spread of some MDRO that remained rare in the country, was not associated with a better adherence to standard precautions. The antibiotic policy and the measures implemented to control antibiotic consumptions have rarely been enforced and have shown inconsistent results. Notably, no significant decrease of antibiotic consumption has been observed. There is no excuse for these poor results, because some authors evaluating the effectiveness of programs for the control of MDRO have reported their positive effects on antimicrobial resistance without any detrimental effects. It is now urgent to deal with the 2 major factors by establishing an educational and persuasive program with quantified and opposable objectives. Firstly, we have to improve the observance of hand hygiene above 70%. Secondly, we have to define and reach a target for the reduction of antibiotic consumption both in community and in hospital settings. PMID:25169940

Zahar, J-R; Lesprit, P



Drug resistance in leishmaniasis: Newer developments  

PubMed Central

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



Drug kinetics and drug resistance in optimal chemotherapy  

Microsoft Academic Search

A system of differential equations for the control of tumor cells growth in a cycle nonspecific chemotherapy is presented. First-order drug kinetics and drug resistance are taken into account in a class of optimal control problems. The results show that the strategy corresponding to the maximum rate of drug injection is optimal for the Malthusian model of cell growth (which

J. L. Boldrini; R. C. Bassanezi



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 1 day-2 years 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



Extensively Drug-Resistant Tuberculosis, Burkina Faso  

PubMed Central

Because data from countries in Africa are limited, we measured the proportion of extensively drug-resistant (XDR) tuberculosis (TB) cases among TB patients in Burkina Faso for whom retreatment was failing. Of 34 patients with multidrug-resistant TB, 2 had an XDR TB strain. Second-line TB drugs should be strictly controlled to prevent further XDR TB increase. PMID:20409379

Saleri, Nuccia; Badoum, Gisèle; Ouedraogo, Martial; Dembélé, Sary M.; Nacanabo, Rachel; Bonkoungou, Victor; Cirillo, Daniela; Pinsi, Gabriele



Drug-resistant plasmids from fish pathogens.  


The epidemiological surveillance of drug-resistant strains of the fish pathogenic bacteria Vibrio anguillarum and Pasteurella piscicida carrying transferable R plasmids in fish farms is described. The DNA structure of R plasmids, and the drug-resistant determinants of R plasmids from the fish pathogens Aeromonas hydrophila,aeromonas salmonicida, Edwardsiella tarda, V. anguillarum, and P. piscicida are discussed. PMID:3079184

Aoki, T




Technology Transfer Automated Retrieval System (TEKTRAN)

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


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

E-print Network

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

Oliver, Douglas L.



Technology Transfer Automated Retrieval System (TEKTRAN)

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


[Extensively drug resistant and extremely drug resistant tuberculosis forms after multi-drug resistant tuberculosis: new faces of the old disease].  


Drug resistance in tuberculosis is a growing global problem. The emergence of multi-drug resistant tuberculosis cases, particularly in the 1990s, has become an important health problem and threatens tuberculosis control worldwide. Resistance to isoniazid and rifampicin, two of the most potent anti-tuberculosis drugs currently available, in multi-drug resistant tuberculosis cases is clinically quite important. The treatment of multi-drug resistant tuberculosis requires prolonged use of costly second-line drugs with significant toxic potentials under supervision and long-term hospitalization of patients. The appropriate management of tuberculosis, clinical/radiological and bacteriological follow-up, and surgery when needed are essential factors in the successful treatment of multi-drug resistant tuberculosis patients. An extensively drug resistant tuberculosis outbreak seen in KwaZulu-Natal region of the Republic of South Africa in 2005 led to certain doubts worldwide; this outbreak, introduced the importance and emergence of the counter measures against multi-drug resistant tuberculosis cases. Extensively drug resistant tuberculosis is defined as resistance to at least isoniazid and rifampicin from the first-line anti-tuberculosis drugs (the definition of multi-drug resistant tuberculosis) in addition to resistance to any fluoroquinolone, and to at least one of the three injectable second-line anti-tuberculosis drugs (kanamycin, capreomycin and amikacin) used in tuberculosis treatment. Mistreatment of multi-drug resistant tuberculosis cases by physicians, the use of anti-tuberculosis drugs with low quality, poor experience in management, lack of laboratories to perform second-line anti-tuberculosis drug susceptibility testing and problems in adherence of patients to treatment are factors associated to the development of extensively drug resistant tuberculosis. With the emergence of extensively drug resistant tuberculosis, World Health Organization gives importance to the mycobacteriology laboratory improvement, better multi-drug resistant tuberculosis case management, adequate drug supply, prevention of tuberculosis transmission and development of new drugs and diagnostics. Recently, a new form of tuberculosis, resistant to all first-and second-line anti-tuberculosis drugs seen in just a few number of cases, has been defined as extremely drug resistant tuberculosis and this is the end point in resistance problem in tuberculosis. In the view of this situation the stages of tuberculosis in terms of developing resistance are as follows: drugsensitive tuberculosis, mono-drug resistant tuberculosis, poly-drug resistant tuberculosis, multi-drug resistant tuberculosis, extensively drug resistant tuberculosis, and extensively drug resistant tuberculosis. In this review, the recent information about drug resistant tuberculosis forms, particularly extremely drug resistant tuberculosis that has been popular since 2005, has been discussed. PMID:21341173

Baylan, Orhan



Epidemiological aspects of antimicrobial drug resistance.  


Micro-organisms resistant to antimicrobial drugs are a problem for health workers worldwide. As scientists discover newer and more effective agents to manage emerging therapeutic challenges, the micro-organisms develop novel mechanisms of resistance hitherto unknown. The challenge in the present day is to understand the mechanisms of resistance in micro-organisms with a view to avoiding the emergence of resistance. For those in developing countries where health budgets are meagre and the cost of newer drugs ever increasing, there is need to develop effective policies to use the existing therapeutic choices in the most appropriate manner. This article highlights various epidemiological aspects of antimicrobial drug resistance in bacteria of medical importance that would be useful in the understanding of the basis for emergence and dissemination of resistance. PMID:9185404

Kariuki, S M; Hart, C A



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


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

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



Metabolic control of antifungal drug resistance.  


Fungi have evolved an elegant repertoire of mechanisms to survive the cellular stress exerted by antifungal drugs such as azoles, which inhibit ergosterol biosynthesis inducing cell membrane stress. The evolution and maintenance of diverse resistance phenotypes is contingent upon cellular circuitry regulated by the molecular chaperone Hsp90 and its client protein calcineurin. Here, we establish a novel role for nutrients and nutrient signaling in azole resistance. The vulnerability of Saccharomyces cerevisiae azole resistance phenotypes to perturbation was contingent upon specific auxotrophies. Using strains that acquired azole resistance by Erg3 loss of function as a model for resistance that depends on cellular stress responses, we delineated genetic and environmental factors that mitigate the translation of genotype into resistance phenotype. Compromising a global regulator that couples growth and metabolism to environmental cues, Tor kinase, provides a powerful strategy to abrogate drug resistance of S. cerevisiae and Candida albicans with broad therapeutic potential. PMID:19595784

Robbins, Nicole; Collins, Cathy; Morhayim, Jess; Cowen, Leah E



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)



Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme  

PubMed Central

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial ?-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 ?-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 ?-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. PMID:21051639

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.



Synthetic lethality to overcome cancer drug resistance.  


A large body of evidence point out that the onset of synthetic lethality may provide a useful tool for amplifying the efficacy of drugs in anticancer regimens, to uncover interdependence between genes and to identify predictive factors that would be extremely useful to guide in the selection of more effective targeted drugs and drug combinations for each patient. Here, we provide an overview on the exploitation of synthetic lethality to overcome drug resistance to conventional chemotherapy in several types of solid tumors. We report recent findings on cellular markers and gene mutations which are specifically essential for the viability of cancer cells and for resistance to chemotherapeutics. In addition, new molecularly targeted strategies to overcome drug resistance are suggested. PMID:22788762

Porcelli, L; Quatrale, A E; Mantuano, P; Silvestris, N; Brunetti, A E; Calvert, H; Paradiso, A; Azzariti, A



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

Schjørring, Susanne; Krogfelt, Karen A.



Bacterial Cheating Limits the Evolution of Antibiotic Resistance  

NASA Astrophysics Data System (ADS)

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

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



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.



Herpes simplex virus resistance to antiviral drugs  

Microsoft Academic Search

Herpes simplex virus (HSV) infections are efficiently treated with antiviral drugs such as acyclovir (ACV). However, resistance has been reported, mainly among immunocompromised patients (prevalence around 5%) and particularly allogeneic bone marrow transplant patients (prevalence reaching 30%). Resistance to ACV is associated with mutations on one of the two viral enzymes involved in the ACV mechanism of action: thymidine kinase

Florence Morfin; Danielle Thouvenot



Bacteriophage Host Range and Bacterial Resistance  

Microsoft Academic Search

Host range describes the breadth of organisms a parasite is capable of infecting, with limits on host range stemming from parasite, host, or environmental characteristics. Parasites can adapt to overcome host or environmental limitations, while hosts can adapt to control the negative impact of parasites. We consider these adaptations as they occur among bacteriophages (phages) and their bacterial hosts, since

Paul Hyman; Stephen T. Abedon



Drug resistance in glioblastoma: a mini review.  


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

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



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



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



Gram-positive bacterial resistance. A challenge for the next millennium.  


Penicillin G was first used in 1941. Since then, the trend in bacterial infections has changed. New antibiotics have been developed and bacterial resistance has spread as a consequence. The spread of Gram positive resistant bacteria is related to an inappropriate use of antibiotics. Antibacterial agents are abused or overused in various fields: medicine itself, veterinary science and zootechnics. Now, at the beginning of the third millennium we have been forced to limit our therapeutic options in order to combat these insidious enemies. Selective antibiotic pressure on the microbial population, notably on enterococci and staphylococci, made these two pathogens recalcitrant to traditional chemotherapy. It is a matter of concern that today, vancomycin-resistant Enterococcus spp. (VRE) and vancomycin-intermediate and resistant Staphylococcus aureus (VISA and VRSA) are now being observed worldwide among emerging pathogens. Most pharmaceutical companies are today developing antimicrobial drugs that are active against Gram-positive bacteria. Quinupristin/dalfopristin and linezolid are the most promising drugs and are available only for serious infections; future agents being developed for multi-resistant Gram-positive infections include daptomycin and the glycyclines, although these are still in the development phase. Nevertheless, our group has had the opportunity to treat some serious infections with these drugs and the good results achieved are reported in this review. PMID:12094131

Bassetti, M; Melica, G; Cenderello, G; Rosso, R; Di Biagio, A; Bassetti, D



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

Adhvaryu, Meghna; Vakharia, Bhasker



Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance.  


In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance. PMID:1681885

Sakata, K; Kwok, T T; Murphy, B J; Laderoute, K R; Gordon, G R; Sutherland, R M



Evolution of antibiotic resistance by human and bacterial niche construction.  


Antibiotic treatment by humans generates strong viability selection for antibiotic-resistant bacterial strains. The frequency of host antibiotic use often determines the strength of this selection, and changing patterns of antibiotic use can generate many types of behaviors in the population dynamics of resistant and sensitive bacterial populations. In this paper, we present a simple model of hosts dimorphic for their tendency to use/avoid antibiotics and bacterial pathogens dimorphic in their resistance/sensitivity to antibiotic treatment. When a constant fraction of hosts uses antibiotics, the two bacterial strain populations can coexist unless host use-frequency is above a critical value; this critical value is derived as the ratio of the fitness cost of resistance to the fitness cost of undergoing treatment. When strain frequencies can affect host behavior, the dynamics may be analyzed in the light of niche construction. We consider three models underlying changing host behavior: conformism, the avoidance of long infections, and adherence to the advice of public health officials. In the latter two, we find that the pathogen can have quite a strong effect on host behavior. In particular, if antibiotic use is discouraged when resistance levels are high, we observe a classic niche-construction phenomenon of maintaining strain polymorphism even in parameter regions where it would not be expected. PMID:15856691

Boni, Maciej F; Feldman, Marcus W



Drug resistance genomics of the antimalarial drug artemisinin.  


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

Winzeler, Elizabeth A; Manary, Micah J



Antimalarial drug resistance and combination chemotherapy.  

PubMed Central

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

White, N



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

E-print Network

) and molecular modeling publications is still modest. Those about cancer cells [23­26] (over 70 publicationsMolecular graphics approach to bacterial AcrB protein­b-lactam antibiotic molecular recognition-negative bacteria, responsible for their resistance to lipophilic and amphiphilic drugs. In this work, a molecular

Ferreira, Márcia M. C.


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


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

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



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



ORIGINAL ARTICLE Resistance to a bacterial parasite in the crustacean  

E-print Network

to the bacterial parasite Pasteuria ramosa. In contrast to previous studies in this system, we use a clone of P; doi:10.1038/hdy.2011.122 Keywords: Mendelian segregation; resistance; Daphnia magna; Pasteuria ramosa. ramosa, not field isolates, which allows for a more definitive interpretation of results. We test

Lazzaro, Brian


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

PubMed Central

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

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



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

PubMed Central

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

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



Efflux-Mediated Antifungal Drug Resistance  

PubMed Central

Summary: Fungi cause serious infections in the immunocompromised and debilitated, and the incidence of invasive mycoses has increased significantly over the last 3 decades. Slow diagnosis and the relatively few classes of antifungal drugs result in high attributable mortality for systemic fungal infections. Azole antifungals are commonly used for fungal infections, but azole resistance can be a problem for some patient groups. High-level, clinically significant azole resistance usually involves overexpression of plasma membrane efflux pumps belonging to the ATP-binding cassette (ABC) or the major facilitator superfamily class of transporters. The heterologous expression of efflux pumps in model systems, such Saccharomyces cerevisiae, has enabled the functional analysis of efflux pumps from a variety of fungi. Phylogenetic analysis of the ABC pleiotropic drug resistance family has provided a new view of the evolution of this important class of efflux pumps. There are several ways in which the clinical significance of efflux-mediated antifungal drug resistance can be mitigated. Alternative antifungal drugs, such as the echinocandins, that are not efflux pump substrates provide one option. Potential therapeutic approaches that could overcome azole resistance include targeting efflux pump transcriptional regulators and fungal stress response pathways, blockade of energy supply, and direct inhibition of efflux pumps. PMID:19366916

Cannon, Richard D.; Lamping, Erwin; Holmes, Ann R.; Niimi, Kyoko; Baret, Philippe V.; Keniya, Mikhail V.; Tanabe, Koichi; Niimi, Masakazu; Goffeau, Andre; Monk, Brian C.



Resistance of bacterial spores to ultraviolet light  

SciTech Connect

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

Setlow, P.



Resistance proof, folding-inhibitor drugs  

E-print Network

Conventional drugs work, as a rule, by inhibiting the enzymatic activity of specific proteins, capping their active site. In this paper we present a model of non- conventional drug design based on the inhibiting effects small peptides obtained from segments of the protein itself have on the folding ability of the system. Such peptides attach to the newly expressed (unfolded) protein and inhibit its folding, inhibition which cannot be avoided but through mutations which in any case denaturate the enzyme. These peptides, or their mimetic molecules, can be used as effective alternative drugs to those already available, displaying the advantage of not suffering from the upraise of resistence.

R. Broglia; G. Tiana; R. Berera



Protein oxidation: key to bacterial desiccation resistance?  


For extremely ionizing radiation-resistant bacteria, survival has been attributed to protection of proteins from oxidative damage during irradiation, with the result that repair systems survive and function with far greater efficiency during recovery than in sensitive bacteria. Here we examined the relationship between survival of dry-climate soil bacteria and the level of cellular protein oxidation induced by desiccation. Bacteria were isolated from surface soils of the shrub-steppe of the US Department of Energy's Hanford Site in Washington State. A total of 63 isolates were used for phylogenetic analysis. The majority of isolates were closely related to members of the genus Deinococcus, with Chelatococcus, Methylobacterium and Bosea also among the genera identified. Desiccation-resistant isolates accumulated high intracellular manganese and low iron concentrations compared to sensitive bacteria. In vivo, proteins of desiccation-resistant bacteria were protected from oxidative modifications that introduce carbonyl groups in sensitive bacteria during drying. We present the case that survival of bacteria that inhabit dry-climate soils are highly dependent on mechanisms, which limit protein oxidation during dehydration. PMID:18273068

Fredrickson, James K; Li, Shu-mei W; Gaidamakova, Elena K; Matrosova, Vera Y; Zhai, Min; Sulloway, Heather M; Scholten, Johannes C; Brown, Mindy G; Balkwill, David L; Daly, Michael J



Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance  

NASA Astrophysics Data System (ADS)

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

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



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 Creutzfeldt–Jakob 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 Creutzfeldt–Jakob 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



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

Federal Register 2010, 2011, 2012, 2013, 2014

...Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment...entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for treat acute bacterial skin and skin structure infections (ABSSSI). This...



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: [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)



Mechanisms of Drug Resistance in Cancer Chemotherapy  

Microsoft Academic Search

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

Y. A. Luqmani



Malaria drug resistance: new observations and developments  

PubMed Central

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

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




PubMed Central

Harada, Kenji (Gunma University, Maebashi, Japan), Mitsuo Kameda, Mitsue Suzuki, and Susumu Mitsuhashi. Drug resistance of enteric bacteria. II. Transduction of transmissible drug-resistance (R) factors with phage epsilon. J. Bacteriol. 86:1332–1338. 1963.—Transmissible drug-resistance (R) factors, which transfer resistance to tetracycline (TC), chloramphenicol, streptomycin, and sulfonamide by cell-to-cell contact, were found to be transduced in the system of Salmonella E group with phage epsilon (?15 and ?34). The R+ transductants of S. newington (S-84) and S. chittagong (S-224) were all found to be unable to transfer their R factors by conjugation, and their R factors were not eliminated by treatment with acridine dyes so far as tested. The R factors containing TC resistance were consistently segregated when transduced. At low multiplicities of infection, the R+ transductants with ?15 were all nonlysogenic and unable to produce normal ?15 phage particles; among the R+ transductants with ?34, 34% were lysogenic and 66% were sensitive to ?34. PMID:14086110

Harada, Kenji; Kameda, Mitsuo; Suzuki, Mitsue; Mitsuhashi, Susumu



Bacterial glyphosate resistance conferred by overexpression of an E. coli membrane efflux transporter.  


Glyphosate herbicide-resistant crop plants, introduced commercially in 1994, now represent approximately 85% of the land area devoted to transgenic crops. Herbicide resistance in commercial glyphosate-resistant crops is due to expression of a variant form of a bacterial 5-enolpyruvylshikimate-3-phosphate synthase with a significantly decreased binding affinity for glyphosate at the target site of the enzyme. As a result of widespread and recurrent glyphosate use, often as the only herbicide used for weed management, increasing numbers of weedy species have evolved resistance to glyphosate. Weed resistance is most often due to changes in herbicide translocation patterns, presumed to be through the activity of an as yet unidentified membrane transporter in plants. To provide insight into glyphosate resistance mechanisms and identify a potential glyphosate transporter, we screened Escherichia coli genomic DNA for alternate sources of glyphosate resistance genes. Our search identified a single non-target gene that, when overexpressed in E. coli and Pseudomonas, confers high-level glyphosate resistance. The gene, yhhS, encodes a predicted membrane transporter of the major facilitator superfamily involved in drug efflux. We report here that an alternative mode of glyphosate resistance in E. coli is due to reduced accumulation of glyphosate in cells that overexpress this membrane transporter and discuss the implications for potential alternative resistance mechanisms in other organisms such as plants. PMID:22089966

Staub, Jeffrey M; Brand, Leslie; Tran, Minhtien; Kong, Yifei; Rogers, Stephen G



Differential resistance of drinking water bacterial populations to monochloramine disinfection.  


The impact of monochloramine disinfection on the complex bacterial community structure in drinking water systems was investigated using culture-dependent and culture-independent methods. Changes in viable bacterial diversity were monitored using culture-independent methods that distinguish between live and dead cells based on membrane integrity, providing a highly conservative measure of viability. Samples were collected from lab-scale and full-scale drinking water filters exposed to monochloramine for a range of contact times. Culture-independent detection of live cells was based on propidium monoazide (PMA) treatment to selectively remove DNA from membrane-compromised cells. Quantitative PCR (qPCR) and pyrosequencing of 16S rRNA genes was used to quantify the DNA of live bacteria and characterize the bacterial communities, respectively. The inactivation rate determined by the culture-independent PMA-qPCR method (1.5-log removal at 664 mg·min/L) was lower than the inactivation rate measured by the culture-based methods (4-log removal at 66 mg·min/L). Moreover, drastic changes in the live bacterial community structure were detected during monochloramine disinfection using PMA-pyrosequencing, while the community structure appeared to remain stable when pyrosequencing was performed on samples that were not subject to PMA treatment. Genera that increased in relative abundance during monochloramine treatment include Legionella, Escherichia, and Geobacter in the lab-scale system and Mycobacterium, Sphingomonas, and Coxiella in the full-scale system. These results demonstrate that bacterial populations in drinking water exhibit differential resistance to monochloramine, and that the disinfection process selects for resistant bacterial populations. PMID:24625288

Chiao, Tzu-Hsin; Clancy, Tara M; Pinto, Ameet; Xi, Chuanwu; Raskin, Lutgarde



Management of antiviral drug resistance in chronic hepatitis B  

PubMed Central

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

Bang, Ki Bae; Kim, Hong Joo



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.



Genetic dissection of drug resistance in trypanosomes.  


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

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



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


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

Mellbye, Brett; Schuster, Martin



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



Absence of bacterial resistance following repeat exposure to photodynamic therapy  

NASA Astrophysics Data System (ADS)

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

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



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


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

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



Stop the Spread of Superbugs: Help Fight Drug Resistant Bacteria  


... superbug increasingly seen outside hospitals is methicillin-resistant Staphylococcus aureus (MRSA). These bacteria don’t respond to methicillin ... misuse of medications. Antimicrobial (Drug) Resistance Methicillin-Resistant Staphylococcus aureus (MRSA) Get Smart: Know When Antibiotics Work (CDC) ( ...


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


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

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



Capsule Polysaccharide Mediates Bacterial Resistance to Antimicrobial Peptides  

PubMed Central

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

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



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



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

PubMed Central

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

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



Drug resistance in chemotherapy for breast cancer.  


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



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


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

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



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


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

Dey, Diganta; Ray, Ratnamala; Hazra, Banasri



Comparative proteomic analysis of bacterial wilt susceptible and resistant tomato cultivars  

Microsoft Academic Search

To investigate the molecular mechanisms of bacterial resistance in susceptible and resistant cultivars of tomato, a proteomic approach was adopted. Four cultivars of tomato were selected on the basis of their response to bacterial (Pseudomonas solanacearum) inoculation wherein cultivar Roma and Riogarande, and cultivar Pusa Ruby and Pant Bahr were considered as resistant and susceptible cultivars, respectively. Proteins were extracted

Amber Afroz; Muhammad Rashid Khan; Nagib Ahsan; Setsuko Komatsu



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

ERIC Educational Resources Information Center

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

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



Newer systems for bacterial resistances to toxic heavy metals.  

PubMed Central

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

Silver, S; Ji, G



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



Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance.  


Many different definitions for multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) bacteria are being used in the medical literature to characterize the different patterns of resistance found in healthcare-associated, antimicrobial-resistant bacteria. A group of international experts came together through a joint initiative by the European Centre for Disease Prevention and Control (ECDC) and the Centers for Disease Control and Prevention (CDC), to create a standardized international terminology with which to describe acquired resistance profiles in Staphylococcus aureus, Enterococcus spp., Enterobacteriaceae (other than Salmonella and Shigella), Pseudomonas aeruginosa and Acinetobacter spp., all bacteria often responsible for healthcare-associated infections and prone to multidrug resistance. Epidemiologically significant antimicrobial categories were constructed for each bacterium. Lists of antimicrobial categories proposed for antimicrobial susceptibility testing were created using documents and breakpoints from the Clinical Laboratory Standards Institute (CLSI), the European Committee on Antimicrobial Susceptibility Testing (EUCAST) and the United States Food and Drug Administration (FDA). MDR was defined as acquired non-susceptibility to at least one agent in three or more antimicrobial categories, XDR was defined as non-susceptibility to at least one agent in all but two or fewer antimicrobial categories (i.e. bacterial isolates remain susceptible to only one or two categories) and PDR was defined as non-susceptibility to all agents in all antimicrobial categories. To ensure correct application of these definitions, bacterial isolates should be tested against all or nearly all of the antimicrobial agents within the antimicrobial categories and selective reporting and suppression of results should be avoided. PMID:21793988

Magiorakos, A-P; Srinivasan, A; Carey, R B; Carmeli, Y; Falagas, M E; Giske, C G; Harbarth, S; Hindler, J F; Kahlmeter, G; Olsson-Liljequist, B; Paterson, D L; Rice, L B; Stelling, J; Struelens, M J; Vatopoulos, A; Weber, J T; Monnet, D L



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


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



Nanomedicine therapeutic approaches to overcome cancer drug resistance.  


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

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



Predicting the unpredictable: Transmission of drug-resistant HIV  

Microsoft Academic Search

We use a mathematical model to understand (from 1996 to 2001) and to predict (from 2001 to 2005) the evolution of the epidemic of drug-resistant HIV in San Francisco. We predict the evolutionary trajectories for 1,000 different drug-resistant strains with each strain having a different fitness relative to a drug-sensitive strain. We calculate that the current prevalence of resistance is

A. N. Aschenbach; H. B. Gershengorn; J. O. Kahn; S. M. Blower



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


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

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



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

PubMed Central

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



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.



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

Microsoft Academic Search

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

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



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 Löscher



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

E-print Network

Tetracycline Resistance Gene Maintenance under Varying Bacterial Growth Rate, Substrate and Oxygen, bacterial growth rate, and medium richness affect the maintenance of plasmid-borne TC resistance (Tet. aeruginosa in the absence of TC, and faster loss was observed in continuous culture at higher growth rates

Alvarez, Pedro J.


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 5 years 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



Use of a bacterial antimicrobial resistance gene microarray for the identification of resistant Staphylococcus aureus.  


As diagnostic and surveillance activities are vital to determine measures needed to control antimicrobial resistance (AMR), new and rapid laboratory methods are necessary to facilitate this important effort. DNA microarray technology allows the detection of a large number of genes in a single reaction. This technology is simple, specific and high-throughput. We have developed a bacterial antimicrobial resistance gene DNA microarray that will allow rapid antimicrobial resistance gene screening for all Gram-positive and Gram-negative bacteria. A prototype microarray was designed using a 70-mer based oligonucleotide set targeting AMR genes of Gram-negative and Gram-positive bacteria. In the present version, the microarray consists of 182 oligonucleotides corresponding to 166 different acquired AMR gene targets, covering most of the resistance genes found in both Gram-negative and -positive bacteria. A test study was performed on a collection of Staphylococcus aureus isolates from milk samples from dairy farms in Québec, Canada. The reproducibility of the hybridizations was determined, and the microarray results were compared with those obtained by phenotypic resistance tests (either MIC or Kirby-Bauer). The microarray genotyping demonstrated a correlation between penicillin, tetracycline and erythromycin resistance phenotypes with the corresponding acquired resistance genes. The hybridizations showed that the 38 antimicrobial resistant S. aureus isolates possessed at least one AMR gene. PMID:21083822

Garneau, P; Labrecque, O; Maynard, C; Messier, S; Masson, L; Archambault, M; Harel, J



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


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



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.


Understanding cellular responses to toxic agents: a model for mechanism-choice in bacterial metal resistance  

Microsoft Academic Search

Summary Bacterial resistances to metals are heterogeneous in both their genetic and biochemical bases. Metal resistance may be chromosomally-, plasmid- or transposonencoded, and one or more genes may be involved; at the biochemical level at least six different mechanisms are responsible for resistance. Various types of resistance mechanisms can occur singly or in combination and for a particular metal different

Duncan A. Rouch; Barry T. O. Lee; Andy P. Morby



The mesenchymal tumor microenvironment: a drug-resistant niche.  


Drug and radiation resistance represent a challenge for most anticancer therapies. Diverse experimental approaches have provided evidence that the tumor-associated microenvironment constitutes both a protective shell that impedes drug or radiation access and a permissive or promotive microenvironment that encourages a nurturing cancer (i.e., cancer stem cell) niche where tumor cells overcome treatment- and cancer-induced stresses. Better understanding of the effects of the tumor microenvironment on cancer cells before, during and immediately after chemo- or radiotherapy is imperative to design new therapies aimed at targeting this tumor-protective niche. This review summarizes some of the known mesenchymal stromal effects that account for drug resistance, the main signal transduction pathways associated with this resistance and the therapeutic efforts directed to increase the success of current therapies. Special emphasis is given to environment-mediated drug resistance in general and to cell adhesion-mediated drug resistance in particular. PMID:22568991

Cukierman, Edna; Bassi, Daniel E



Drug resistance in tuberculosis: how to counter the menace?  


Tuberculosis is one of the leading global health issues responsible for a significant mortality. The emergence of multidrug resistant (MDR), extensively drug resistant (XDR) and total drug resistant (TDR) strains have further hampered the disease control. Drug resistance has emerged as imperative concern resulting in genetic selection of drug resistance strains making them unresponsive to most of the drugs. In addition iron has been implicated in promoting Mycobacterium tuberculosis (MTB) replication, infection and progression to clinical disease. ideR is an essential gene in Mycobacterium tuberculosis and controls the transcription of mycobacterium by binding to promoters of ideR regulated gene in presence of iron. Iron chelators have the potential to sequester this excess iron hence hampering MTB replication and restoring host defence mechanisms. Iron chelators could be envisaged as promising candidates in iron overload associated prevention and treatment of MTB. PMID:25420725

Talukdar, Daisy; Sharma, Rohit; Sharma, Anil K; Kumar, Raman



Bacterial lipopolysaccharides as inducers of disease resistance in tobacco.  

PubMed Central

The cell wall component of Pseudomonas solanacearum that induces disease resistance in tobacco was highly heat stable at neutral or alkaline pH but highly labile at acid pH. Activity was unaffected by nucleases and proteases but destroyed by a mixture of beta-glycosidases. Washing of bacterial cell walls released a lipopolysaccharide (LPS) fraction with high inducer activity. Purified LPS, extracted by a variety of procedures from whole cells, isolated cell walls, and culture filtrates of both smooth and rough forms of P. solanacearum, induced disease resistance in tobacco at concentrations as low as 50 microgram/ml. The LPS from the non-plant pathogens Escherichia coli B, E. coli K, and Serratia marcescens was also active. Cell wall protein, free phospholipid, and nucleic acids were not necessary for activity. Moreover, since LPS from rough forms was active, the O-specific polysaccharide of the LPS was not required for activity. Hydrolysis of the remaining core-lipid A linkage or deacylation of lipid A destroyed inducer activity. When injected into tobacco leaves, purified LPS attached to tobacco mesophyll cell walls and induced ultrastructural changes in the host cell similar to those induced by attachment of whole heat-killed bacteria. Images PMID:21613

Graham, T L; Sequeira, L; Huang, T S



Mechanisms and insights into drug resistance in cancer  

PubMed Central

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

Zahreddine, Hiba; Borden, Katherine L. B.



Drug resistance and the microenvironment: nature and nurture  

Microsoft Academic Search

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

Patrice J Morin



Efflux-Mediated Drug Resistance in Bacteria: an Update  

PubMed Central

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

Li, Xian-Zhi; Nikaido, Hiroshi



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



Relatively low primary drug resistant tuberculosis in southwestern Ethiopia  

PubMed Central

Background The prevalence of drug resistant tuberculosis (TB) in Ethiopia in general, and Jimma area in particular, is not well documented. We conducted a study at Jimma University specialized hospital in southwest Ethiopia among new cases of smear positive TB patients to determine the pattern of resistance to first-line drugs. Methods A health institution based cross sectional study was conducted from November 2010 to September 2011. Any newly diagnosed smear positive TB patient 18?years and above was included in the study. Demographic and related data were collected by trained personnel using a pretested structured questionnaire. Mycobacterial drug susceptibility testing (DST) to the first line drugs isoniazid (INH), rifampicin (RIF), ethambutol (EMB) and streptomycin (STM) was performed on cultures using the indirect proportion method. M. tuberculosis complex (MTBC) was identified with the Capilia TB-Neo test. Results 136 patients were enrolled in the study. Resistance to at least one drug was identified in 18.4%. The highest prevalence of resistance to any drug was identified against INH (13.2%) followed by STM (8.1%). There was no statistically significant difference in the proportion of any resistance by sex, age, HIV status and history of being imprisoned. The highest mono resistance was observed against INH (7.4%). Mono resistance to streptomycin was associated with HIV infection (crude OR 15.63, 95%CI: 1.31, 187). Multidrug-resistance TB (MDR-TB) was observed in two patients (1.5%). Conclusion Resistance to at least one drug was 18.4% (INH-13.2% and STM-8.1%). STM resistance was associated with HIV positivity. There was relatively low prevalence of MDR-TB yet INH resistance was common around Jimma. The capacity of laboratories for TB culture and DST should be strengthened, in order to correctly manage TB patients and avoid amplification of drug resistance. PMID:22574696



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.



Epidemiological control of drug resistance and compensatory mutation under resistance testing and second-line therapy.  


The fitness cost of antibiotic resistance in the absence of treatment raises the possibility that prudent use of drugs may slow or reverse the rise of resistance. Unfortunately, compensatory mutations that lower this cost may lead to entrenched resistance. Here, we develop a mathematical model of resistance evolution and compensatory mutation to determine whether reversion to sensitivity can occur, and how disease control might be facilitated by a second-line therapy. When only a single antibiotic is available, sensitive bacteria reach fixation only under treatment rates so low that hardly any cases are treated. We model a scenario in which drug sensitivity can be accurately tested so that a second-line therapy is administered to resistant cases. Before the rise of resistance to the second drug, disease eradication is possible if resistance testing and second-line treatment are conducted at a high enough rate. However, if double drug resistance arises, the possibility of disease eradication is greatly reduced and compensated resistance prevails in most of the parameter space. The boundary separating eradication from fixation of compensated resistance is strongly influenced by the underlying basic reproductive number of the pathogen and drug efficacy in sensitive cases, but depends less on the resistance cost and compensation. When double resistance is possible, the boundary is affected by the relative strengths of resistance against the two drugs in the double-resistant-compensated strain. PMID:24267872

Saddler, Clare A; Wu, Yue; Valckenborgh, Frank; Tanaka, Mark M



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



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


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

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



Molecular structure and dynamics in bacterial mercury resistance  

SciTech Connect

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

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



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

PubMed Central

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

Williams, Julia J.; Hergenrother, Paul J.



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


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


Understanding Drug Resistance in Breast Cancer with Mathematical Oncology.  


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

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



Drug Resistance among Pulmonary Tuberculosis Patients in Calabar, Nigeria  

PubMed Central

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

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



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


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



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



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



Drug-Resistant Candida glabrata Infection in Cancer Patients  

PubMed Central

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

Farmakiotis, Dimitrios; Tarrand, Jeffrey J.



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



Drug resistance in the sexually transmitted protozoan Trichomonas vaginalis.  


Trichomoniasis is the most common, sexually transmitted infection. It is caused by the flagellated protozoan parasite Trichomonas vaginalis. Symptoms include vaginitis and infections have been associated with preterm delivery, low birth weight and increased infant mortality, as well as predisposing to HIV/AIDS and cervical cancer. Trichomoniasis has the highest prevalence and incidence of any sexually transmitted infection. The 5-nitroimidazole drugs, of which metronidazole is the most prescribed, are the only approved, effective drugs to treat trichomoniasis. Resistance against metronidazole is frequently reported and cross-resistance among the family of 5-nitroimidazole drugs is common, leaving no alternative for treatment, with some cases remaining unresolved. The mechanism of metronidazole resistance in T. vaginalis from treatment failures is not well understood, unlike resistance which is developed in the laboratory under increasing metronidazole pressure. In the latter situation, hydrogenosomal function which is involved in activation of the prodrug, metronidazole, is down-regulated. Reversion to sensitivity is incomplete after removal of drug pressure in the highly resistant parasites while clinically resistant strains, so far analysed, maintain their resistance levels in the absence of drug pressure. Although anaerobic resistance has been regarded as a laboratory induced phenomenon, it clearly has been demonstrated in clinical isolates. Pursuit of both approaches will allow dissection of the underlying mechanisms. Many alternative drugs and treatments have been tested in vivo in cases of refractory trichomoniasis, as well as in vitro with some successes including the broad spectrum anti-parasitic drug nitazoxanide. Drug resistance incidence in T. vaginalis appears to be on the increase and improved surveillance of treatment failures is urged. PMID:12974614

Dunne, Rebecca L; Dunn, Linda A; Upcroft, Peter; O'Donoghue, Peter J; Upcroft, Jacqueline A



Origin of robustness in generating drug-resistant malaria parasites.  


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

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



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

PubMed Central

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

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



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


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

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



New mechanisms of drug resistance in parasitic protozoa.  


The main line of defense now available against parasitic protozoa--which are responsible for major diseases of humans and domestic animals--is chemotherapy. This defense is being eroded by drug resistance and, with few new drugs in the pipeline, prevention and circumvention of resistance are medical and veterinary priorities. Although studies of resistance mechanisms in parasites have lagged behind similar studies in bacteria and cancer cells, the tools to tackle this problem are rapidly improving. Transformation with exogenous DNA is now possible with all major parasitic protozoa of humans. Hence, putative resistance genes can be tested in sensitive protozoa, allowing an unambiguous reconstruction of resistance mechanisms. Gene cloning, the polymerase chain reaction, and monoclonal antibodies against resistance-related proteins have made it possible to analyze potential resistance mechanisms in the few parasites that can be obtained from infected people. Hence, the prospect of applying new knowledge about resistance mechanisms to parasites in patients is good, even though today virtually all knowledge pertains to parasites selected for resistance in the laboratory. Resistance mechanisms highlighted in this review include: 1. Decrease of drug uptake because of the loss of a transporter required for uptake. This decrease contributes to resistance to arsenicals and diamidines in African trypanosomes. 2. The export of drugs from the parasite by P-glycoproteins and other traffic ATPases. This export could potentially be an important mechanism of resistance, as these proteins are richly represented in the few protozoa analyzed. There are indications that such transmembrane transporters can be involved in resistance to emetine in Entamoeba spp., to mefloquine in Plasmodium spp., and to antimonials in Leishmania spp. 3. The possible involvement of the P-glycoprotein encoded by the Plasmodium falciparum pfmdr1 gene in chloroquine resistance. We present the available data that lead to the conclusion that overproduction of the wild-type version of this protein results in chloroquine hypersensitivity rather than resistance. 4. The involvement of the PgpA P-glycoprotein of Leishmania spp. in low-level resistance to arsenite and antimonials. We raise the possibility that this protein transports glutathione conjugates of arsenite and antimonials rather than the compounds themselves. 5. Loss of drug activation as the main mechanism of metronidazole resistance in Trichomonas and Giardia spp. Recent evidence indicates that a decrease of the proximal cellular electron donor for metronidazole activation, ferredoxin, is the main cause of resistance in Trichomonas. 6. Resistance arising through alteration of drug targets. The amino acid substitutions in the dihydrofolate reductase-thymidylate synthase of Plasmodium spp. are good examples of this mechanism.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8561467

Borst, P; Ouellette, M



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


... Marketing Share this: Main Content Area Methicillin-Resistant Staphylococcus aureus (MRSA) Scanning electron micrograph (SEM) depicting MRSA bacteria ... NIAID During the past four decades, methicillin-resistant Staphylococcus aureus , or MRSA, has evolved from a controllable nuisance ...


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

PubMed Central

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



Drug resistance in African trypanosomiasis: the melarsoprol and pentamidine story  

PubMed Central

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

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



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


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 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites. PMID:23375541

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



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 Zürich;); Sebastian Bonhoeffer (Institute of Integrative Biology, ETH Zürich;)



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


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



Serotype Distribution and Drug Resistance in Streptococcus pneumoniae, Palestinian Territories  

PubMed Central

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

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



Team finds gene that promotes drug resistance in cancer

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.


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

E-print Network

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

Hook, Andrew L.


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



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



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



African bovine trypanosomiasis: the problem of drug resistance  

Microsoft Academic Search

The three trypanocides used to control tsetse-transmitted trypanosomiasis in domestic animals in Africa have been in use for over 40 years and, not surprisingly, resistance of trypanosomes to these drugs has emerged. Because of the relatively limited market in Africa and the high costs of developing and licensing new drugs, international pharmaceutical companies have shown little interest in the development

Stanny Geerts; Peter H Holmes; Mark C Eisler; Oumar Diall



Sequence Note Low Prevalence of Drug Resistance Transmitted Virus  

E-print Network

Sequence Note Low Prevalence of Drug Resistance Transmitted Virus in HIV Type 1-Infected ARV inhibitors was detected in 59 amplified protease genes. The 1.49% (IC 95%: 0.04­8.04%) prevalence access to ARV drugs in resource-limited coun- tries, studies addressing the prevalence of primary muta

Paris-Sud XI, Université de


Modeling recombination's role in the evolution of HIV drug resistance  

E-print Network

Modeling recombination's role in the evolution of HIV drug resistance Richard K. Belew, Max W associated only with sexually reproducing species and also a controversial aspect of many evolutionary phenotypic virions (viral particles). Third, current drug therapies designed to attack the virus typically

Kirsh, David


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

PubMed Central

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

Martínez, José L.; Baquero, Fernando



MicroRNA-mediated drug resistance in breast cancer  

Microsoft Academic Search

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

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


Emergence of HIV1 Drug Resistance During Antiretroviral Treatment  

Microsoft Academic Search

Treating HIV-infected patients with a combination of several antiretroviral drugs usually contributes to a substantial decline\\u000a in viral load and an increase in CD4+ T cells. However, continuing viral replication in the presence of drug therapy can lead to the emergence of drug-resistant\\u000a virus variants, which subsequently results in incomplete viral suppression and a greater risk of disease progression. In

Libin Rong; Zhilan Feng; Alan S. Perelson



Duke researchers describe how breast cancer cells acquire drug resistance

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.


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 José Martins; Santin, Katiane; Nogueira, Christiane Lourenço



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.




E-print Network

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

Baillie, David


A Reservoir of Drug-Resistant Pathogenic Bacteria in Asymptomatic Hosts  

PubMed Central

The population genetics of pathogenic bacteria has been intensively studied in order to understand the spread of disease and the evolution of virulence and drug resistance. However, much less attention has been paid to bacterial carriage populations, which inhabit hosts without producing disease. Since new virulent strains that cause disease can be recruited from the carriage population of bacteria, our understanding of infectious disease is seriously incomplete without knowledge on the population structure of pathogenic bacteria living in an asymptomatic host. We report the first extensive survey of the abundance and diversity of a human pathogen in asymptomatic animal hosts. We have found that asymptomatic swine from livestock productions frequently carry populations of Salmonella enterica with a broad range of drug-resistant strains and genetic diversity greatly exceeding that previously described. This study shows how agricultural practice and human intervention may lead and influence the evolution of a hidden reservoir of pathogens, with important implications for human health. PMID:19015729

Perron, Gabriel G.; Quessy, Sylvain; Bell, Graham



Drug resistance in metastatic castration-resistant prostate cancer  

Microsoft Academic Search

Docetaxel in combination with prednisone is the standard of care in men with symptomatic castration-resistant prostate cancer (CRPC). However, a substantial proportion of men with CRPC do not benefit from docetaxel or other systemic therapy and those who do benefit invariably progress and die of (or with) prostate cancer. Resistance to chemotherapy in metastatic CRPC is a result of cellular

Bostjan Seruga; Alberto Ocana; Ian F. Tannock



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


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

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



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



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

PubMed Central

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

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



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


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



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. PMID:25191052

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



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 Gouvêa, Erika Ferraz



Genetic engineering for increasing fungal and bacterial disease resistance in crop plants.  


We review the current and future potential of genetic engineering strategies used to make fungal and bacterial pathogen-resistant GM crops, illustrating different examples of the technologies and the potential benefits and short-falls of the strategies. There are well- established procedures for the production of transgenic plants with resistance towards these pathogens and considerable progress has been made using a range of new methodologies. There are no current commercially available transgenic plant species with increased resistance towards fungal and bacterial pathogens; only plants with increased resistance towards viruses are available. With an improved understanding of plant signaling pathways in response to a range of other pathogens, such as fungi, additional candidate genes for achieving resistance are being investigated. The potential for engineering plants for resistance against individual devastating diseases or for plants with resistance towards multiple pathogens is discussed in detail. PMID:21844674

Wally, Owen; Punja, Zamir K



Convergence and coevolution of Hepatitis B virus drug resistance  

PubMed Central

Treatment with lamivudine of patients infected with hepatitis B virus (HBV) results in a high rate of drug resistance, which is primarily associated with the rtM204I/V substitution in the HBV reverse transcriptase domain. Here we show that the rtM204I/V substitution, although essential, is insufficient for establishing resistance against lamivudine. The analysis of 639 HBV whole-genome sequences obtained from 11 patients shows that rtM204I/V is independently acquired by more than one intra-host HBV variant, indicating the convergent nature of lamivudine resistance. The differential capacity of HBV variants to develop drug resistance suggests that fitness effects of drug-resistance mutations depend on the genetic structure of the HBV genome. An analysis of Bayesian networks that connect rtM204I/V to many sites of HBV proteins confirms that lamivudine resistance is a complex trait encoded by the entire HBV genome rather than by a single mutation. These findings have implications for public health and offer a more general framework for understanding drug resistance. PMID:22510694

Thai, Hong; Campo, David S.; Lara, James; Dimitrova, Zoya; Ramachandran, Sumathi; Xia, Guoliang; Ganova-Raeva, Lilia; Teo, Chong-Gee; Lok, Anna; Khudyakov, Yury



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.



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


Drug-resistant ventilator associated pneumonia in a tertiary care hospital in Saudi Arabia  

PubMed Central

BACKGROUND: There is a wide geographic and temporal variability of bacterial resistance among microbial causes of ventilator-associated pneumonia (VAP). The contribution of multi-drug resistant (MDR) pathogens to the VAP etiology in Saudi Arabia was never studied. We sought to examine the extent of multiple-drug resistance among common microbial causes of VAP. MATERIALS AND METHODS: We conducted a retrospective susceptibility study in the adult intensive care unit (ICU) of King Abdulaziz Medical City, Riyadh, Saudi Arabia. Susceptibility results of isolates from patients diagnosed with VAP between October 2004 and June 2009 were examined. The US National Healthcare Safety Network definition of MDR was adopted. RESULTS: A total of 248 isolates including 9 different pathogens were included. Acinetobacter spp. was highly (60-89%) resistant to all tested antimicrobials, including carbapenems (three- and four-class MDR prevalence were 86% and 69%, respectively). Pseudomonas aeruginosa was moderately (13-31%) resistant to all tested antimicrobials, including antipseudomonal penicillins (three- and four-class MDR prevalence were 13% and 10%, respectively). With an exception of ampicillin (fully resistant), Klebsiella spp. had low (0-13%) resistance to other tested antimicrobials with no detected MDR. Staphylococcus aureus was fully susceptible to vancomycin with 42% resistance to oxacillin. There were significant increasing trends of MDR Acinetobacter spp. however not P. aeruginosa during the study. Resistant pathogens were associated with worse profile of ICU patients but not patients’ outcomes. CONCLUSION: Acinetobacter in the current study was an increasingly resistant VAP-associated pathogen more than seen in many parts of the world. The current finding may impact local choice of initial empiric antibiotics. PMID:24791174

Balkhy, Hanan H.; El-Saed, Aiman; Maghraby, Rana; Al-Dorzi, Hasan M.; Khan, Raymond; Rishu, Asgar H.; Arabi, Yaseen M.




Technology Transfer Automated Retrieval System (TEKTRAN)

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


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.



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

E-print Network

A Bacterial Pathogen Co-opts Host Plasmin to Resist Killing by Cathelicidin Antimicrobial Peptides, promoting GAS resistance to the antimicrobial peptide. Conclusion: Ska contributes to GAS innate immune innate antimicrobial peptide LL-37, the human cathe- licidin. Cleavage products of plasmin-degraded LL-37

Nizet, Victor


[Evolution of bacterial resistance to certain antibacterial agents in horses in a veterinary hospital].  


Evolution of bacterial resistance to certain antibacterial agents in horses in a veterinary hospital. A total of 255 antibiograms, conducted according to the Kirby-Bauer method from bacterial isolates collected from horses at the Hôpital Vétérinaire d'Enseignement at the Université de Montréal between 1996 and 1998 were compared with the results obtained about 10 years ago with corresponding bacterial species. A significant increase in the percentage of strains resistant to trimethoprim-sulfamethoxazole (TMP-SXT), penicilline, tetracycline, and to gentamicin was observed. The percentages of isolates of Actinobacillus spp. and coagulase-positive staphylococci resistant to TMP-SXT increased from 0% to 17% and from 0% to 33%, respectively, (P < 0.05). The percentage of isolates of Actinobacillus spp resistant to penicilline also increased from 33% to 73% (P < 0.05). Regular monitoring of the evolution of bacterial resistance to antibacterial agents is indispensable in a hospital structure. The adoption of "good antibiotherapy practices" is essential to guarantee a decrease in the risks of selection and dissemination of a resistant bacterial strain. PMID:14703083

Peyrou, Mathieu; Higgins, Robert; Lavoie, Jean-Pierre



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


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

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



Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection  

PubMed Central

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

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



Drug-resistant tuberculosis in the WHO Western Pacific Region  

PubMed Central

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

Hiatt, Tom; Hennig, Cornelia; Nishikiori, Nobuyuki



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


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

Groenendijk, Floris H; Bernards, René



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

PubMed Central

Objective To evaluate the antibacterial properties of Allium sativum (garlic) cloves and Zingiber officinale (ginger) rhizomes against multi-drug resistant clinical pathogens causing nosocomial infection. Methods The cloves of garlic and rhizomes of ginger were extracted with 95% (v/v) ethanol. The ethanolic extracts were subjected to antibacterial sensitivity test against clinical pathogens. Results Anti-bacterial potentials of the extracts of two crude garlic cloves and ginger rhizomes were tested against five gram negative and two gram positive multi-drug resistant bacteria isolates. All the bacterial isolates were susceptible to crude extracts of both plants extracts. Except Enterobacter sp. and Klebsiella sp., all other isolates were susceptible when subjected to ethanolic extracts of garlic and ginger. The highest inhibition zone was observed with garlic (19.45 mm) against Pseudomonas aeruginosa (P. aeruginosa). The minimal inhibitory concentration was as low as 67.00 µg/mL against P. aeruginosa. Conclusions Natural spices of garlic and ginger possess effective anti-bacterial activity against multi-drug clinical pathogens and can be used for prevention of drug resistant microbial diseases and further evaluation is necessary. PMID:23569978

Karuppiah, Ponmurugan; Rajaram, Shyamkumar



Bacterial cheating drives the population dynamics of cooperative antibiotic resistance plasmids  

PubMed Central

Inactivation of ?-lactam antibiotics by resistant bacteria is a ‘cooperative' behavior that may allow sensitive bacteria to survive antibiotic treatment. However, the factors that determine the fraction of resistant cells in the bacterial population remain unclear, indicating a fundamental gap in our understanding of how antibiotic resistance evolves. Here, we experimentally track the spread of a plasmid that encodes a ?-lactamase enzyme through the bacterial population. We find that independent of the initial fraction of resistant cells, the population settles to an equilibrium fraction proportional to the antibiotic concentration divided by the cell density. A simple model explains this behavior, successfully predicting a data collapse over two orders of magnitude in antibiotic concentration. This model also successfully predicts that adding a commonly used ?-lactamase inhibitor will lead to the spread of resistance, highlighting the need to incorporate social dynamics into the study of antibiotic resistance. PMID:23917989

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



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


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



Structural pharmacogenomics, drug resistance and the design of anti-infective super-drugs.  


Large-scale comparative analysis of drug-target polymorphism structures enables the rational design of next generation 'super drugs'--drugs that are less prone to development of drug resistance or that work for the largest possible fraction of the patient population. Furthermore, knowledge of the drug-target-shape repertoire that exists within the patient population enables predictions of likely clinical trial outcomes and response rates for drug efficacy. This gives information on the optimal drug candidates before the initiation of clinical trials. The economic impact of incorporating pharmacogenomics insights early on in the drug discovery process will be substantial and will afford significant competitive advantages to companies that successfully incorporate this technology. PMID:12547004

Maggio, Edward T; Shenderovich, Mark; Kagan, Ron; Goddette, Dean; Ramnarayan, Kal



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


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

Padwal, Priyanka; Bandyopadhyaya, Rajdip; Mehra, Sarika



Expression of the Bs2 Pepper Gene Confers Resistance to Bacterial Spot Disease in Tomato  

Microsoft Academic Search

The Bs2 resistance gene of pepper specifically recognizes and confers resistance to strains of Xanthomonas campestris pv. vesicatoria that contain the corresponding bacterial avirulence gene, avrBs2. The involvement of avrBs2 in pathogen fitness and its prevalence in many X. campestris pathovars suggests that the Bs2 gene may be durable in the field and provide resistance when introduced into other plant

Thomas H. Tai; Douglas Dahlbeck; Eszter T. Clark; Paresh Gajiwala; Romela Pasion; Maureen C. Whalen; Robert E. Stall; Brian J. Staskawicz



Bypassing Fluoroquinolone Resistance with Quinazolinediones: Studies of Drug-Gyrase-DNA Complexes Having Implications for Drug Design.  


Widespread fluoroquinolone resistance has drawn attention to quinazolinediones (diones), fluoroquinolone-like topoisomerase poisons that are unaffected by common quinolone-resistance mutations. To better understand differences between quinolones and diones, we examined their impact on the formation of cleaved complexes (drug-topoisomerase-DNA complexes in which the DNA moiety is broken) with gyrase, one of two bacterial targets of the drugs. Formation of cleaved complexes, measured by linearization of a circular DNA substrate, required lower concentrations of quinolone than dione. The reverse reaction, detected as resealing of DNA breaks in cleaved complexes, required higher temperatures and EDTA concentrations for quinolones than diones. The greater stability of quinolone-containing complexes was attributed to the unique ability of the quinolone C3/C4 keto acid to complex with magnesium and form a previously described drug-magnesium-water bridge with GyrA-Ser83 and GyrA-Asp87. A nearby substitution in GyrA (G81C) reduced activity differences between quinolone and dione, indicating that resistance due to this variation derives from perturbation of the magnesium-water bridge. To increase dione activity, we examined a relatively small, flexible C-7-3-(aminomethyl)pyrrolidinyl substituent, which is distal to the bridging C3/C4 keto acid substituent of quinolones. The 3-(aminomethyl)pyrrolidinyl group at position C-7 was capable of forming binding interactions with GyrB-Glu466, as indicated by inspection of crystal structures, computer-aided docking, and measurement of cleaved-complex formation with mutant and wild-type GyrB proteins. Thus, modification of dione C-7 substituents constitutes a strategy for obtaining compounds active against common quinolone-resistant mutants. PMID:25310082

Drlica, Karl; Mustaev, Arkady; Towle, Tyrell R; Luan, Gan; Kerns, Robert J; Berger, James M



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



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.  


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

Böttner, A; Schmid, P; Humke, R



Role of integrin alpha4 in drug resistance of leukemia.  


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

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



Role of Integrin Alpha4 in Drug Resistance of Leukemia  

PubMed Central

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

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



Cross resistance pattern towards anticancer drugs of a human carcinoma multidrug-resistant cell line.  


Puromycin-resistant (PurR) mutants/variants of a human carcinoma cell line (HeLa), which show greatly reduced cellular uptake of 3H-puromycin and 3H-daunomycin have been isolated after one- and two-step selections in presence of the drug. The cross-resistance pattern of these mutant cell lines towards numerous anticancer drugs and other inhibitors has been examined. Both the first- and the second-step mutants exhibited increased resistance to a number of antimitotic drugs (viz. vinblastine, vincristine, colchicine, taxol and maytansine), several protein synthesis inhibitors (viz. chalcomycin, bruceantin, harringtonine, homoharringtonine), a large number of DNA interactive compounds (viz. aclacinomycin A, actinomycin D, adriamycin, m-AMSA, chromomycin A3, coralyne sulphoacetate, daunomycin, ellipticine, mithramycin, mitoxantrone, 5-methoxysterigmatocystin, rubidazone, variamycin, VM26 and VP16-213) and a number of other drugs acting via other mechanisms (viz. Baker's antifol, nitidine chloride and rhodamine 123). Whereas the first-step mutants showed stable resistance to these drugs, the second-step lines partially reverted upon growth in non-selective medium. Further, treatment of these mutant lines with non-cytotoxic doses of the calcium channel blocker verapamil reverted or abolished their resistance to the above drugs in a dose-dependent manner. In contrast to the above compounds, the PurR mutants showed no significant cross-resistance to a large number of other drugs which included asaley, AT-125, 5-azacytidine, azaserine, cyclocytidine, cis-platin, cytosine arabinoside, chlorambucil, chlorpromazine, alpha-difluoromethyl ornithine, 5-fluorouracil, ftorafur, gallium nitrate, hydroxyurea, ICRF-159, ICRF-187, imipramine, methotraxate, 6-methylmercaptopurine riboside, mycophenolic acid, melphalan, mitomycin C, methyl GAG, nafoxidine, reumycin, 6-selenoguanosine, 6-thioguanine, tiazofurin, tamoxifen, thalicarpine, tiapamil and verapamil). These cross-resistance data should prove useful in developing suitable drug combinations to which cellular resistance would not develop readily. PMID:3207599

Gupta, R S; Murray, W; Gupta, R



Cross resistance pattern towards anticancer drugs of a human carcinoma multidrug-resistant cell line.  

PubMed Central

Puromycin-resistant (PurR) mutants/variants of a human carcinoma cell line (HeLa), which show greatly reduced cellular uptake of 3H-puromycin and 3H-daunomycin have been isolated after one- and two-step selections in presence of the drug. The cross-resistance pattern of these mutant cell lines towards numerous anticancer drugs and other inhibitors has been examined. Both the first- and the second-step mutants exhibited increased resistance to a number of antimitotic drugs (viz. vinblastine, vincristine, colchicine, taxol and maytansine), several protein synthesis inhibitors (viz. chalcomycin, bruceantin, harringtonine, homoharringtonine), a large number of DNA interactive compounds (viz. aclacinomycin A, actinomycin D, adriamycin, m-AMSA, chromomycin A3, coralyne sulphoacetate, daunomycin, ellipticine, mithramycin, mitoxantrone, 5-methoxysterigmatocystin, rubidazone, variamycin, VM26 and VP16-213) and a number of other drugs acting via other mechanisms (viz. Baker's antifol, nitidine chloride and rhodamine 123). Whereas the first-step mutants showed stable resistance to these drugs, the second-step lines partially reverted upon growth in non-selective medium. Further, treatment of these mutant lines with non-cytotoxic doses of the calcium channel blocker verapamil reverted or abolished their resistance to the above drugs in a dose-dependent manner. In contrast to the above compounds, the PurR mutants showed no significant cross-resistance to a large number of other drugs which included asaley, AT-125, 5-azacytidine, azaserine, cyclocytidine, cis-platin, cytosine arabinoside, chlorambucil, chlorpromazine, alpha-difluoromethyl ornithine, 5-fluorouracil, ftorafur, gallium nitrate, hydroxyurea, ICRF-159, ICRF-187, imipramine, methotraxate, 6-methylmercaptopurine riboside, mycophenolic acid, melphalan, mitomycin C, methyl GAG, nafoxidine, reumycin, 6-selenoguanosine, 6-thioguanine, tiazofurin, tamoxifen, thalicarpine, tiapamil and verapamil). These cross-resistance data should prove useful in developing suitable drug combinations to which cellular resistance would not develop readily. PMID:3207599

Gupta, R. S.; Murray, W.; Gupta, R.



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.



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


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

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



Antibiotic residues and drug resistance in human intestinal flora.  

PubMed Central

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

Corpet, D E



The new concepts on overcoming drug resistance in lung cancer  

PubMed Central

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

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



Persistence of HIV-1 Transmitted Drug Resistance Mutations  

PubMed Central

There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models. PMID:23904291

Castro, Hannah; Pillay, Deenan; Cane, Patricia; Asboe, David; Cambiano, Valentina; Phillips, Andrew; Dunn, David T.; Aitken, Celia; Asboe, David; Webster, Daniel; Cane, Patricia; Castro, Hannah; Chadwick, David; Churchill, Duncan; Clark, Duncan; Collins, Simon; Delpech, Valerie; Geretti, Anna Maria; Goldberg, David; Hale, Antony; Hué, Stéphane; Kaye, Steve; Kellam, Paul; Lazarus, Linda; Leigh-Brown, Andrew; Mackie, Nicola; Orkin, Chloe; Rice, Philip; Pillay, Deenan; Smit, Erasmus; Templeton, Kate; Tilston, Peter; Tong, William; Williams, Ian; Zhang, Hongyi; Zuckerman, Mark; Greatorex, Jane; Wildfire, Adrian; O'Shea, Siobhan; Mullen, Jane; Mbisa, Tamyo; Cox, Alison; Tandy, Richard; Hale, Tony; Fawcett, Tracy; Hopkins, Mark; Ashton, Lynn; Garcia-Diaz, Ana; Shepherd, Jill; Schmid, Matthias L; Payne, Brendan; Chadwick, David; Hay, Phillip; Rice, Phillip; Paynter, Mary; Clark, Duncan; Bibby, David; Kaye, Steve; Kirk, Stuart; MacLean, Alasdair; Aitken, Celia; Gunson, Rory



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

PubMed Central

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




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

E-print Network

Quantitative Predictions of Binding Free Energy Changes in Drug-Resistant Influenza Neuraminidase identified mutations in influenza neuraminidase (NA) that confer drug resistance to two antiviral drugs Changes in Drug-Resistant Influenza Neuraminidase. PLoS Comput Biol 8(8): e1002665. doi:10.1371/journal


Phages limit the evolution of bacterial antibiotic resistance in experimental microcosms  

PubMed Central

The evolution of multi-antibiotic resistance in bacterial pathogens, often resulting from de novo mutations, is creating a public health crisis. Phages show promise for combating antibiotic-resistant bacteria, the efficacy of which, however, may also be limited by resistance evolution. Here, we suggest that phages may be used as supplements to antibiotics in treating initially sensitive bacteria to prevent resistance evolution, as phages are unaffected by most antibiotics and there should be little cross-resistance to antibiotics and phages. In vitro experiments using the bacterium Pseudomonas fluorescens, a lytic phage, and the antibiotic kanamycin supported this prediction: an antibiotic–phage combination dramatically decreased the chance of bacterial population survival that indicates resistance evolution, compared with antibiotic treatment alone, whereas the phage alone did not affect bacterial survival. This effect of the combined treatment in preventing resistance evolution was robust to immigration of bacteria from an untreated environment, but not to immigration from environment where the bacteria had coevolved with the phage. By contrast, an isogenic hypermutable strain constructed from the wild-type P. fluorescens evolved resistance to all treatments regardless of immigration, but typically suffered very large fitness costs. These results suggest that an antibiotic–phage combination may show promise as an antimicrobial strategy. PMID:23028398

Zhang, Quan-Guo; Buckling, Angus




EPA Science Inventory

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


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

PubMed Central

We report the whole-genome sequence of an extensively drug-resistant (XDR) tuberculosis (TB) strain of Latin American–Mediterranean (LAM) lineage. This strain is phenotypically resistant to aminoglycosides, but carries no related mutations in rrs, tlyA, and eis. Through genome analysis comparison with 16 XDR strains, we found 218 non-synonymous single nucleotide polymorphisms (SNPs) shared that could confer resistance. PMID:25081269

Tarazona, D.; Galarza, M.; Borda, V.; Curitomay, R.



Clustering of Antimicrobial Resistance Outbreaks Across Bacterial Species in the Intensive Care Unit  

PubMed Central

Background?There are frequent reports of intensive care unit (ICU) outbreaks due to transmission of particular antibiotic-resistant bacteria. Less is known about the burden of outbreaks of resistance due to horizontal transfer of mobile genetic elements between species. Moreover, the potential of existing statistical software as a preliminary means for detecting such events has never been assessed. This study uses a software package to determine the burden of species and resistance outbreaks in 2 adjacent ICUs and to look for evidence of clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Methods?A retrospective analysis of data from 2 adjacent 15-bed adult ICUs between 2002 and 2009 was undertaken. Detection of bacterial species-groups and resistance outbreaks was conducted using SaTScan and WHONet-SaTScan software. Resampling and permutation methods were applied to investigate temporal clustering of outbreaks. Results?Outbreaks occurred for 69% of bacterial species-groups (18/26), and resistance outbreaks were detected against 63% of antibiotics (10/16). Resistance outbreaks against 7 of 10 antibiotics were observed in multiple species-groups simultaneously and there was evidence of inter–species-group dependence for 4 of 7 antibiotics; background temporal changes in resistance did not explain the temporal aggregation of outbreaks in 3 of 7 antibiotics. Conclusions?Species outbreaks occurred for the majority of bacteria commonly identified in the ICU. There was evidence for frequent temporal clustering of resistance outbreaks consistent with interspecies transmission of resistance elements. Wider application of outbreak detection software combined with targeted sequencing of bacterial genomes is needed to understand the contribution of interspecies gene transfer to resistance emergence. PMID:23549524

Vlek, Anne L. M.; Cooper, Ben S.; Kypraios, Theodore; Cox, Andy; Edgeworth, Jonathan D.; Auguet, Olga Tosas



Detection of minor drug-resistant populations by  

E-print Network

active antiretroviral therapy (HAART) is the primary approach to treat HIV infection. However individuals infected with human immunodeficiency viruses (HIV), we successfully detected and quantified minor. This assay may serve as a useful tool to study drug resistance in HIV and other infectious agents. Highly

Cai, Long


"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.



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 Laboratory has isolated Salmonella Group C2 from cultures submitted from 4 different horse farms in either to most antibiotics. A Salmonella newport strain (Group C2) was recently associated with the closing

Keinan, Alon


Extracting causal relations on HIV drug resistance from literature  

Microsoft Academic Search

BACKGROUND: In HIV treatment it is critical to have up-to-date resistance data of applicable drugs since HIV has a very high rate of mutation. These data are made available through scientific publications and must be extracted manually by experts in order to be used by virologists and medical doctors. Therefore there is an urgent need for a tool that partially

Quoc-Chinh Bui; Breanndán Ó Nualláin; Charles A. Boucher; Peter M. A. Sloot



Clinical factors of drug resistance in juvenile myoclonic epilepsy  

Microsoft Academic Search

Juvenile myoclonic epilepsy is a comparatively benign form of idiopathic generalised epilepsy. Little is known about the prevalence of difficult to treat or drug resistant patients. Among 155 consecutive patients with newly diagnosed juvenile myoclonic epilepsy evaluated between 1981 and 1998 and followed up for at least 1 year (61 men, 94 women; aged 15–70 years, mean 33 (SD 10.3);

P Gelisse; P Genton; P Thomas; M Rey; J C Samuelian; C Dravet



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

Federal Register 2010, 2011, 2012, 2013, 2014 drugs to treat drug-resistant bacterial pathogens implicated in ABSSSI, such as methicillin-resistant Staphylococcus aureus. The definitions of ABSSSI and the designs of ABSSSI clinical trials were discussed at a meeting of the...



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; Vögtli, Manuel; Batchelor, Matthew; Cooper, Matthew A.; Strunz, Torsten; Horton, Mike A.; Abell, Chris; Rayment, Trevor; Aeppli, Gabriel; McKendry, Rachel A.




E-print Network

conditions affect basic aspects of bacterial physiology, such as growth, conjugation efficiencyGravitational and Space Biology 19(2) August 2006 31 INCREASED BACTERIAL RESISTANCE AND VIRULENCE effect resembles the well studied bacterial general stress response. The latter is centrally controlled

Matin, A.C.


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


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



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

PubMed Central

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

Beceiro, Alejandro; Tomás, María



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


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



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.



Bacterial antibiotic resistance in soils irrigated with reclaimed municipal wastewater  

Technology Transfer Automated Retrieval System (TEKTRAN)

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


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.



Bacterial Resistance to Trimethoprim in Geriatric Medical Wards  

Microsoft Academic Search

Urinary tract infections (UTI) caused by organisms resistant to trimethoprim (TMP), as well as their faecal carriage were studied in two geriatric wards. TMP-resistant UTI was common (26 and 50% of admission and ward-acquired infections, respectively) and was associated with male sex, recurrent and transferred admissions and length of stay. There was a strong relationship between faecal carriage and isolation

M. J. Bendall; S. Ebrahim; R. G. Finch; R. C. B. Slack; K. J. Towner



Bacterial disease resistance in Arabidopsis through flagellin perception  

Microsoft Academic Search

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

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



Lipid A Acylation and Bacterial Resistance against Vertebrate Antimicrobial Peptides  

Microsoft Academic Search

The Salmonellae PhoP-PhoQ virulence regulators induce resistance to host cationic antimicrobial peptides (CAMP) after infection of vertebrate tissues, and Mg2+ or Ca2+ limitation. The PhoP-PhoQ activated gene, pagP, was identified as important to inducible CAMP resistance and increased acylation of lipid A, the major component of the outer leaflet of the outer membrane. pagP mutants demonstrated increased outer membrane permeability

Lin Guo; Kheng B Lim; Cristina M Poduje; Morad Daniel; John S Gunn; Murray Hackett; Samuel I Miller



Absence of bacterial resistance to medical-grade manuka honey.  


Clinical use of honey in the topical treatment of wounds has increased in Europe and North America since licensed wound care products became available in 2004 and 2007, respectively. Honey-resistant bacteria have not been isolated from wounds, but there is a need to investigate whether honey has the potential to select for honey resistance. Two cultures of bacteria from reference collections (Staphylococcus aureus NCTC 10017 and Pseudomonas aeruginosa ATCC 27853) and four cultures isolated from wounds (Escherichia coli, methicillin-resistant S. aureus (MRSA), Pseudomonas aeruginosa and S. epidermidis) were exposed to sub-lethal concentrations of manuka honey in continuous and stepwise training experiments to determine whether the susceptibility to honey diminished. Reduced susceptibilities to manuka honey in the test organisms during long-term stepwise resistance training were found, but these changes were not permanent and honey-resistant mutants were not detected. The risk of bacteria acquiring resistance to honey will be low if high concentrations are maintained clinically. PMID:20549529

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



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

PubMed Central

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

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



Pyramiding transgenes for multiple resistance in rice against bacterial blight, yellow stem borer and sheath blight.  


Here we describe the development of transgene-pyramided stable elite rice lines resistant to disease and insect pests by conventional crossing of two transgenic parental lines transformed independently with different genes. The Xa21 gene (resistance to bacterial blight), the Bt fusion gene (for insect resistance) and the chitinase gene (for tolerance of sheath blight) were combined in a single rice line by reciprocal crossing of two transgenic homozygous IR72 lines. F4 plant lines carrying all the genes of interest stably were identified using molecular methods. The identified lines, when exposed to infection caused by Xanthomonas oryzae pv oryzae, showed resistance to bacterial blight. Neonate larval mortality rates of yellow stem borer ( Scirpophaga incertulas) in an insect bioassay of the same identified lines were 100%. The identified line pyramided with different genes to protect against yield loss showed high tolerance of sheath blight disease caused by Rhizoctonia solani. PMID:12582865

Datta, K; Baisakh, N; Thet, K Maung; Tu, J; Datta, S K



Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer.  


After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer. PMID:24927631

Chism, David D; De Silva, Dinuka; Whang, Young E



Genetic and molecular basis of drug resistance and species-specific drug action in schistosome parasites.  


Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally derived second-generation progeny, and identified a single quantitative trait locus (logarithm of odds = 31) on chromosome 6. A sulfotransferase was identified as the causative gene by using RNA interference knockdown and biochemical complementation assays, and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide. PMID:24263136

Valentim, Claudia L L; Cioli, Donato; Chevalier, Frédéric D; Cao, Xiaohang; Taylor, Alexander B; Holloway, Stephen P; Pica-Mattoccia, Livia; Guidi, Alessandra; Basso, Annalisa; Tsai, Isheng J; Berriman, Matthew; Carvalho-Queiroz, Claudia; Almeida, Marcio; Aguilar, Hector; Frantz, Doug E; Hart, P John; LoVerde, Philip T; Anderson, Timothy J C



Genetic and molecular basis of drug resistance and species-specific drug action in Schistosome parasites  

PubMed Central

Oxamniquine resistance evolved in the human blood fluke (Schistosoma mansoni) in Brazil in the 1970s. We crossed parental parasites differing ~500-fold in drug response, determined drug sensitivity and marker segregation in clonally-derived F2s, and identified a single QTL (LOD=31) on chromosome 6. A sulfotransferase was identified as the causative gene using RNAi knockdown and biochemical complementation assays and we subsequently demonstrated independent origins of loss-of-function mutations in field-derived and laboratory-selected resistant parasites. These results demonstrate the utility of linkage mapping in a human helminth parasite, while crystallographic analyses of protein-drug interactions illuminate the mode of drug action and provide a framework for rational design of oxamniquine derivatives that kill both S. mansoni and S. haematobium, the two species responsible for >99% of schistosomiasis cases worldwide. PMID:24263136

Valentim, Claudia L. L.; Cioli, Donato; Chevalier, Frédéric D.; Cao, Xiaohang; Taylor, Alexander B.; Holloway, Stephen P.; Pica-Mattoccia, Livia; Guidi, Alessandra; Basso, Annalisa; Tsai, Isheng J.; Berriman, Matthew; Carvalho-Queiroz, Claudia; Almeida, Marcio; Aguilar, Hector; Frantz, Doug E.; Hart, P. John; LoVerde, Philip T.; Anderson, Timothy J.C.



Integration of Biological Control Agents and Systemic Acquired Resistance Inducers Against Bacterial Spot on Tomato  

Microsoft Academic Search

Obradovic, A., Jones, J. B., Momol, M. T., Olson, S. M., Jackson, L. E., Balogh, B., Guven, K., and Iriarte, F. B. 2005. Integration of biological control agents and systemic acquired resistance inducers against bacterial spot on tomato. Plant Dis. 89:712-716. Two strains of plant growth-promoting rhizobacteria, two systemic acquired resistance inducers (harpin and acibenzolar-S-methyl), host-specific unformulated bacteriophages, and two

A. Obradovic; J. B. Jones; M. T. Momol; S. M. Olson; L. E. Jackson; B. Balogh; K. Guven; F. B. Iriarte



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



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


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

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



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

PubMed Central

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

Park, Miseon



Breeding Strains of Cotton Resistant to Bacterial Blight.  

E-print Network

that susceptibility was dominant and resistance was recessive. The nature of the genetic data, along with the results of indi- vidual plant selections, indicated that minor genes greatly in- fluence the degree of resistance given by the major genes. CONTENTS... was attributed to a complex of minor and modifying genes in G. arboreum. Another factor, B,, was found by Knight (11) in G. barbadense, variety Grenadines White Pollen. B, appeared to be partially dominant and additive in conjunction with B,, B,, B, and B...

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



Linking Surveillance with Action against Drug-Resistant Tuberculosis  

PubMed Central

The speed at which most countries with high burdens of multidrug-resistant tuberculosis (MDRTB) have scaled up their capacity to diagnose and treat individuals with these forms of TB has failed to keep pace with the problem. Limited availability of drug susceptibility testing, high costs and inefficiencies in the supply of second-line drugs, and inadequate capacity for the management of patients with MDRTB have contributed to the wide gap between the estimated need for and the delivery of MDRTB treatment. The most recent global estimates indicate that only about 1 in 20 individuals with incident MDRTB will be properly diagnosed; fewer still receive quality-assured treatment. As policy makers confront the threat of growing levels of drug-resistant TB, there is a clear role for improved surveillance methods that can facilitate more effective public health responses. In countries that cannot yet test all incident cases for drug resistance, analysis of programmatic data and use of periodic, efficient surveys can provide information to help prioritize the use of limited resources to geographic areas or population subgroups of greatest concern. We describe methods for the analysis of routinely collected data and alternative surveys that can help tighten the link between surveillance activities and interventions. PMID:22592806

Manjourides, Justin; Hedt-Gauthier, Bethany



[Resistance to second-line anti-tuberculosis drugs among peruvian multidrug resistant Mycobacterium tuberculosis strains].  


Objectives. To determine the drug resistance profiles for quinolones: ciprofloxacin (CFX), ofloxacin (OFX), moxifloxacin (MFX), and gatifloxacin (GFX); and for injectables: kanamycin (KAN), amikacin (AMK), and capreomycin (CAP) in multidrug resistant (MDR) strains. We also investigated the correlation between mutations in rrs, tlyA and gyrA/B genes, and the in vitro resistance to the second-line anti-tuberculosis drugs. Materials and methods. In this pilot study we selected MDR clinical isolates collected from June-December 2004 in the Tropical Medicine Institute "Alexander von Humboldt" (Lima, Perú). The Minimum Inhibitory Concentration (MIC) of CFX, OFX, MFX, GFX, KAN, AMK and CAP for 14 clinical isolates were determined and the sequences of rrs, tlyA and gyrA/B genes were analyzed by conventional PCR followed by sequencing. Results. We obtained valid results for 11 samples. Four isolates were resistant to injectable drugs, and in all the cases the MICs were; >120 µg/mL for KAN and >160 µg/mL for AMK and CAP. Only 2 isolates were resistant to OFX with MIC = 4 µg/mL. Sequencing results suggested that the mutation A1401T in rrs gene could be the molecular cause of the resistance to injectable drugs. In this study we did not find any mutation in tlyA and gyrA/B associated to resistance. Conclusions. Our study suggests a possible association between the mutation A1401T in rrs and resistance to injectable drugs. However further studies should be done to confirm this hypothesis in Perú. PMID:25597717

Barletta, Francesca; Zamudio, Carlos; Rigouts, Leen; Seas, Carlos



A benefit of high temperature: increased effectiveness of a rice bacterial blight disease resistance gene  

E-print Network

challenges for plant disease management (Coakley et al., 1999; Garrett et al., 2006). While the specificA benefit of high temperature: increased effectiveness of a rice bacterial blight disease single disease resistance (R) genes imposes a strong selection for virulence in pathogen populations

Garrett, Karen A.


Registration of Common Bacterial Blight Resistant Dark Red Kidney Bean Germplasm Line USDK-CBB-15  

Technology Transfer Automated Retrieval System (TEKTRAN)

Dark red kidney bean (Phaseolus vulgaris L.) germplasm line USDK-CBB-15 was developed by USDA-ARS in cooperation with the Idaho Agricultural Experiment Station and released in 2005. This line was bred specifically for a high level of resistance to common bacterial blight (Xanthomonas axonopodis pv. ...


Enhanced tomato resistance to bacterial canker by application of turtle oil  

Microsoft Academic Search

Pretreatment with oil of sea turtle Caretta caretta protected tomato plants against bacterial canker caused by Clavibacter michiganensis subsp. michiganensis (Cmm). The turtle oil was ineffective in inhibiting Cmm in an agar diffusion test, suggesting a mechanism of induced resistance. Under controlled conditions in the greenhouse, turtle oil lowered the disease index and had reduced the growth of bacteria up

Ömür Baysal; Y. Ziya Gürsoy; Hakan Örnek; Ahmet Duru



The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates indicators  

E-print Network

The bacterial signal indole increases epithelial-cell tight-junction resistance and attenuates) are produced by the 1014 nonpathogenic commensal bacteria that coexist with host cells in the GI tract the enteric nervous system. The close proximity of bacteria and the host cells in the GI tract, as well

Wood, Thomas K.


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


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



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


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



The prevalence of multidrug-resistant bacterial strains has substantially  

E-print Network

against methicillin-resistant Staphylococcus aureus (MRSA). S. aureus is the leading cause of many human infections, particularly those of the skin and soft tissues. Moreover, MRSA -- a variation of this bacterium MRSA. Such virulence-factor-based approaches offer a new direction for therapies targeting multidrug

Nizet, Victor


Antibiotic Resistant Bacterial Profiles of Anaerobic Swine Lagoon Effluent  

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Antibiotic resistant bacterial profiles of anaerobic swine lagoon effluent  

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Structural basis for the inhibition of Mycobacterium tuberculosis L,D-transpeptidase by meropenem, a drug effective against extensively drug-resistant strains.  


Difficulty in the treatment of tuberculosis and growing drug resistance in Mycobacterium tuberculosis (Mtb) are a global health issue. Carbapenems inactivate L,D-transpeptidases; meropenem, when administered with clavulanate, showed in vivo activity against extensively drug-resistant Mtb strains. LdtMt2 (Rv2518c), one of two functional L,D-transpeptidases in Mtb, is predominantly expressed over LdtMt1 (Rv0116c). Here, the crystal structure of N-terminally truncated LdtMt2 (residues Leu131-Ala408) is reported in both ligand-free and meropenem-bound forms. The structure of meropenem-inhibited LdtMt2 provides a detailed structural view of the interactions between a carbapenem drug and Mtb L,D-transpeptidase. The structures revealed that the catalytic L,D-transpeptidase domain of LdtMt2 is preceded by a bacterial immunogloblin-like Big_5 domain and is followed by an extended C-terminal tail that interacts with both domains. Furthermore, it is shown using mass analyses that meropenem acts as a suicide inhibitor of LdtMt2. Upon acylation of the catalytic Cys354 by meropenem, the `active-site lid' undergoes a large conformational change to partially cover the active site so that the bound meropenem is accessible to the bulk solvent via three narrow paths. This work will facilitate structure-guided discovery of L,D-transpeptidase inhibitors as novel antituberculosis drugs against drug-resistant Mtb. PMID:23519417

Kim, Hyoun Sook; Kim, Jieun; Im, Ha Na; Yoon, Ji Young; An, Doo Ri; Yoon, Hye Jin; Kim, Jin Young; Min, Hye Kyeoung; Kim, Soon-Jong; Lee, Jae Young; Han, Byung Woo; Suh, Se Won



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


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



Coherent feedforward transcriptional regulatory motifs enhance drug resistance  

NASA Astrophysics Data System (ADS)

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

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



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

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


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



Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment.  


Antifungal resistance continues to grow and evolve and complicate patient management, despite the introduction of new antifungal agents. In vitro susceptibility testing is often used to select agents with likely activity for a given infection, but perhaps its most important use is in identifying agents that will not work, i.e., to detect resistance. Standardized methods for reliable in vitro antifungal susceptibility testing are now available from the Clinical and Laboratory Standards Institute (CLSI) in the United States and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) in Europe. Data gathered by these standardized tests are useful (in conjunction with other forms of data) for calculating clinical breakpoints and epidemiologic cutoff values (ECVs). Clinical breakpoints should be selected to optimize detection of non-wild-type (WT) strains of pathogens, and they should be species-specific and not divide WT distributions of important target species. ECVs are the most sensitive means of identifying strains with acquired resistance mechanisms. Various mechanisms can lead to acquired resistance of Candida species to azole drugs, the most common being induction of the efflux pumps encoded by the MDR or CDR genes, and acquisition of point mutations in the gene encoding for the target enzyme (ERG11). Acquired resistance of Candida species to echinocandins is typically mediated via acquisition of point mutations in the FKS genes encoding the major subunit of its target enzyme. Antifungal resistance is associated with elevated minimum inhibitory concentrations, poorer clinical outcomes, and breakthrough infections during antifungal treatment and prophylaxis. Candidemia due to Candida glabrata is becoming increasingly common, and C glabrata isolates are increasingly resistant to both azole and echinocandin antifungal agents. This situation requires continuing attention. Rates of azole-resistant Aspergillus fumigatus are currently low, but there are reports of emerging resistance, including multi-azole resistant isolates in parts of Europe. PMID:22196207

Pfaller, Michael A



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


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; Lionço, Livia Caprara; Tovo, Cristiane Valle



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; Lionço, Livia Caprara; Tovo, Cristiane Valle



Development of cetuximab-resistant human nasopharyngeal carcinoma cell lines and mechanisms of drug resistance  

Microsoft Academic Search

This work aimed to explore the induction of cetuximab-resistant human nasopharyngeal carcinoma (hNPC) 5-8F\\/Erbitux cells and the mechanisms of drug resistance. The 5-8F cells with high EGFR expression and cetuximab sensitivity were screened and then induced by stepwise exposure to increasing doses of cetuximab. Western blot was conducted to detect protein levels. Our results are as follows: we successfully induced

Qiang Zuo; Min Shi; Libo Li; Jinzhang Chen; Rongcheng Luo



Drug delivery by a self-assembled DNA tetrahedron for overcoming drug resistance in breast cancer cells.  


A DNA tetrahedron is employed for efficient delivery of doxorubicin into drug-resistant breast cancer cells. The drug delivered with the DNA nanoconstruct is considerably cytotoxic, whereas free doxorubicin is virtually non-cytotoxic for the drug-resistant cells. Thus, the DNA tetrahedron, made of the inherently natural and biocompatible material, can be a good candidate for the drug carrier to overcome MDR in cancer cells. PMID:23380739

Kim, Kyoung-Ran; Kim, Da-Rae; Lee, Taemin; Yhee, Ji Young; Kim, Byeong-Su; Kwon, Ick Chan; Ahn, Dae-Ro



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

Microsoft Academic Search

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.

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



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



Bacterial infections in Lilongwe, Malawi: aetiology and antibiotic resistance  

PubMed Central

Background Life-threatening infections present major challenges for health systems in Malawi and the developing world because routine microbiologic culture and sensitivity testing are not performed due to lack of capacity. Use of empirical antimicrobial therapy without regular microbiologic surveillance is unable to provide adequate treatment in the face of emerging antimicrobial resistance. This study was conducted to determine antimicrobial susceptibility patterns in order to inform treatment choices and generate hospital-wide baseline data. Methods Culture and susceptibility testing was performed on various specimens from patients presenting with possible infectious diseases at Kamuzu Central Hospital, Lilongwe, Malawi. Results Between July 2006 and December 2007 3104 specimens from 2458 patients were evaluated, with 60.1% from the adult medical service. Common presentations were sepsis, meningitis, pneumonia and abscess. An etiologic agent was detected in 13% of patients. The most common organisms detected from blood cultures were Staphylococcus aureus, Escherichia coli, Salmonella species and Streptococcus pneumoniae, whereas Streptococcus pneumoniae and Cryptococcus neoformans were most frequently detected from cerebrospinal fluid. Haemophilus influenzae was rarely isolated. Resistance to commonly used antibiotics was observed in up to 80% of the isolates while antibiotics that were not commonly in use maintained susceptibility. Conclusions There is widespread resistance to almost all of the antibiotics that are empirically used in Malawi. Antibiotics that have not been widely introduced in Malawi show better laboratory performance. Choices for empirical therapy in Malawi should be revised accordingly. A microbiologic surveillance system should be established and prudent use of antimicrobials promoted to improve patient care. PMID:22436174



Drug Resistance and the Kinetics of Metastatic Cancer  

NASA Astrophysics Data System (ADS)

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

Blagoev, Krastan B.



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



Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase  

SciTech Connect

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

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



Peptide IDR-1018: modulating the immune system and targeting bacterial biofilms to treat antibiotic-resistant bacterial infections.  


Host defense (antimicrobial) peptides, produced by all complex organisms, typically contain an abundance of positively charged and hydrophobic amino acid residues. A small synthetic peptide termed innate defense regulator (IDR-)1018 was derived by substantial modification of the bovine neutrophil host defense peptide bactenecin. Here, we review its intriguing properties that include anti-infective, anti-inflammatory, wound healing, and anti-biofilm activities. It was initially developed as an immune modulator with an ability to selectively enhance chemokine production and polarize cellular differentiation while suppressing/balancing the pro-inflammatory response. In this regard, it has demonstrated in vivo activity in murine models including enhancement of wound healing and an ability to protect against Staphylococcus aureus, multidrug resistant Mycobacterium tuberculosis, herpes virus, and inflammatory disorders, including cerebral malaria and neuronal damage in a pre-term birth model. More recently, IDR-1018 was shown, in a broad-spectrum fashion, to selectively target bacterial biofilms, which are adaptively resistant to many antibiotics and represent the most common growth state of bacteria in human infections. Furthermore, IDR-1018 demonstrated synergy with conventional antibiotics to both prevent biofilm formation and treat pre-existing biofilms. These data are consistent with a strong potential as an adjunctive therapy against antibiotic-resistant infections. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. PMID:25358509

Mansour, Sarah C; de la Fuente-Núñez, César; Hancock, Robert E W



Gram-positive bacterial resistance: future treatment options.  


Gram-positive infections are a major burden on patients and healthcare systems globally, and the need to treat these infections correctly in an empirical manner has become paramount. Further complicating this changing etiology is the emergence of resistant strains which are no longer predictably susceptible to standard first-line antimicrobials such as oxacillin or vancomycin. Thus, new agents such as linezolid have been developed to alleviate the 'guesswork' of initial empirical prescribing in infections where Gram-positive pathogens may be present. Future agents also being developed for multiresistant Gram-positive infections include evernimicin antibiotics, daptomycin, oritavancin, glycylcyclines and novel broad-spectrum cephalosporins; however, these are still in the development phase. PMID:14508878

Bassetti, Matteo; Melica, Giovanna; Di Biagio, Antonio; Rosso, Raffaella; Gatti, Giorgio; Bassetti, Dante



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

E-print Network

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

Modrzynska, Katarzyna Kinga



Host ecology shapes geographical variation for resistance to bacterial infection in Drosophila melanogaster  

PubMed Central

Summary 1. Geographically distinct host populations often experience very different ecological conditions. These variable ecological conditions impact the strength of selection that these hosts experience from their parasites. 2. Numerous studies have characterized geographical patterns of resistance to infection among natural populations in the context of host–parasite local adaptation, but what other factors might contribute to these differences? 3. Here, we determined whether 20 naturally isolated populations of Drosophila melanogaster collected along the East Coast of the United States varied for survival after being inoculated with one of two species of bacteria – Lactococcus lactis and Pseudomonas aeruginosa. We then asked whether host environment accounted for the observed patterns of resistance. 4. Resistance to both types of infection varied spatially. The hosts' natural environment was predictive of the observed spatial variation in resistance to L. lactis, but not P. aeruginosa, infection. Specifically, hosts exposed to species-rich bacterial communities were more likely to survive the infection. 5. We conclude that biotic characteristics of the host environment, specifically the number of species of bacteria hosts encounter, shape host resistance to bacterial infection in nature. We discuss our results in the context of what is known about the evolutionary ecology of resistance in invertebrate systems. PMID:18489569

Corby-Harris, Vanessa; Promislow, Daniel E. L.



Overcoming Platinum Drug Resistance with Copper-lowering Agents  

PubMed Central

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




Antibody-targeted drugs and drug resistance-Challenges and solutions.  


Antibody-based therapy of various human malignancies has shown efficacy in the past 30 years and is now one of the most successful and leading strategies for targeted treatment of patients harboring hematological malignancies and solid tumors. Antibody-drug conjugates (ADCs) aim to take advantage of the affinity and specificity of monoclonal antibodies (mAbs) to selectively deliver potent cytotoxic drugs to antigen-expressing tumor cells. Key parameters for ADC include choosing the optimal components of the ADC (the antibody, the linker and the cytotoxic drug) and selecting the suitable cell-surface target antigen. Building on the success of recent FDA approval of brentuximab vedotin (Adcetris(®)) and ado-trastuzumab emtansine (Kadcyla(®)), ADCs are currently a class of drugs with a robust pipeline with clinical applications that are rapidly expanding. The more ADCs are being evaluated in preclinical models and clinical trials, the clearer are becoming the parameters and the challenges required for their therapeutic success. This rapidly growing knowledge and clinical experience are revealing novel modalities and mechanisms of resistance to ADCs, hence offering plausible solutions to such challenges. Here, we review the key parameters for designing a powerful ADC, focusing on how ADCs are addressing the challenge of multiple drug resistance (MDR) and its rational overcoming. PMID:25476546

Shefet-Carasso, LeeRon; Benhar, Itai




Technology Transfer Automated Retrieval System (TEKTRAN)

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


Activity of Eugenia jambolana, an ethnomedical plant, against drug-resistant bacteria.  


Seeds of Eugenia jambolana Lam. (Myrtaceae) are used by many tribes in India to treat diarrhea and dysentery. The crude extracts of seeds of this plant demonstrated zones of inhibition in the range of 14- 21 mm against the isolated beta-lactamase-producing drug-resistant bacteria. The methanol extract showed promising antibacterial activity which was subjected to fractionation. The effective fraction (F2) showed a minimum inhibitory concentration (MIC) ranging from 31.75 to 62.5 microg/mL. Phytochemical analysis and thin layer chromatography of the most promising fraction showed the presence of saponin as the active phytoconstituent. The active fraction was further tested for its in vitro hemolytic activity in sheep and human erythrocytes and no hemolysis was seen. Thus, the use of this plant by tribals to treat bacterial infections has some scientific basis. PMID:20645718

Jasmine, R; Selvakumar, B N; Daisy, P; Ignacimuthu, S



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.



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


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



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


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



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


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

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



The Role of Antimicrobial Peptides in Preventing Multidrug-Resistant Bacterial Infections and Biofilm Formation  

PubMed Central

Over the last decade, decreasing effectiveness of conventional antimicrobial-drugs has caused serious problems due to the rapid emergence of multidrug-resistant pathogens. Furthermore, biofilms, which are microbial communities that cause serious chronic infections and dental plaque, form environments that enhance antimicrobial resistance. As a result, there is a continuous search to overcome or control such problems, which has resulted in antimicrobial peptides being considered as an alternative to conventional drugs. Antimicrobial peptides are ancient host defense effector molecules in living organisms. These peptides have been identified in diverse organisms and synthetically developed by using peptidomimic techniques. This review was conducted to demonstrate the mode of action by which antimicrobial peptides combat multidrug-resistant bacteria and prevent biofilm formation and to introduce clinical uses of these compounds for chronic disease, medical devices, and oral health. In addition, combinations of antimicrobial peptides and conventional drugs were considered due to their synergetic effects and low cost for therapeutic treatment. PMID:22016639

Park, Seong-Cheol; Park, Yoonkyung; Hahm, Kyung-Soo



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 Löwenstein-Jensen medium proportion method drug susceptibility testing (DST; 78.7%), but significantly less than those with common, undisputed mutations (96.3%). With 63% of patients experiencing failure or relapse in both groups, there was no difference in outcome of first-line retreatment between patients carrying a strain with disputed versus common mutations. We conclude that rifampin resistance that is difficult to detect by the gold standard, phenotypic DST, is clinically and epidemiologically highly relevant. Sensitivity rather than specificity is imperfect with any rifampin DST method. Even at a low prevalence of rifampin resistance, a rifampin-resistant result issued by a competent laboratory may not warrant confirmation, although the absence of a necessity for confirmation needs to be confirmed for molecular results among new cases. However, a result of rifampin susceptibility should be questioned when suspicion is very high, and further DST using a different system (i.e., genotypic after phenotypic testing) would be fully justified. PMID:23761144

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.



Secondary mutations of BRCA1/2 and drug resistance  

PubMed Central

Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 cause increased risk of developing various cancers, especially breast and ovarian cancers. Tumors that develop in patients with inherited BRCA1/2 mutations are generally believed to be BRCA1/2 deficient. Cancer cells with BRCA1/2 deficiency are defective in DNA repair by homologous recombination and sensitive to interstrand DNA crosslinking agents, such as cisplatin and carboplatin, and poly(ADP-ribose) polymerase (PARP) inhibitors. Therefore, these agents are logical choices for the treatment for BRCA1/2-deficient tumors and have shown to be clinically effective. However, BRCA1/2-mutated tumors often develop resistance to these drugs. Restoration of BRCA1/2 functions due to secondary BRCA1/2 mutations has been recognized as a mechanism of acquired resistance to cisplatin and PARP inhibitors in BRCA1/2-mutated cancer cells. This indicates that even disease-causing inherited mutations of tumor suppressor genes can be genetically reverted in cancer cells, if the genetic reversion is advantageous for the cells' survival. In this review, we will discuss this drug resistance mechanism. PMID:21205087

Dhillon, Kiranjit K.; Swisher, Elizabeth M.; Taniguchi, Toshiyasu



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


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



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



Comparison of Rhizosphere Bacterial Communities in Arabidopsis thaliana Mutants for Systemic Acquired Resistance  

Microsoft Academic Search

Systemic acquired resistance (SAR) is an inducible systemic plant defense against a broad spectrum of plant pathogens, with\\u000a the potential to secrete antimicrobial compounds into the soil. However, its impact on rhizosphere bacteria is not known.\\u000a In this study, we examined fingerprints of bacterial communities in the rhizosphere of the model plant Arabidopsis thaliana to determine the effect of SAR

John W. Hein; Gordon V. Wolfe; Kristopher A. Blee



Association mapping of common bacterial blight resistance QTL in Ontario bean breeding populations  

Microsoft Academic Search

Background  Common bacterial blight (CBB), incited by Xanthomonas axonopodis pv. phaseoli (Xap), is a major yield-limiting factor of common bean (Phaseolus vulgaris L.) production around the world. Host resistance is practically the most effective and environmentally-sound approach to\\u000a control CBB. Unlike conventional QTL discovery strategies, in which bi-parental populations (F2, RIL, or DH) need to be developed, association mapping-based strategies can

Chun Shi; Alireza Navabi; Kangfu Yu



A Decade of Spore-Forming Bacterial Infections Among European Injecting Drug Users: Pronounced Regional Variation  

PubMed Central

The recent anthrax outbreak among injecting drug users (IDUs) in Europe has highlighted an ongoing problem with severe illness resulting from spore-forming bacteria in IDUs. We collated the numbers of cases of 4 bacterial illnesses (botulism, tetanus, Clostridium novyi, and anthrax) in European IDUs for 2000 to 2009 and calculated population rates. Six countries reported 367 cases; rates varied from 0.03 to 7.54 per million people. Most cases (92%) were reported from 3 neighboring countries: Ireland, Norway, and the United Kingdom. This geographic variation needs investigation. PMID:22095355

Palmateer, Norah; Wiessing, Lucas; Marongiu, Andrea; White, Joanne; Ncube, Fortune; Goldberg, David



Role of integrated cancer nanomedicine in overcoming drug resistance.  


Cancer remains a major killer of mankind. Failure of conventional chemotherapy has resulted in recurrence and development of virulent multi drug resistant (MDR) phenotypes adding to the complexity and diversity of this deadly disease. Apart from displaying classical physiological abnormalities and aberrant blood flow behavior, MDR cancers exhibit several distinctive features such as higher apoptotic threshold, aerobic glycolysis, regions of hypoxia, and elevated activity of drug-efflux transporters. MDR transporters play a pivotal role in protecting the cancer stem cells (CSCs) from chemotherapy. It is speculated that CSCs are instrumental in reviving tumors after the chemo and radiotherapy. In this regard, multifunctional nanoparticles that can integrate various key components such as drugs, genes, imaging agents and targeting ligands using unique delivery platforms would be more efficient in treating MDR cancers. This review presents some of the important principles involved in development of MDR and novel methods of treating cancers using multifunctional-targeted nanoparticles. Illustrative examples of nanoparticles engineered for drug/gene combination delivery and stimuli responsive nanoparticle systems for cancer therapy are also discussed. PMID:23880506

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



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


The emergence of artemisinin resistance in Southeast Asia imperils efforts to reduce the global malaria burden. We genetically modified the Plasmodium falciparum K13 locus using zinc-finger nucleases and measured ring-stage survival rates after drug exposure in vitro; these rates correlate with parasite clearance half-lives in artemisinin-treated patients. With isolates from Cambodia, where resistance first emerged, survival rates decreased from 13 to 49% to 0.3 to 2.4% after the removal of K13 mutations. Conversely, survival rates in wild-type parasites increased from ?0.6% to 2 to 29% after the insertion of K13 mutations. These mutations conferred elevated resistance to recent Cambodian isolates compared with that of reference lines, suggesting a contemporary contribution of additional genetic factors. Our data provide a conclusive rationale for worldwide K13-propeller sequencing to identify and eliminate artemisinin-resistant parasites. PMID:25502314

Straimer, Judith; Gnädig, Nina F; Witkowski, Benoit; Amaratunga, Chanaki; Duru, Valentine; Ramadani, Arba Pramundita; Dacheux, Mélanie; Khim, Nimol; Zhang, Lei; Lam, Stephen; Gregory, Philip D; Urnov, Fyodor D; Mercereau-Puijalon, Odile; Benoit-Vical, Françoise; Fairhurst, Rick M; Ménard, Didier; Fidock, David A



Pharmacokinetic/Pharmacodynamic Analysis of the Influence of Inoculum Size on the Selection of Resistance in Escherichia coli by a Quinolone in a Mouse Thigh Bacterial Infection Model?  

PubMed Central

Maintaining quinolone concentrations outside the mutant selection window (MSW) between the MIC and mutant prevention concentration (MPC) was suggested by in vitro and in vivo studies to prevent the selection of resistant mutants. However, selection also may depend on the presence of resistant bacterial mutants at the start of treatment, which is highly dependent on the initial inoculum size. In this study, a mouse thigh bacterial infection model was used to test the influence of different exposures to marbofloxacin on the selection of resistant bacteria after infection with a low (105 CFU) or high (108 CFU) initial inoculum of Escherichia coli. The inoculum size was shown to influence the exposure to marbofloxacin and the values of pharmacokinetic/pharmacodynamic indices. When the abilities of the indices time within the MSW (TMSW), area under the concentration-time curve of 0 to 24 h divided by the MIC, and the maximum concentration of drug in plasma divided by the MIC to predict the selection of resistant bacteria were compared, only TMSW appeared to be a good predictor of the prevention of resistance for values less than 30%. When the TMSW was higher than 34%, the selection of resistant bacteria occurred less often in thighs initially infected with the low inoculum (11/24; 46%) than in those infected with the high inoculum (30/36; 80%), suggesting that the selection of resistant mutants depends on both the TMSW and inoculum size. The relevance of these results merits further investigation to test different strategies of antibiotic therapy depending on the expected bacterial burden at the infectious site. PMID:19487439

Ferran, Aude A.; Kesteman, Anne-Sylvie; Toutain, Pierre-Louis; Bousquet-Mélou, Alain



Pharmacokinetic/pharmacodynamic analysis of the influence of inoculum size on the selection of resistance in Escherichia coli by a quinolone in a mouse thigh bacterial infection model.  


Maintaining quinolone concentrations outside the mutant selection window (MSW) between the MIC and mutant prevention concentration (MPC) was suggested by in vitro and in vivo studies to prevent the selection of resistant mutants. However, selection also may depend on the presence of resistant bacterial mutants at the start of treatment, which is highly dependent on the initial inoculum size. In this study, a mouse thigh bacterial infection model was used to test the influence of different exposures to marbofloxacin on the selection of resistant bacteria after infection with a low (10(5) CFU) or high (10(8) CFU) initial inoculum of Escherichia coli. The inoculum size was shown to influence the exposure to marbofloxacin and the values of pharmacokinetic/pharmacodynamic indices. When the abilities of the indices time within the MSW (T(MSW)), area under the concentration-time curve of 0 to 24 h divided by the MIC, and the maximum concentration of drug in plasma divided by the MIC to predict the selection of resistant bacteria were compared, only T(MSW) appeared to be a good predictor of the prevention of resistance for values less than 30%. When the T(MSW) was higher than 34%, the selection of resistant bacteria occurred less often in thighs initially infected with the low inoculum (11/24; 46%) than in those infected with the high inoculum (30/36; 80%), suggesting that the selection of resistant mutants depends on both the T(MSW) and inoculum size. The relevance of these results merits further investigation to test different strategies of antibiotic therapy depending on the expected bacterial burden at the infectious site. PMID:19487439

Ferran, Aude A; Kesteman, Anne-Sylvie; Toutain, Pierre-Louis; Bousquet-Mélou, Alain



Outwitting Evolution: Fighting Drug Resistance in the Treatment of TB, Malaria and HIV  

PubMed Central

Although caused by vastly different pathogens, the world’s three most serious infectious diseases, tuberculosis, malaria and HIV-1 infection, share the common problem of drug resistance. The pace of drug development has been very slow for tuberculosis and malaria and rapid for HIV-1. But for each disease, resistance to most drugs has appeared quickly after the introduction of the drug. Learning how to manage and prevent resistance is a major medical challenge that requires an understanding of the evolutionary dynamics of each pathogen. This review summarized the similarities and differences in the evolution of drug resistance for these three pathogens. PMID:22424234

Goldberg, Daniel E.; Siliciano, Robert F.; Jacobs, William R.



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.



Post-irradiation "acquired cavernous angiomas" with drug resistant seizures.  


Cavernomas are well-known congenital vascular lesions with presumably high epileptogenicity. We report two patients who developed cavernomas; both were in remission from childhood acute lymphoblastic leukemia following standard chemo-radiotherapy. They developed drug-resistant focal epilepsy secondary to cavernomas and were subjected to surgical/medical management. This report highlights the ictogenesis of radiation-induced "acquired" cavernous angiomatosis in the brain. Appropriate treatment, including resection of these lesions in selected cases, improves the quality of life in such patients. PMID:21680152

Menon, Ramshekhar N; Baheti, Neeraj N; Cherian, Ajith; Rathore, Chaturbhuj; Iyer, Rajesh S; Radhakrishnan, Ashalatha




E-print Network



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



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

E-print Network

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


Multi-drug-resistant Staphylococcus aureus and future chemotherapy.  


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



A 7-year national survey on bacterial resistance in bronchoalveolar lavage from patients hospitalized in Argentina.  


The purpose of this study is to undertake a nationwide survey on bacterial resistance in bronchoalveolar lavage (BAL) from patients hospitalized in Argentina. A 2-month point prevalence study was conducted twice yearly (April-May and October-November) from 1997 to 2003 by 36 Argentinean centers. Antimicrobial susceptibility data of the potential pathogens recovered from the BAL (samples containing <1% of squamous epithelial cells and bacterial counts >or=10(4) CFU/mL) of inpatients (i.e., >or=48-h hospital length of stay) with suspected hospital-acquired pneumonia (HAP) were collected on a computerized system (SIR) described previously. The survey was split into 2 periods for comparison purposes, 1997 to 2000 and 2001 to 2003. A total of 752 organisms were included. Staphylococcus aureus was the most frequent species, followed by Acinetobacter spp. and Pseudomonas aeruginosa. In both periods, more than a half of the Klebsiella pneumoniae strains displayed a phenotype of extended-spectrum beta-lactamase producer. A doubling of imipenem-resistant Acinetobacter frequency was shown from the 1st period to the 2nd one (25-48%). More than two-thirds of the S. aureus strains proved to be methicillin resistant in both periods, and a pronounced decrease of resistance rates to trimethoprim/sulfamethoxazole and rifampin was shown in the 2nd period. The present study shows the worrisome increasing bacterial resistance in BAL samples to most available antimicrobial options for treating patients with suspected HAP. Variations over time support the need for systematic tailored surveillance and compel us to establish a rational usage of antimicrobial agents in our country. PMID:17888608

Bantar, Carlos; Famiglietti, Angela; Radice, Marcela; Quinteros, Mirta



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

E-print Network

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

Hergenrother, Paul J.


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 Gómez; César López-Camarillo; D. Guillermo Pérez


Major Histocompatibility Complex Based Resistance to a Common Bacterial Pathogen of Amphibians  

PubMed Central

Given their well-developed systems of innate and adaptive immunity, global population declines of amphibians are particularly perplexing. To investigate the role of the major histocompatibilty complex (MHC) in conferring pathogen resistance, we challenged Xenopus laevis tadpoles bearing different combinations of four MHC haplotypes (f, g, j, and r) with the bacterial pathogen Aeromonas hydrophila in two experiments. In the first, we exposed ff, fg, gg, gj, and jj tadpoles, obtained from breeding MHC homozygous parents, to one of three doses of A. hydrophila or heat-killed bacteria as a control. In the second, we exposed ff, fg, fr, gg, rg, and rr tadpoles, obtained from breeding MHC heterozygous parents and subsequently genotyped by PCR, to A. hydrophila, heat-killed bacteria or media alone as controls. We thereby determined whether the same patterns of MHC resistance emerged within as among families, independent of non-MHC heritable differences. Tadpoles with r or g MHC haplotypes were more likely to die than were those with f or j haplotypes. Growth rates varied among MHC types, independent of exposure dose. Heterozygous individuals with both susceptible and resistant haplotypes were intermediate to either homozygous genotype in both size and survival. The effect of the MHC on growth and survival was consistent between experiments and across families. MHC alleles differentially confer resistance to, or tolerance of, the bacterial pathogen, which affects tadpoles' growth and survival. PMID:18629002

Barribeau, Seth M.; Villinger, Jandouwe; Waldman, Bruce



Exposure of juvenile Leghorn chickens to lead acetate enhances antibiotic resistance in enteric bacterial flora.  


Heavy metals have been implicated for their ability to increase antibiotic resistance in bacteria collected from polluted waters, independent of antibiotic exposure. Specific-pathogen-free Leghorn chickens were therefore given Pb acetate in the drinking water to expose the enteric bacteria to Pb and to determine if antibiotic resistance changed in these bacteria. Concentrations of Pb used were 0.0, 0.01, 0.1, 1.0, or 10.0 mM; birds given the highest 2 concentrations showed signs of moribundity and dehydration and were removed from the study. Vent culture samples were collected for bacterial cultures on d 0 before Pb exposure, d 7 and 14, and then birds were euthanized by CO2 gas for necropsy on d 14, at which time intestinal contents were also collected for bacterial cultures. Fecal swabs but not intestinal samples from Pb-exposed birds contained isolates that had significantly elevated antibiotic resistance. Some of the isolates contained bacteria that were resistant to up to 20 antibiotics. These results suggest the need for repeated studies in chickens infected with zoonotic pathogens. PMID:24706966

Nisanian, M; Holladay, S D; Karpuzoglu, E; Kerr, R P; Williams, S M; Stabler, L; McArthur, J Vaun; Tuckfield, R Cary; Gogal, R M



Emerging technologies for monitoring drug-resistant tuberculosis at the point-of-care.  


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

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



[Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria?].  


The development of multi-drug resistance to antibiotics during the last years and the few number of new active molecules launched on the market have limited the treatment of some infectious diseases. Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria? Considering the bibliographic data, we can note different facts: (1) some alternatives already exist, but correspond more to targeted useful and usable therapeutics as phage therapy, honey therapy, or maggot therapy; (2) some "old" antibiotics can find new bacterial targets and reinforce the anti-infectious therapy towards some multi-drug resistant bacteria; (3) new formulations can allow targeted drug delivery via nanoparticles and the association of molecules can reinforce the antibiotic antimicrobial effect; (4) new treatment could be potentially usable as: antimicrobial peptides, probiotics, herbal medicines, statins, phosphonosulfonates, fecal transplants...; (5) at least, we must not forget that "it's better to prevent than cure". So, besides the principles of hygiene that must be respected, it is necessary to promote (if possible) the development of new vaccines against bacteria responsible for nosocomial infections. Facing with this potential, we can say that new orientations are open with very different levels of success and that it is urgent to find new targets ignored or forgotten until now. PMID:23622693

Bourlioux, P



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; Vilchèze, Catherine; Gulten, Gulcin; Langley, Robert; Schiehser, Guy A.; Jacobus, David P.; Jacobs, Jr., William R.; Sacchettini, James C.; (Einstein); (TAM); (Jacobus)



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; Návarová, Hana; Zeier, Jürgen



Drug resistance pattern and outcome of treatment in recurrent episodes of tuberculosis.  


Patterns of drug resistance in recurrent cases of tuberculosis may be different than in those without a history of treatment. In this retrospective study, the drug resistance pattern and outcome of treatment with DOTS category I (CAT I) regimen was compared in 63 recurrent cases and 872 new cases of pulmonary tuberculosis from April 2003 to January 2008 at the National Research Institute of Tuberculosis and Lung Disease in Tehran, Islamic Republic of Iran. Resistance to isoniazid and ethambutol was significantly more common in recurrent cases, but there were no differences in rates of resistance to rifampin, pyrazinamide, streptomycin or the rate of multi-drug resistant strains. Resistance to streptomycin was the most common. No significant differences in treatment outcome and deaths were found between the 2 groups. Due to the low frequency of multi-drug resistance in the recurrent cases, a CAT I regimen may be suitable for empirical therapy before drug sensitivity results become available. PMID:23057389

Marjani, M; Baghaei, P; Tabarsi, P; Shamaei, M; Mansouri, D; Masjedi, M R; Velayati, A



Thomas Jefferson University study finds leukemia drug reverses tamoxifen resistance in breast cancer cells:

Taking a leukemia chemotherapy drug may help breast cancer patients who don’t respond to tamoxifen overcome resistance to the widely-used drug, new research from the Kimmel Cancer Center at Jefferson suggests.


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.



Drug resistance reversal potential of ursolic acid derivatives against nalidixic acid and multidrug resistant Escherichia coli.  


As a part of our drug discovery programme, ursolic acid (UA) was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid (NA) against the nalidixic acid sensitive (NASEC) and nalidixic acid resistant (NAREC) strains of Escherichia coli. Although UA and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration (MIC) of NA up to eight folds. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of UA reduced the MIC of NA by eight fold against NAREC and four and eight folds against NASEC, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline (TET) against the multidrug resistant clinical isolate of E. coli (MDREC-KG4). The results showed that both these derivatives in combination with TET reduced the cell viability in concentration dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These UA derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram negative infections. This article is protected by copyright. All rights reserved. PMID:25476148

Dwivedi, Gaurav Raj; Maurya, Anupam; Yadav, Dharmendra Kumar; Khan, Feroz; Darokar, Mahendra P; Srivastava, Santosh Kumar



The First Report of Drug Resistant Bacteria Isolated from the Brown-Banded Cockroach, Supella longipalpa, in Ahvaz, South-western Iran  

PubMed Central

Background The brown-banded cockroach, Supella longipalpa is known as a carrier of pathogenic bacteria in urban environments, but its role is not well documented regarding the carriage of antibiotic-resistant pathogenic bacteria in Iran. The aim of this study was to determine the resistance bacteria isolated from the brown-banded cockroach in Ahvaz, south west of Iran. Methods: Totally 39 cockroaches were collected from kitchen area of houses and identified. All specimens were cultured to isolate the bacterial agents on blood agar and MacConky agar media. The microorganisms were identified using necessary differential and biochemical tests. Antimicrobial susceptibility tests were performed for isolated organisms by Kirby-Bauer’s disk diffusion according to NCLI guideline, using 18 antibiotics. Results: From the 39 collected S. langipalpa, 179 bacterial agents were isolated, 92 of alimentary ducts and 87 of external body surfaces. Isolated bacteria from cockroaches were identified as Enterobacter spp., Klebsiella spp., Citrobacter spp., Escherichia coli, Salmonella spp., Proteus spp., coagulase negative staphylococci, Serratia marcescens, Staphylococcus aureus, and Bacillus species. The pattern resistance rates were determined for gram negative bacilli and gram positive cocci regarding 18 antibiotics. Conclusion: The brown-banded cockroach can be involved in the spread of drug resistant bacteria and increases the possibility of contacting human environment to drug resistant bacteria. Therefore, the potential of removing this insect should be improved. This is the first original report of drug resistant bacteria isolated from the brown-banded cockroach of Iran.

Vazirianzadeh, Babak; Dehghani, Rouhullah; Mehdinejad, Manijeh; Sharififard, Mona; Nasirabadi, Nersi



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-Ming Jack Hu, Liangfang Zhang * Department of Nanoengineering and Moores Cancer Center, University . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1106 3. Combinatorial nanoparticles against multidrug resistance in cancer

Zhang, Liangfang


An Affordable HIV-1 Drug Resistance Monitoring Method for Resource Limited Settings  

PubMed Central

HIV-1 drug resistance has the potential to seriously compromise the effectiveness and impact of antiretroviral therapy (ART). As ART programs in sub-Saharan Africa continue to expand, individuals on ART should be closely monitored for the emergence of drug resistance. Surveillance of transmitted drug resistance to track transmission of viral strains already resistant to ART is also critical. Unfortunately, drug resistance testing is still not readily accessible in resource limited settings, because genotyping is expensive and requires sophisticated laboratory and data management infrastructure. An open access genotypic drug resistance monitoring method to manage individuals and assess transmitted drug resistance is described. The method uses free open source software for the interpretation of drug resistance patterns and the generation of individual patient reports. The genotyping protocol has an amplification rate of greater than 95% for plasma samples with a viral load >1,000 HIV-1 RNA copies/ml. The sensitivity decreases significantly for viral loads <1,000 HIV-1 RNA copies/ml. The method described here was validated against a method of HIV-1 drug resistance testing approved by the United States Food and Drug Administration (FDA), the Viroseq genotyping method. Limitations of the method described here include the fact that it is not automated and that it also failed to amplify the circulating recombinant form CRF02_AG from a validation panel of samples, although it amplified subtypes A and B from the same panel. PMID:24747156

Manasa, Justen; Danaviah, Siva; Pillay, Sureshnee; Padayachee, Prevashinee; Mthiyane, Hloniphile; Mkhize, Charity; Lessells, Richard John; Seebregts, Christopher; de Wit, Tobias F. Rinke; Viljoen, Johannes; Katzenstein, David; De Oliveira, Tulio



A model of HIV drug resistance driven by heterogeneities in host immunity and adherence patterns  

PubMed Central

Background Population transmission models of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) use simplistic assumptions – typically constant, homogeneous rates – to represent the short-term risk and long-term effects of drug resistance. In contrast, within-host models of drug resistance allow for more detailed dynamics of host immunity, latent reservoirs of virus, and drug PK/PD. Bridging these two levels of modeling detail requires an understanding of the “levers” – model parameters or combinations thereof – that change only one independent observable at a time. Using the example of accidental tenofovir-based pre-exposure prophyaxis (PrEP) use during HIV infection, we will explore methods of implementing host heterogeneities and their long-term effects on drug resistance. Results We combined and extended existing models of virus dynamics by incorporating pharmacokinetics, pharmacodynamics, and adherence behavior. We identified two “levers” associated with the host immune pressure against the virus, which can be used to independently modify the setpoint viral load and the shape of the acute phase viral load peak. We propose parameter relationships that can explain differences in acute and setpoint viral load among hosts, and demonstrate their influence on the rates of emergence and reversion of drug resistance. The importance of these dynamics is illustrated by modeling long-lived latent reservoirs of virus, through which past intervals of drug resistance can lead to failure of suppressive drug regimens. Finally, we analyze assumptions about temporal patterns of drug adherence and their impact on resistance dynamics, finding that with the same overall level of adherence, the dwell times in drug-adherent versus not-adherent states can alter the levels of drug-resistant virus incorporated into latent reservoirs. Conclusions We have shown how a diverse range of observable viral load trajectories can be produced from a basic model of virus dynamics using immunity-related “levers”. Immune pressure, in turn, influences the dynamics of drug resistance, with increased immune activity delaying drug resistance and driving more rapid return to dominance of drug-susceptible virus after drug cessation. Both immune pressure and patterns of drug adherence influence the long-term risk of drug resistance. In the case of accidental PrEP use during infection, rapid transitions between adherence states and/or weak immunity fortifies the “memory” of previous PrEP exposure, increasing the risk of future drug resistance. This model framework provides a means for analyzing individual-level risks of drug resistance and implementing heterogeneities among hosts, thereby achieving a crucial prerequisite for improving population-level models of drug resistance. PMID:23379669



Mutations in the Pneumocystis jirovecii DHPS Gene Confer Cross-Resistance to Sulfa Drugs  

PubMed Central

Pneumocystis jirovecii is a major opportunistic pathogen that causes Pneumocystis pneumonia (PCP) and results in a high degree of mortality in immunocompromised individuals. The drug of choice for PCP is typically sulfamethoxazole (SMX) or dapsone in conjunction with trimethoprim. Drug treatment failure and sulfa drug resistance have been implicated epidemiologically with point mutations in dihydropteroate synthase (DHPS) of P. jirovecii. P. jirovecii cannot be cultured in vitro; however, heterologous complementation of the P. jirovecii trifunctional folic acid synthesis (PjFAS) genes with an E. coli DHPS-disrupted strain was recently achieved. This enabled the evaluation of SMX resistance conferred by DHPS mutations. In this study, we sought to determine whether DHPS mutations conferred sulfa drug cross-resistance to 15 commonly available sulfa drugs. It was established that the presence of amino acid substitutions (T517A or P519S) in the DHPS domain of PjFAS led to cross-resistance against most sulfa drugs evaluated. The presence of both mutations led to increased sulfa drug resistance, suggesting cooperativity and the incremental evolution of sulfa drug resistance. Two sulfa drugs (sulfachloropyridazine [SCP] and sulfamethoxypyridazine [SMP]) that had a higher inhibitory potential than SMX were identified. In addition, SCP, SMP, and sulfadiazine (SDZ) were found to be capable of inhibiting the clinically observed drug-resistant mutants. We propose that SCP, SMP, and SDZ should be considered for clinical evaluation against PCP or for future development of novel sulfa drug compounds. PMID:15673759

Iliades, Peter; Meshnick, Steven R.; Macreadie, Ian G.



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



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

PubMed Central

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; Fernández-Gutiérrez, Mar; Selvam, Shivaram; Parra-Ruiz, Francisco J.; Lehman, Susan M.; Román, Julio San; García, Ernesto; García, José L.; García, Andrés J.; Prieto, María Auxiliadora



Parallel Loss-of-Function at the RPM1 Bacterial Resistance Locus in Arabidopsis thaliana  

PubMed Central

Dimorphism at the Resistance to Pseudomonas syringae pv. maculicola 1 (RPM1) locus is well documented in natural populations of Arabidopsis thaliana and has been portrayed as a long-term balanced polymorphism. The haplotype from resistant plants contains the RPM1 gene, which enables these plants to recognize at least two structurally unrelated bacterial effector proteins (AvrB and AvrRpm1) from bacterial crop pathogens. A complete deletion of the RPM1 coding sequence has been interpreted as a single event resulting in susceptibility in these individuals. Consequently, the ability to revert to resistance or for alternative R-gene specificities to evolve at this locus has also been lost in these individuals. Our survey of variation at the RPM1 locus in a large species-wide sample of A. thaliana has revealed four new loss-of-function alleles that contain most of the intervening sequence of the RPM1 open reading frame. Multiple loss-of-function alleles may have originated due to the reported intrinsic cost to plants expressing the RPM1 protein. The frequency and geographic distribution of rpm1 alleles observed in our survey indicate the parallel origin and maintenance of these loss-of-function mutations and reveal a more complex history of natural selection at this locus than previously thought. PMID:23272006

Rose, Laura; Atwell, Susanna; Grant, Murray; Holub, Eric B.



Mechanisms of drug resistance to the platinum complex ZD0473 in ovarian cancer cell lines  

Microsoft Academic Search

Acquired drug resistance to the sterically hindered platinum drug ZD0473 (formerly known as JM473 and AMD473) and currently being tested in phase I clinical trials, has been studied in two human ovarian carcinoma cell lines (CH1 and A2780) where previously, acquired cisplatin resistance has been described. Common mechanisms of resistance were observed in A2780 acquired cisplatin and ZD0473R (resistant) lines

J. Holford; P. J. Beale; F. E. Boxall; S. Y. Sharp; L. R. Kelland



Rates and risk factors for drug resistance tuberculosis in Northeastern China  

PubMed Central

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



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


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; Müller, Frank A; Kralisch, Dana; Hipler, Uta-Christina; Fischer, Dagmar



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


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

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




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



High-resolution genetic mapping of rice bacterial blight resistance gene Xa23.  


Bacterial blight (BB) caused by Xanthomonas oryzae pv. oryzae (Xoo) is the most devastating bacterial disease of rice (Oryza sativa L.), a staple food crop that feeds half of the world's population. In management of this disease, the most economical and effective approach is cultivating resistant varieties. Due to rapid change of pathogenicity in the pathogen, it is necessary to identify and characterize more host resistance genes for breeding new resistant varieties. We have previously identified the BB resistance (R) gene Xa23 that confers the broadest resistance to Xoo strains isolated from different rice-growing regions and preliminarily mapped the gene within a 1.7 cm region on the long arm of rice chromosome 11. Here, we report fine genetic mapping and in silico analysis of putative candidate genes of Xa23. Based on F2 mapping populations derived from crosses between Xa23-containing rice line CBB23 and susceptible varieties JG30 or IR24, six new STS markers Lj36, Lj46, Lj138, Lj74, A83B4, and Lj13 were developed. Linkage analysis revealed that the new markers were co-segregated with or closely linked to the Xa23 locus. Consequently, the Xa23 gene was mapped within a 0.4 cm region between markers Lj138 and A83B4, in which the co-segregating marker Lj74 was identified. The corresponding physical distance between Lj138 and A83B4 on Nipponbare genome is 49.8 kb. Six Xa23 candidate genes have been annotated, including four candidate genes encoding hypothetical proteins and the other two encoding a putative ADP-ribosylation factor protein and a putative PPR protein. These results will facilitate marker-assisted selection of Xa23 in rice breeding and molecular cloning of this valuable R gene. PMID:24715026

Wang, Chunlian; Fan, Yinglun; Zheng, Chongke; Qin, Tengfei; Zhang, Xiaoping; Zhao, Kaijun



Bayesian Analysis of Complex Interacting Mutations in HIV Drug Resistance and Cross-Resistance.  


A successful treatment of AIDS world-wide is severely hindered by the HIV virus' drug resistance capability resulting from complicated mutation patterns of viral proteins. Such a system of mutations enables the virus to survive and reproduce despite the presence of various antiretroviral drugs by disrupting their binding capability. Although these interacting mutation patterns are extremely difficult to efficiently uncover and interpret, they contribute valuable information to personalized therapeutic regimen design. The use of Bayesian statistical modeling provides an unprecedented opportunity in the field of anti-HIV therapy to understand detailed interaction structures of drug resistant mutations. Multiple Bayesian models equipped with Markov Chain Monte Carlo (MCMC) methods have been recently proposed in this field (Zhang et al. in PNAS 107:1321, 2010 [1]; Zhang et al. in J Proteome Sci Comput Biol 1:2, 2012 [2]; Svicher et al. in Antiviral Res 93(1):86-93, 2012 [3]; Svicher et al. in Antiviral Therapy 16(7):1035-1045, 2011 [4]; Svicher et al. in Antiviral Ther 16(4):A14-A14, 2011 [5]; Svicher et al. in Antiviral Ther 16(4):A85-A85, 2011 [6]; Alteri et al. in Signature mutations in V3 and bridging sheet domain of HIV-1 gp120 HIV-1 are specifically associated with dual tropism and modulate the interaction with CCR5 N-Terminus, 2011 [7]). Probabilistically modeling mutations in the HIV-1 protease or reverse transcriptase (RT) isolated from drug-treated patients provides a powerful statistical procedure that first detects mutation combinations associated with single or multiple-drug resistance, and then infers detailed dependence structures among the interacting mutations in viral proteins (Zhang et al. in PNAS 107:1321, 2010 [1]; Zhang et al. in J Proteome Sci Comput Biol 1:2, 2012 [2]). Combined with molecular dynamics simulations and free energy calculations, Bayesian analysis predictions help to uncover genetic and structural mechanisms in the HIV treatment resistance. Results obtained with such stochastic methods pave the way not only for optimization of the use for existing HIV drugs, but also for the development of the new more efficient antiretroviral medicines. In this chapter we survey current challenges in the bioinformatics of anti-HIV therapy, and outline how recently emerged Bayesian methods can help with the clinical management of HIV-1 infection. We will provide a rigorous review of the Bayesian variable partition model and the recursive model selection procedure based on probability theory and mathematical data analysis techniques while highlighting real applications in HIV and HBV studies including HIV drug resistance (Zhang et al. in PNAS 107:1321, 2010 [1]), cross-resistance (Zhang et al. in J Proteome Sci Comput Biol 1:2, 2012 [2]), HIV coreceptor usage (Svicher et al. in Antiviral Therapy 16(7):1035-1045, 2011 [4]; Svicher et al. in Antiviral Ther 16(4):A14-A14, 2011 [5]; Alteri et al. in Signature mutations in V3 and bridging sheet domain of HIV-1 gp120 HIV-1 are specifically associated with dual tropism and modulate the interaction with CCR5 N-Terminus, 2011 [7]), and occult HBV infection (Svicher et al. in Antiviral Res 93(1):86-93, 2012 [3]; Svicher et al. in Antiviral Ther 16(4):A85-A85, 2011 [6]). PMID:25387976

Kozyryev, Ivan; Zhang, Jing



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



Role of the Mycobacterium tuberculosis P55 Efflux Pump in Intrinsic Drug Resistance, Oxidative Stress Responses, and Growth?  

PubMed Central

Bacterial efflux pumps have traditionally been studied as low-level drug resistance determinants. Recent insights have suggested that efflux systems are often involved with fundamental cellular physiological processes, suggesting that drug extrusion may be a secondary function. In Mycobacterium tuberculosis, little is known about the physiological or drug resistance roles of efflux pumps. Using Mycobacterium bovis BCG as a model system, we showed that deletion of the Rv1410c gene encoding the P55 efflux pump made the strain more susceptible to a range of toxic compounds, including rifampin (rifampicin) and clofazimine, which are first- and second-line antituberculosis drugs. The efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and valinomycin inhibited the P55-determined drug resistance, suggesting the active export of the compounds by use of the transmembrane proton and electrochemical gradients as sources of energy. In addition, the P55 efflux pump mutant was more susceptible to redox compounds and displayed increased intracellular redox potential, suggesting an essential role of the efflux pump in detoxification processes coupled to oxidative balance within the cell. Finally, cells that lacked the p55 gene displayed smaller colony sizes and had a growth defect in liquid culture. This, together with an increased susceptibility to the cell wall-targeting compounds bacitracin and vancomycin, suggested that P55 is needed for proper cell wall assembly and normal growth in vitro. Thus, P55 plays a fundamental role in oxidative stress responses and in vitro cell growth, in addition to contributing to intrinsic antibiotic resistance. Inhibitors of the P55 efflux pump could help to improve current treatments for tuberculosis. PMID:19564371

Ramón-García, Santiago; Martín, Carlos; Thompson, Charles J.; Aínsa, José A.



Role of the Mycobacterium tuberculosis P55 efflux pump in intrinsic drug resistance, oxidative stress responses, and growth.  


Bacterial efflux pumps have traditionally been studied as low-level drug resistance determinants. Recent insights have suggested that efflux systems are often involved with fundamental cellular physiological processes, suggesting that drug extrusion may be a secondary function. In Mycobacterium tuberculosis, little is known about the physiological or drug resistance roles of efflux pumps. Using Mycobacterium bovis BCG as a model system, we showed that deletion of the Rv1410c gene encoding the P55 efflux pump made the strain more susceptible to a range of toxic compounds, including rifampin (rifampicin) and clofazimine, which are first- and second-line antituberculosis drugs. The efflux pump inhibitors carbonyl cyanide m-chlorophenylhydrazone (CCCP) and valinomycin inhibited the P55-determined drug resistance, suggesting the active export of the compounds by use of the transmembrane proton and electrochemical gradients as sources of energy. In addition, the P55 efflux pump mutant was more susceptible to redox compounds and displayed increased intracellular redox potential, suggesting an essential role of the efflux pump in detoxification processes coupled to oxidative balance within the cell. Finally, cells that lacked the p55 gene displayed smaller colony sizes and had a growth defect in liquid culture. This, together with an increased susceptibility to the cell wall-targeting compounds bacitracin and vancomycin, suggested that P55 is needed for proper cell wall assembly and normal growth in vitro. Thus, P55 plays a fundamental role in oxidative stress responses and in vitro cell growth, in addition to contributing to intrinsic antibiotic resistance. Inhibitors of the P55 efflux pump could help to improve current treatments for tuberculosis. PMID:19564371

Ramón-García, Santiago; Martín, Carlos; Thompson, Charles J; Aínsa, José A



UPenn researchers find that blocking autophagy with malaria drug may help overcome resistance to melanoma BRAF drugs

A new preclinical study published in the Journal of Clinical Investigation found that the root of BRAF drug resistance may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors vermurafenib and dabrafenib.



E-print Network

Summary: Sputum culture of 803 smear positive peases of pulmonary tuberculosis attending for the first time at the five Chest Clinics located in different parts of Madras, was positive m 750. These were further subjected to drug sensitivity tests’, 24.1 % cultures were resistant to one drug, 17.6 % to two drugs and 3.3 % to three drugs, giving a total initial drug resistance of 45%. Total initial resistance to Isoniazid was 28.9 %, significantly higher than for any other drug. In the case of Ethambutol and Streptomycin, it was 18.7 % and 17.9 % respectively. Total initial resistance to Rifampicin was found to be the lowest as compared to all other drugs.

unknown authors


Molecular detection of drug-resistant Mycobacterium tuberculosis with a scanning-frame oligonucleotide microarray.  


The increasing emergence of drug-resistant Mycobacterium tuberculosis poses significant threat to the treatment of tuberculosis (TB). Conventional drug susceptibility testing is time-consuming and takes several weeks because of the slow growth rate of M. tuberculosis and the requirement for the drugs to show antimycobacterial activity. Resistance to TB drugs in M. tuberculosis is caused by mutations in the corresponding drug resistance genes (e.g., katG, inhA, rpoB, pncA, embB, rrs, gyrA, gyrB), and detection of these mutations can be a molecular indicator of drug resistance. In this chapter, we describe the utility of a microarray-based approach exploiting short overlapping oligonucleotides (sliding-frame array) to rapidly detect drug resistance-associated mutations (substitutions, deletions, and insertions) in the pncA gene responsible for resistance ofM. tuberculosis to pyrazinamide (PZA) as an example for this approach. Hybridization of pncA-derived RNA or DNA with the microarray enables easy and simple screening of nucleotide changes in the pncA gene. Sliding-frame microarrays can be used to identify other drug-resistant TB strains that have mutations in relevant drug resistance genes. PMID:20560062

Volokhov, Dmitriy V; Chizhikov, Vladimir E; Denkin, Steven; Zhang, Ying



The Bacterial Symbiont Wolbachia Induces Resistance to RNA Viral Infections in Drosophila melanogaster  

PubMed Central

Wolbachia are vertically transmitted, obligatory intracellular bacteria that infect a great number of species of arthropods and nematodes. In insects, they are mainly known for disrupting the reproductive biology of their hosts in order to increase their transmission through the female germline. In Drosophila melanogaster, however, a strong and consistent effect of Wolbachia infection has not been found. Here we report that a bacterial infection renders D. melanogaster more resistant to Drosophila C virus, reducing the load of viruses in infected flies. We identify these resistance-inducing bacteria as Wolbachia. Furthermore, we show that Wolbachia also increases resistance of Drosophila to two other RNA virus infections (Nora virus and Flock House virus) but not to a DNA virus infection (Insect Iridescent Virus 6). These results identify a new major factor regulating D. melanogaster resistance to infection by RNA viruses and contribute to the idea that the response of a host to a particular pathogen also depends on its interactions with other microorganisms. This is also, to our knowledge, the first report of a strong beneficial effect of Wolbachia infection in D. melanogaster. The induced resistance to natural viral pathogens may explain Wolbachia prevalence in natural populations and represents a novel Wolbachia–host interaction. PMID:19222304

Teixeira, Luís; Ferreira, Álvaro; Ashburner, Michael



A comparison of bacterial resistance to antimicrobials in Riyadh, Medina, and Oklahoma City.  


Many bacteria are known to develop resistance to anti-microbial agents following their clinical use. The resistance pattern varies from one geographic location to another depending upon the patient population and local history of antibiotic use. The bacterial resistance to commonly used antimicrobial agents in Oklahoma City was found to be different from two cities in Saudi Arabia, especially amongst Gram-negative bacilli. A total of 13,575 fresh clinical isolates from the Veterans Administration Medical Center (VAMC), Oklahoma City, Oklahoma; the King Faisal Specialist Hospital and Research Centre (KFSH), Riyadh; and the King Fahad Hospital (KFH), Medina, Saudi Arabia; were used. There were 6,270 isolates of Enterobacteriaceae, 2,799 pseudomonads and Acinetobacter, and 4,506 Gram positive strains of staphylococcus bacteria. Gram-negative bacteria from KFH were considerably more resistant to ampicillin, gentamicin, and trimethoprim-sulfamethoxazole than at KFSH and VAMC. On the other hand, Staphylococcus aureus isolated from VAMC exhibited a significantly higher degree of resistance to oxacillin and trimethoprim-sulfamethoxazole than those at KFSH and KFH. PMID:1744780

Qadri, S M; Ali, S I; Flournoy, D J; Miskeen, A K; Tharwat, J D; Miller, J



The bacterial symbiont Wolbachia induces resistance to RNA viral infections in Drosophila melanogaster.  


Wolbachia are vertically transmitted, obligatory intracellular bacteria that infect a great number of species of arthropods and nematodes. In insects, they are mainly known for disrupting the reproductive biology of their hosts in order to increase their transmission through the female germline. In Drosophila melanogaster, however, a strong and consistent effect of Wolbachia infection has not been found. Here we report that a bacterial infection renders D. melanogaster more resistant to Drosophila C virus, reducing the load of viruses in infected flies. We identify these resistance-inducing bacteria as Wolbachia. Furthermore, we show that Wolbachia also increases resistance of Drosophila to two other RNA virus infections (Nora virus and Flock House virus) but not to a DNA virus infection (Insect Iridescent Virus 6). These results identify a new major factor regulating D. melanogaster resistance to infection by RNA viruses and contribute to the idea that the response of a host to a particular pathogen also depends on its interactions with other microorganisms. This is also, to our knowledge, the first report of a strong beneficial effect of Wolbachia infection in D. melanogaster. The induced resistance to natural viral pathogens may explain Wolbachia prevalence in natural populations and represents a novel Wolbachia-host interaction. PMID:19222304

Teixeira, Luís; Ferreira, Alvaro; Ashburner, Michael



Development of cetuximab-resistant human nasopharyngeal carcinoma cell lines and mechanisms of drug resistance.  


This work aimed to explore the induction of cetuximab-resistant human nasopharyngeal carcinoma (hNPC) 5-8F/Erbitux cells and the mechanisms of drug resistance. The 5-8F cells with high EGFR expression and cetuximab sensitivity were screened and then induced by stepwise exposure to increasing doses of cetuximab. Western blot was conducted to detect protein levels. Our results are as follows: we successfully induced the cetuximab-resistant 5-8F/Erbitux hNPC cells. After treatment with cetuximab for 3 and 5 days, the RI was 1.2 and 1.1, respectively. The 5-8F/Erbitux cells showed cross-resistance to 5-FU (P<0.01) and some resistance to Taxol (P>0.05) as well as enhanced sensitivity to DDP (P>0.05). The cells had increased levels of P-gP, IGF-1R, P-IGF-1R, K-ras, H-ras, and PTEN protein expression (P<0.001), while survivin decreased (P<0.001). Through sequence alignments, gene mutations in the PTEN gene at exons 5, 7, and 8, as well as the H-ras and K-ras genes in codons 12, 13, 59, and 61, were not observed. After transfection with H-ras-shRNA plasmid, the 5-8F/Erbitux cells showed reduced levels of gene and protein expression of H-ras and elevated sensitivity to cetuximab. In conclusion, gene amplification and overexpression of H-ras was the major mechanism that caused resistance of 5-8F/Erbitux cells to cetuximab, while the overexpression of the H-ras gene was probably associated with the over-activity of the IGF-1R signaling pathway. Gene deletion or mutation of PTEN was not associated with resistance of 5-8F/Erbitux cells to cetuximab. PMID:20630698

Zuo, Qiang; Shi, Min; Li, Libo; Chen, Jinzhang; Luo, Rongcheng



“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.



Autophagy and Transporter-Based Multi-Drug Resistance  

PubMed Central

All the therapeutic strategies for treating cancers aim at killing the cancer cells via apoptosis (programmed cell death type I). Defective apoptosis endow tumor cells with survival. The cell can respond to such defects with autophagy. Autophagy is a cellular process by which cytoplasmic material is either degraded to maintain homeostasis or recycled for energy and nutrients in starvation. A plethora of evidence has shown that the role of autophagy in tumors is complex. A lot of effort is needed to underline the functional status of autophagy in tumor progression and treatment, and elucidate how to tweak autophagy to treat cancer. Furthermore, during the treatment of cancer, the limitation for the cure rate and survival is the phenomenon of multi drug resistance (MDR). The development of MDR is an intricate process that could be regulated by drug transporters, enzymes, anti-apoptotic genes or DNA repair mechanisms. Reports have shown that autophagy has a dual role in MDR. Furthermore, it has been reported that activation of a death pathway may overcome MDR, thus pointing the importance of other death pathways to regulate tumor cell progression and growth. Therefore, in this review we will discuss the role of autophagy in MDR tumors and a possible link amongst these phenomena. PMID:24710490

Kumar, Priyank; Zhang, Dong-Mei; Degenhardt, Kurt; Chen, Zhe-Sheng



Genome Analysis of Multi and Extensively-Drug-Resistant Tuberculosis from KwaZulu-Natal, South Africa  

Microsoft Academic Search

The KZN strain family of Mycobacterium tuberculosis is a highly virulent strain endemic to the KwaZulu-Natal region of South Africa, which has recently experienced an outbreak of extensively-drug resistant tuberculosis. To investigate the causes and evolution of drug-resistance, we determined the DNA sequences of several clinical isolates - one drug-susceptible, one multi-drug resistant, and nine extensively drug-resistant - using whole-genome

Thomas R. Ioerger; Sunwoo Koo; Eun-Gyu No; Xiaohua Chen; Michelle H. Larsen; William R. Jacobs; Manormoney Pillay; A. Willem Sturm; James C. Sacchettini



New drugs to treat multidrug-resistant tuberculosis: the case for bedaquiline  

PubMed Central

Mycobacterium tuberculosis develops spontaneous resistance mutants to virtually every drug in use. Courses of therapy select for these mutants and drug-resistant organisms emerge. The development of drug-resistant organisms has reached the point that drug resistance now threatens to undermine global success against tuberculosis (TB). New drugs are needed. The last new class of drugs specifically developed for treatment of TB was the rifamycins over 40 years ago. New funding sources and the development of product development partnerships have energized the TB drug development effort. There are now more TB drugs in development than at any time in the past. The first of these drugs to be developed and marketed was bedaquiline. Bedaquiline has an entirely novel mechanism of action and so should be active against otherwise highly resistant organisms. It acts on the transmembrane component of adenosine triphosphate synthase and acts by preventing electron transport. This raises the exciting possibility that bedaquiline may be active against less metabolically active organisms. Drug–drug interactions between rifamycins and the cytochrome P450-3A system will limit bedaquiline’s utility and create complexity in treatment regimens. In clinical trials, treatment with bedaquiline added to a background multidrug-resistant TB regimen was associated with earlier culture conversion and higher cure rates, but there were unexplained excess deaths in the bedaquiline arms of these trials. Food and Drug Administration approved bedaquiline for the treatment of multidrug-resistant TB when an effective treatment regimen cannot otherwise be provided. They required a black box warning about excess deaths and require that a phase III trial be completed. A planned Phase III trial is being reorganized. While bedaquiline is an exciting drug and marks a dramatic moment in the history of TB treatment, its ultimate place in the anti-TB drug armamentarium is unclear pending the Phase III trial and the development of other new drugs that are in the pipeline. PMID:25114537

Leibert, Eric; Danckers, Mauricio; Rom, William N



Phytochemical Screening and Antimicrobial Activity of Some Medicinal Plants Against Multi-drug Resistant Bacteria from Clinical Isolates  

PubMed Central

The in vitro antibacterial activity of various solvents and water extracts of aloe vera, neem, bryophyllum, lemongrass, tulsi, oregano, rosemary and thyme was assessed on 10 multi-drug resistant clinical isolates from both Gram-positive and Gram-negative bacteria and two standard strains including Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922. The zone of inhibition as determined by agar well diffusion method varied with the plant extract, the solvent used for extraction, and the organism tested. Klebsiella pneumoniae 2, Escherichia coli 3 and Staphylococcus aureus 3 were resistant to the plant extracts tested. Moreover, water extracts did not restrain the growth of any tested bacteria. Ethanol and methanol extracts were found to be more potent being capable of exerting significant inhibitory activities against majority of the bacteria investigated. Staphylococcus aureus 1 was the most inhibited bacterial isolate with 24 extracts (60%) inhibiting its growth whereas Escherichia coli 2 exhibited strong resistance being inhibited by only 11 extracts (28%). The results obtained in the agar diffusion plates were in fair correlation with that obtained in the minimum inhibitory concentration tests. The minimum inhibitory concentration of tulsi, oregano, rosemary and aloe vera extracts was found in the range of 1.56-6.25 mg/ml for the multi-drug resistant Staphylococcus aureus isolates tested whereas higher values (6.25-25 mg/ml) were obtained against the multi-drug resistant isolates Klebsiella pneumoniae 1 and Escherichia coli 1 and 2. Qualitative phytochemical analysis demonstrated the presence of tannins and saponins in all plants tested. Thin layer chromatography and bioautography agar overlay assay of ethanol extracts of neem, tulsi and aloe vera indicated flavonoids and tannins as major active compounds against methicillin-resistant Staphylococcus aureus. PMID:23716873

Dahiya, Praveen; Purkayastha, Sharmishtha



Toward repurposing ciclopirox as an antibiotic against drug-resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae.  


Antibiotic-resistant infections caused by gram-negative bacteria are a major healthcare concern. Repurposing drugs circumvents the time and money limitations associated with developing new antimicrobial agents needed to combat these antibiotic-resistant infections. Here we identified the off-patent antifungal agent, ciclopirox, as a candidate to repurpose for antibiotic use. To test the efficacy of ciclopirox against antibiotic-resistant pathogens, we used a curated collection of Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae clinical isolates that are representative of known antibiotic resistance phenotypes. We found that ciclopirox, at 5-15 µg/ml concentrations, inhibited bacterial growth regardless of the antibiotic resistance status. At these same concentrations, ciclopirox reduced growth of Pseudomonas aeruginosa clinical isolates, but some of these pathogens required higher ciclopirox concentrations to completely block growth. To determine how ciclopirox inhibits bacterial growth, we performed an overexpression screen in E. coli. This screen revealed that galE, which encodes UDP-glucose 4-epimerase, rescued bacterial growth at otherwise restrictive ciclopirox concentrations. We found that ciclopirox does not inhibit epimerization of UDP-galactose by purified E. coli GalE; however, ?galU, ?galE, ?rfaI, or ?rfaB mutant strains all have lower ciclopirox minimum inhibitory concentrations than the parent strain. The galU, galE, rfaI, and rfaB genes all encode enzymes that use UDP-galactose or UDP-glucose for galactose metabolism and lipopolysaccharide (LPS) biosynthesis. Indeed, we found that ciclopirox altered LPS composition of an E. coli clinical isolate. Taken together, our data demonstrate that ciclopirox affects galactose metabolism and LPS biosynthesis, two pathways important for bacterial growth and virulence. The lack of any reported fungal resistance to ciclopirox in over twenty years of use in the clinic, its excellent safety profiles, novel target(s), and efficacy, make ciclopirox a promising potential antimicrobial agent to use against multidrug-resistant problematic gram-negative pathogens. PMID:23936064

Carlson-Banning, Kimberly M; Chou, Andrew; Liu, Zhen; Hamill, Richard J; Song, Yongcheng; Zechiedrich, Lynn



Nondigestible oligosaccharides enhance bacterial colonization resistance against Clostridium difficile in vitro.  


Clostridium difficile is the principal etiologic agent of pseudomembranous colitis and is a major cause of nosocomial antibiotic-associated diarrhea. A limited degree of success in controlling C. difficile infection has been achieved by using probiotics; however, prebiotics can also be used to change bacterial community structure and metabolism in the large gut, although the effects of these carbohydrates on suppression of clostridial pathogens have not been well characterized. The aims of this study were to investigate the bifidogenicity of three nondigestible oligosaccharide (NDO) preparations in normal and antibiotic-treated fecal microbiotas in vitro and their abilities to increase barrier resistance against colonization by C. difficile by using cultural and molecular techniques. Fecal cultures from three healthy volunteers were challenged with a toxigenic strain of C. difficile, and molecular probes were used to monitor growth of the pathogen, together with growth of bifidobacterial and bacteroides populations, over a time course. Evidence of colonization resistance was assessed by determining viable bacterial counts, short-chain fatty acid formation, and cytotoxic activity. Chemostat studies were then performed to determine whether there was a direct correlation between bifidobacteria and C. difficile suppression. NDO were shown to stimulate bifidobacterial growth, and there were concomitant reductions in C. difficile populations. However, in the presence of clindamycin, activity against bifidobacteria was augmented in the presence of NDO, resulting in a further loss of colonization resistance. In the absence of clindamycin, NDO enhanced colonization resistance against C. difficile, although this could not be attributed to bifidobacterium-induced inhibitory phenomena. PMID:12676665

Hopkins, Mark J; Macfarlane, George T



A Typology and Analysis of Drug Resistance Strategies of Rural Native Hawaiian Youth  

PubMed Central

This study examines the drug resistance strategies described by Native Hawaiian youth residing in rural communities. Sixty-four youth from 7 middle and intermediate schools on the Island of Hawai‘i participated in a series of gender-specific focus groups. Youth responded to 15 drug-related problem situations developed and validated from prior research. A total of 509 responses reflecting primary or secondary drug resistance strategies were identified by the youth, which were qualitatively collapsed into 16 different categories. Primary drug resistance strategies were those that participants listed as a single response, or the first part of a two-part response, while secondary drug resistance strategies were those that were used in tandem with primary drug resistance strategies. Over half of the responses reflecting primary drug resistance strategies fell into three different categories (“refuse,” “explain,” or “angry refusal”), whereas over half of the responses reflecting secondary drug resistance strategies represented one category (“explain”). Significant gender differences were found in the frequency of using different strategies as well as variations in the frequency of using different strategies based on the type of drug offerer (family versus friends/peers). Implications for prevention practice are discussed. PMID:20640939

Helm, Susana; Giroux, Danielle; Kaliades, Alexis; Kawano, Kaycee Nahe; Kulis, Stephen



Direct susceptibility testing for multi drug resistant tuberculosis: A meta-analysis  

Microsoft Academic Search

BACKGROUND: One of the challenges facing the tuberculosis (TB) control programmes in resource-limited settings is lack of rapid techniques for detection of drug resistant TB, particularly multi drug resistant tuberculosis (MDR TB). Results obtained with the conventional indirect susceptibility testing methods come too late to influence a timely decision on patient management. More rapid tests directly applied on sputum samples

Freddie Bwanga; Sven Hoffner; Melles Haile; Moses L Joloba




Technology Transfer Automated Retrieval System (TEKTRAN)

Salmonella Typhimurium is one of the most common Salmonella serovars associated with human foodborne infections and has been associated with multi-drug resistance properties. It is important to establish the ability of multi-drug resistant Salmonella to survive food processing interventions. Lactic ...


Cross-drug resistance to sunitinib induced by doxorubicin in endothelial cells  

PubMed Central

Multiple drug resistance remains an unsolved problem in cancer therapy. A previous study has demonstrated that the chemotherapeutic drug doxorubicin (Dox) induced upregulation of P-glycoprotein in endothelial cells, resulting in a 20-fold increase in drug resistance and reduced efficiency of doxorubicin treatment in a mouse tumor model. In the present study, the cross-resistance and sensitivity of HMECd1 and HMECd2 established cell lines to anti-angiogenic drugs, particularly sunitinib, was explored. The results revealed that Dox treatment induced a significant increase in the breast cancer resistance protein (ABCG2) gene transcription and protein expression. This increase gave rise to a 4- to 5-fold increase in the half maximal inhibitory concentration of the HMECd1 and HMECd2 cells in response to sunitinib treatment in vitro. Functionally, the role of ABCG2 in the resistance to sunitinib was confirmed by the use of the ABCG2 inhibitors fumitremorgin C and diethylstilbestrol, which blocked cell resistance. The present study indicates that endothelial cells exhibit cross-resistance between cytotoxic drugs and anti-angiogenic drugs. This suggests that multiple drug resistance induced by chemotherapy in endothelial cells may affect the efficiency of anti-angiogenic drugs. PMID:25663899




Prevalence of Transmitted Drug Resistance and Impact of Transmitted Resistance on Treatment Success in the German HIV-1 Seroconverter Cohort  

PubMed Central

Background The aim of this study is to analyse the prevalence of transmitted drug resistance, TDR, and the impact of TDR on treatment success in the German HIV-1 Seroconverter Cohort. Methods Genotypic resistance analysis was performed in treatment-naïve study patients whose sample was available 1,312/1,564 (83.9% October 2008). A genotypic resistance result was obtained for 1,276/1,312 (97.3%). The resistance associated mutations were identified according to the surveillance drug resistance mutations list recommended for drug-naïve patients. Treatment success was determined as viral suppression below 500 copies/ml. Results Prevalence of TDR was stable at a high level between 1996 and 2007 in the German HIV-1 Seroconverter Cohort (N?=?158/1,276; 12.4%; CIwilson 10.7–14.3; p for trend?=?0.25). NRTI resistance was predominant (7.5%) but decreased significantly over time (CIWilson: 6.2–9.1, p for trend?=?0.02). NNRTI resistance tended to increase over time (NNRTI: 3.5%; CIWilson: 2.6–4.6; p for trend ?=?0.07), whereas PI resistance remained stable (PI: 3.0%; CIWilson: 2.1–4.0; p for trend ?=?0.24). Resistance to all drug classes was frequently caused by singleton resistance mutations (NRTI 55.6%, PI 68.4%, NNRTI 99.1%). The majority of NRTI-resistant strains (79.8%) carried resistance-associated mutations selected by the thymidine analogues zidovudine and stavudine. Preferably 2NRTI/1PIr combinations were prescribed as first line regimen in patients with resistant HIV as well as in patients with susceptible strains (susceptible 45.3%; 173/382 vs. resistant 65.5%; 40/61). The majority of patients in both groups were treated successfully within the first year after ART-initiation (susceptible: 89.9%; 62/69; resistant: 7/9; 77.8%). Conclusion Overall prevalence of TDR remained stable at a high level but trends of resistance against drug classes differed over time. The significant decrease of NRTI-resistance in patients newly infected with HIV might be related to the introduction of novel antiretroviral drugs and a wider use of genotypic resistance analysis prior to treatment initiation. PMID:20949104

Houareau, Claudia; Werning, Johanna; Keeren, Kathrin; Somogyi, Sybille; Kollan, Christian; Jessen, Heiko; Dupke, Stephan; Hamouda, Osamah



Nereis cuticle collagen. Isolation and properties of a large fragment resistant to proteolysis by bacterial collagenase.  


Native cuticle collagen, obtained from Nereis virens, was incubated with purified bacterial collagenase (EC The kinetics of proteolysis were monitored by viscometry, in parallel with similar digestions of calf skin collagen. Comparison of the kinetics of digestion of the two collagens, at similar enzyme to substrate ratios (w/w), showed that the native cuticle collagen was relatively refractory to digestion by bacterial collagenase. Characterization of the cuticle collagen digest by sodium dodecyl sulfate-polyacrylamide electrophoresis and agarose gel filtration in CaCl2 showed a large polypeptide, of about 300,000 daltons, to be a major product. The native form of this product, a unique fragment, was isolated from the digest by ethanol precipitation. It was found to have an intrinsic viscosity of 120 dl/g, to have an optical rotary dispersion curve characteristic of collagen, to undergo a typical collagenous thermal transition with a Tm of 23.2 degrees, and to have a calculated molar mass of 900,000 g with molecular dimensions of 9,000 X 13 A. It had an amino acid composition which was similar, but not identical with the native cuticle collagen. Although the original substrate contained two dissimilar chains, A and B, in a molar ratio of 1:2, the collagenase-resistant product appeared to be composed of only one type of polypeptide fragment. Possibly, the original subunits contain similar, if not identical collagenase-resistant regions. PMID:199599

Kimura, S; Tanzer, M L



Tolerance to drug-induced cell death favours the acquisition of multidrug resistance in Leishmania  

PubMed Central

The control of the protozoan parasite Leishmania relies on few drugs with unknown cellular targets and unclear mode of action. Several antileishmanials, however, were shown to induce apoptosis in Leishmania and this death mechanism was further studied in drug-sensitive and drug-resistant Leishmania infantum. In sensitive parasites, antimonials (SbIII), miltefosine (MF) and amphotericin B (AMB), but not paromomycin (PARO), triggered apoptotic cell death associated with reactive oxygen species (ROS). In contrast, Leishmania mutants resistant to SbIII, MF or AMB not only failed to undergo apoptosis following exposure to their respective drugs, but also were more tolerant towards apoptosis induced by other antileishmanials, provided that these killed Leishmania via ROS production. Such tolerance favored the rapid acquisition of multidrug resistance. PARO killed Leishmania in a non-apoptotic manner and failed to produce ROS. PARO resistance neither protected against drug-induced apoptosis nor provided an increased rate of acquisition of resistance to other antileishmanials. However, the PARO-resistant mutant, but not SbIII-, MF- or AMB-resistant mutants, became rapidly cross-resistant to methotrexate, a model drug also not producing ROS. Our results therefore link the mode of killing of drugs to tolerance to cell death and to a facilitated emergence of multidrug resistance. These findings may have fundamental implications in the field of chemotherapeutic interventions. PMID:21881603

Moreira, W; Leprohon, P; Ouellette, M



Composite films of poly(vinyl alcohol)-chitosan-bacterial cellulose for drug controlled release.  


Mono and multilayer composite films of poly(vinyl alcohol)-chitosan-bacterial cellulose (PVA/chitosan/BC) have been prepared to achieve controlled release of ibuprofen sodium salt (IbuNa) as model drug. The composite films have been characterized by Fourier transformed infrared spectroscopy (FTIR) and X-ray diffraction (XRD). Surface morphology was investigated by scanning electron microscopy (SEM). Equilibrium swelling was measured in water at two different pH values and in vitro release of IbuNa in pH 1.2 and pH 7.4 media was studied. The release experiments revealed that drug release is pH sensitive. The release kinetics of IbuNa could be described by the Fickian model of diffusion with a good agreement. The IbuNa release rate was decreasing for all the films as the BC concentration was increased in the films composition, the decrease being higher for the multilayer films. PMID:24769089

Pavaloiu, Ramona-Daniela; Stoica-Guzun, Anicuta; Stroescu, Marta; Jinga, Sorin Ion; Dobre, Tanase



Mutation in katG315 is, possibly, a good prognostic marker for treatment with second-line drugs in multi-drug resistant tuberculosis: a preliminary study.  


The aim of this study was to explore baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response to second line tuberculosis regimens. Of a total number of 50 multi-drug resistant tuberculosis (MDR-TB) patients starting second-line drug MDR-TB treatment in Iraq, only 21 showed treatment adherence and thus, included in this study. Response to treatment was monitored for 11 months by sputum microscopy and culture. We explored baseline data, laboratory and molecular analyses to determine if any could serve as potential prognostic marker(s) for treatment response. Highly significant association (P = 0.019) was detected between mutations in katG315 codon and good response to second-line anti-TB drugs. Spoligotyping and mycobacterial interspersed repetitive unit variable number tandem repeat confirmed that katG315-mutatnt isolates were genotypically unrelated. The katG315 mutation is a potential prognostic marker for treatment response to second-line anti-tuberculosis drugs. One possible explanation of our results is that the katG315-mutants are sensitive to bacterial killing by "oxidative killing.". PMID:24064650

Ahmed, Mohanad M; Mohammed, Suhad H; Nasurallah, Hassan A A



Riboswitches: discovery of drugs that target bacterial gene-regulatory RNAs  

PubMed Central

Conspectus Riboswitches, which were discovered in the first years of the XXI century, are gene-regulatory mRNA domains that respond to the intracellular concentration of a variety of metabolites and second messengers. They control essential genes in many pathogenic bacteria, and represent a new class of biomolecular target for the development of antibiotics and chemical-biological tools. Five mechanisms of gene regulation are known for riboswitches. Most bacterial riboswitches modulate transcription termination or translation initiation in response to ligand binding. All known examples of eukaryotic riboswitches and some bacterial riboswitches control gene expression by alternative splicing. The glmS riboswitch, widespread in Gram-positive bacteria, is a catalytic RNA activated by ligand binding. Its self-cleavage destabilizes the mRNA of which it is part. Finally, one example of trans-acting riboswitch is known. Three-dimensional (3D) structures have been determined of representatives of thirteen structurally distinct riboswitch classes, providing atomic-level insight into their mechanisms of ligand recognition. While cellular and viral RNAs in general have attracted interest as potential drug targets, riboswitches show special promise due to the diversity and sophistication of small molecule recognition strategies on display in their ligand binding pockets. Moreover, uniquely among known structured RNA domains, riboswitches evolved to recognize small molecule ligands. Structural and biochemical advances in the study of riboswitches provide an impetus for the development of methods for the discovery of novel riboswitch activators and inhibitors. Recent rational drug design efforts focused on select riboswitch classes have yielded a small number of candidate antibiotic compounds, including one active in a mouse model of Staphylococcus aureus infection. The development of high-throughput methods suitable for riboswitch-specific drug discovery is ongoing. A fragment-based screening approach employing equilibrium dialysis that may be generically useful has had early success. Riboswitch-mediated gene regulation is widely employed by bacteria; however, only the thiamine pyrophosphate-responsive riboswitch has thus far been found in eukaryotes. Thus, riboswitches are particularly attractive as targets for antibacterials. Indeed, antimicrobials with previously unknown mechanisms have been found to function by binding riboswitches and leading to aberrant gene expression. PMID:21615107

Deigan, Katherine E.; Ferré-D’Amaré, Adrian R.



Molecular diagnosis and treatment of drug-resistant hepatitis B virus  

PubMed Central

Oral antiviral agents have been developed in the last two decades for the treatment of chronic hepatitis B (CHB). However, antiviral resistance remains an important challenge for long-term CHB therapy. All of the clinically available oral antiviral agents are nucleoside or nucleotide analogues that target the activity of viral reverse transcriptase (RT), and all are reported to have resistant mutations. Since the hepatitis B virus (HBV) RT, like other viral polymerases, lacks proofreading activity, the emergence of drug-resistance occurs readily under selective pressure from the administration of antiviral agents. The molecular diagnosis of drug-resistant HBV is based on sequence variations, and current diagnostic methods include sequencing, restriction fragment polymorphism analysis, and hybridization. Here, we will discuss the currently available molecular diagnosis tools, in vitro phenotypic assays for validation of drug-resistant HBV, and treatment options for drug-resistant HBV. PMID:24914332

Kim, Jeong Han; Park, Yong Kwang; Park, Eun-Sook; Kim, Kyun-Hwan



Molecular Mechanisms of Drug Resistance in Natural Leishmania Populations Vary with Genetic Background  

PubMed Central

The evolution of drug-resistance in pathogens is a major global health threat. Elucidating the molecular basis of pathogen drug-resistance has been the focus of many studies but rarely is it known whether a drug-resistance mechanism identified is universal for the studied pathogen; it has seldom been clarified whether drug-resistance mechanisms vary with the pathogen's genotype. Nevertheless this is of critical importance in gaining an understanding of the complexity of this global threat and in underpinning epidemiological surveillance of pathogen drug resistance in the field. This study aimed to assess the molecular and phenotypic heterogeneity that emerges in natural parasite populations under drug treatment pressure. We studied lines of the protozoan parasite Leishmania (L.) donovani with differential susceptibility to antimonial drugs; the lines being derived from clinical isolates belonging to two distinct genetic populations that circulate in the leishmaniasis endemic region of Nepal. Parasite pathways known to be affected by antimonial drugs were characterised on five experimental levels in the lines of the two populations. Characterisation of DNA sequence, gene expression, protein expression and thiol levels revealed a number of molecular features that mark antimonial-resistant parasites in only one of the two populations studied. A final series of in vitro stress phenotyping experiments confirmed this heterogeneity amongst drug-resistant parasites from the two populations. These data provide evidence that the molecular changes associated with antimonial-resistance in natural Leishmania populations depend on the genetic background of the Leishmania population, which has resulted in a divergent set of resistance markers in the Leishmania populations. This heterogeneity of parasite adaptations provides severe challenges for the control of drug resistance in the field and the design of molecular surveillance tools for widespread applicability. PMID:22389733

Decuypere, Saskia; Vanaerschot, Manu; Brunker, Kirstyn; Imamura, Hideo; Müller, Sylke; Khanal, Basudha; Rijal, Suman; Dujardin, Jean-Claude; Coombs, Graham H.



Diagnosis of Antifungal Drug Resistance Mechanisms in Fungal Pathogens: Transcriptional Gene Regulation  

Microsoft Academic Search

Several fungal species can cause mild to severe diseases in humans. Antifungal strategies have been made possible by the development\\u000a of several drugs with antifungal activity against these pathogenic fungi. Fungi have counteracted antifungal agents in several\\u000a cases by developing resistance mechanisms. These mechanisms are based on the modifications of drug target genes and on the\\u000a regulation of drug-resistance genes.

Dominique Sanglard



Cancer 'Roadmap' Could Help Combat Resistance to Targeted Drug Therapies | Physical Sciences in Oncology

New drugs that specifically target the mutated genes responsible for cancer growth have shown great success in extending the lives of patients, with far fewer side effects than conventional anti-cancer therapies. Unfortunately, many patients become resistant to these drugs when secondary mutations arise. Now, a multidisciplinary team of researchers at UCLA has developed a "roadmap" of the complex signaling processes involved in cancer that could lead to new methods for diagnosing and overcoming clinical drug resistance.


Reduced Virulence of an Extensively Drug-Resistant Outbreak Strain of Mycobacterium tuberculosis in a Murine Model  

PubMed Central

Bacterial drug resistance is often associated with a fitness cost. Large outbreaks of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB have been described that predominately affect persons with HIV infection. We obtained four closely-related Mycobacterium tuberculosis strains (genotype F15/LAM4/KZN) from an outbreak in KwaZulu-Natal (KZN), South Africa, including drug-sensitive, MDR, and XDR clinical isolates. We compared the virulence of these strains in a murine model of aerosol M. tuberculosis infection for four phenotypes: (1) competitive in vivo growth in lung and spleen, (2) non-competitive in vivo growth in lung and spleen, (3) murine survival time, and (4) lung pathology. When mixtures of sensitive, MDR, and XDR KZN strains were aerosolized (competitive model), lung CFUs were similar at 60 days after infection, and spleen CFUs were ordered as follows: sensitive > MDR > XDR. When individual strains were aerosolized (non-competitive model), modest differences in lung and spleen CFUs were observed with the same ordering. C57BL/6, C3H/FeJ, and SCID mice all survived longer after infection with MDR as compared to sensitive strains. SCID mice infected with an XDR strain survived longer than those infected with MDR or sensitive strains. Lung pathology was reduced after XDR TB infection compared to sensitive or MDR TB infection. In summary, increasing degrees of drug resistance were associated with decreasing murine virulence in this collection of KZN strains as measured by all four virulence phenotypes. The predominance of HIV-infected patients in MDR and XDR TB outbreaks may be explained by decreased virulence of these strains in humans. PMID:24733050

Smith, Kristen L. Jurcic; Saini, Divey; Bardarov, Svetoslav; Larsen, Michelle; Frothingham, Richard; Gandhi, Neel R.; Jacobs Jr., William R.; Sturm, A. Willem; Lee, Sunhee



Prior antimicrobial drug exposure: a risk factor for trimethoprim- sulfamethoxazole-resistant urinary tract infections  

Microsoft Academic Search

Objectives: Antimicrobial drug use is believed to be an important risk factor for the emerging problem of antimicrobial drug resistance, yet strong evidence for the causal relationship in com- munity settings has been limited. Detailed analysis of this risk factor at the level of the individual patient has been hampered by limited availability of drug exposure data among patients with

Joshua P. Metlay; Brian L. Strom; David A. Asch


Resistance to currently used drugs is a serious problem in most fields of antimicrobial chemotherapy. Crossresistance  

E-print Network

H 7.4) and diamidines (two positive charges at pH 7.4), these drugs do not readily pass the blood­brain drug', it has proved highly effective in curing late-stage in- fections with Trypanosoma bruceiResistance to currently used drugs is a serious problem in most fields of antimicrobial

Schnaufer, Achim


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

Code of Federal Regulations, 2012 CFR

...immunodeficiency virus (HIV) drug resistance genotype...Section 866.3950 Food and Drugs FOOD AND DRUG...with these primers and probes. It is intended for use in detecting HIV genomic aid in monitoring and treating HIV infection....



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

Code of Federal Regulations, 2011 CFR

...immunodeficiency virus (HIV) drug resistance genotype...Section 866.3950 Food and Drugs FOOD AND DRUG...with these primers and probes. It is intended for use in detecting HIV genomic aid in monitoring and treating HIV infection....



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

Code of Federal Regulations, 2014 CFR

...immunodeficiency virus (HIV) drug resistance genotype...Section 866.3950 Food and Drugs FOOD AND DRUG...with these primers and probes. It is intended for use in detecting HIV genomic aid in monitoring and treating HIV infection....



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

Code of Federal Regulations, 2013 CFR

...immunodeficiency virus (HIV) drug resistance genotype...Section 866.3950 Food and Drugs FOOD AND DRUG...with these primers and probes. It is intended for use in detecting HIV genomic aid in monitoring and treating HIV infection....



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

Code of Federal Regulations, 2010 CFR

...immunodeficiency virus (HIV) drug resistance genotype...Section 866.3950 Food and Drugs FOOD AND DRUG...with these primers and probes. It is intended for use in detecting HIV genomic aid in monitoring and treating HIV infection....



Genetic and phenotypic characterization of drug-resistant Mycobacterium tuberculosis isolates in Hong Kong  

Microsoft Academic Search

Methods: The MIC values of the aforementioned anti-tuberculosis drugs were determined for each of the 250 drug-resistant MTB clinical isolates by the absolute concentration method. Genetic mutations in the corresponding resistance genes in these MTB isolates were identified by PCR-single-stranded conformation polymorphism\\/multiplex PCR amplimer conformation analysis (SSCP\\/MPAC), followed by DNA sequencing of the purified PCR products. Results: Resistance to four

Raphael C. Y. Chan; Mamie Hui; Edward W. C. Chan; T. K. Au; Miu L. Chin; Chun K. Yip; Carrie K. W. AuYeang; Christina Y. L. Yeung; Kai M. Kam; Peter C. W. Yip; Augustine F. B. Cheng



Drug-Resistant Tuberculosis, KwaZulu-Natal, South Africa, 2001–2007  

PubMed Central

In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified. PMID:22000370

Scano, Fabio; Nunn, Paul; Margot, Bruce; Buthelezi, Sandile S.S.; Williams, Brian; Pym, Alexander; Samuel, Elisabeth Y.; Mirzayev, Fuad; Nkhoma, Wilfred; Mvusi, Lindiwe; Pillay, Yogan



Drug-Resistant tuberculosis, KwaZulu-Natal, South Africa, 2001-2007.  


In Africa, incidence and prevalence of drug-resistant tuberculosis have been assumed to be low. However, investigation after a 2005 outbreak of extensively drug-resistant tuberculosis in KwaZulu-Natal Province, South Africa, found that the incidence rate for multidrug-resistant tuberculosis in KwaZulu-Natal was among the highest globally and would be higher if case-finding efforts were intensified. PMID:22000370

Wallengren, Kristina; Scano, Fabio; Nunn, Paul; Margot, Bruce; Buthelezi, Sandile S S; Williams, Brian; Pym, Alexander; Samuel, Elisabeth Y; Mirzayev, Fuad; Nkhoma, Wilfred; Mvusi, Lindiwe; Pillay, Yogan



ARG-ANNOT, a New Bioinformatic Tool To Discover Antibiotic Resistance Genes in Bacterial Genomes  

PubMed Central

ARG-ANNOT (Antibiotic Resistance Gene-ANNOTation) is a new bioinformatic tool that was created to detect existing and putative new antibiotic resistance (AR) genes in bacterial genomes. ARG-ANNOT uses a local BLAST program in Bio-Edit software that allows the user to analyze sequences without a Web interface. All AR genetic determinants were collected from published works and online resources; nucleotide and protein sequences were retrieved from the NCBI GenBank database. After building a database that includes 1,689 antibiotic resistance genes, the software was tested in a blind manner using 100 random sequences selected from the database to verify that the sensitivity and specificity were at 100% even when partial sequences were queried. Notably, BLAST analysis results obtained using the rmtF gene sequence (a new aminoglycoside-modifying enzyme gene sequence that is not included in the database) as a query revealed that the tool was able to link this sequence to short sequences (17 to 40 bp) found in other genes of the rmt family with significant E values. Finally, the analysis of 178 Acinetobacter baumannii and 20 Staphylococcus aureus genomes allowed the detection of a significantly higher number of AR genes than the Resfinder gene analyzer and 11 point mutations in target genes known to be associated with AR. The average time for the analysis of a genome was 3.35 ± 0.13 min. We have created a concise database for BLAST using a Bio-Edit interface that can detect AR genetic determinants in bacterial genomes and can rapidly and easily discover putative new AR genetic determinants. PMID:24145532

Gupta, Sushim Kumar; Padmanabhan, Babu Roshan; Diene, Seydina M.; Lopez-Rojas, Rafael; Kempf, Marie; Landraud, Luce



ARG-ANNOT, a new bioinformatic tool to discover antibiotic resistance genes in bacterial genomes.  


ARG-ANNOT (Antibiotic Resistance Gene-ANNOTation) is a new bioinformatic tool that was created to detect existing and putative new antibiotic resistance (AR) genes in bacterial genomes. ARG-ANNOT uses a local BLAST program in Bio-Edit software that allows the user to analyze sequences without a Web interface. All AR genetic determinants were collected from published works and online resources; nucleotide and protein sequences were retrieved from the NCBI GenBank database. After building a database that includes 1,689 antibiotic resistance genes, the software was tested in a blind manner using 100 random sequences selected from the database to verify that the sensitivity and specificity were at 100% even when partial sequences were queried. Notably, BLAST analysis results obtained using the rmtF gene sequence (a new aminoglycoside-modifying enzyme gene sequence that is not included in the database) as a query revealed that the tool was able to link this sequence to short sequences (17 to 40 bp) found in other genes of the rmt family with significant E values. Finally, the analysis of 178 Acinetobacter baumannii and 20 Staphylococcus aureus genomes allowed the detection of a significantly higher number of AR genes than the Resfinder gene analyzer and 11 point mutations in target genes known to be associated with AR. The average time for the analysis of a genome was 3.35 ± 0.13 min. We have created a concise database for BLAST using a Bio-Edit interface that can detect AR genetic determinants in bacterial genomes and can rapidly and easily discover putative new AR genetic determinants. PMID:24145532

Gupta, Sushim Kumar; Padmanabhan, Babu Roshan; Diene, Seydina M; Lopez-Rojas, Rafael; Kempf, Marie; Landraud, Luce; Rolain, Jean-Marc



Trade-offs between drug toxicity and benefit in the multi-antibiotic resistance system underlie optimal growth of E. coli  

PubMed Central

Background Efflux is a widespread mechanism of reversible drug resistance in bacteria that can be triggered by environmental stressors, including many classes of drugs. While such chemicals when used alone are typically toxic to the cell, they can also induce the efflux of a broad range of agents and may therefore prove beneficial to cells in the presence of multiple stressors. The cellular response to a combination of such chemical stressors may be governed by a trade-off between the fitness costs due to drug toxicity and benefits mediated by inducible systems. Unfortunately, disentangling the cost-benefit interplay using measurements of bacterial growth in response to the competing effects of the drugs is not possible without the support of a theoretical framework. Results Here, we use the well-studied multiple antibiotic resistance (MAR) system in E. coli to experimentally characterize the trade-off between drug toxicity (“cost”) and drug-induced resistance (“benefit”) mediated by efflux pumps. Specifically, we show that the combined effects of a MAR-inducing drug and an antibiotic are governed by a superposition of cost and benefit functions that govern these trade-offs. We find that this superposition holds for all drug concentrations, and it therefore allows us to describe the full dose–response diagram for a drug pair using simpler cost and benefit functions. Moreover, this framework predicts the existence of optimal growth at a non-trivial concentration of inducer. We demonstrate that optimal growth does not coincide with maximum induction of the mar promoter, but instead results from the interplay between drug toxicity and mar induction. Finally, we derived and experimentally validated a general phase diagram highlighting the role of these opposing effects in shaping the interaction between two drugs. Conclusions Our analysis provides a quantitative description of the MAR system and highlights the trade-off between inducible resistance and the toxicity of the inducing agent in a multi-component environment. The results provide a predictive framework for the combined effects of drug toxicity and induction of the MAR system that are usually masked by bulk measurements of bacterial growth. The framework may also be useful for identifying optimal growth conditions in more general systems where combinations of environmental cues contribute to both transient resistance and toxicity. PMID:22631053



Genome Sequence of an Extensively Drug-Resistant Strain of Klebsiella pneumoniae, Strain YN-1, with Carbapenem Resistance  

PubMed Central

The emergence and spread of multidrug-resistant (MDR) Klebsiella pneumoniae has been regarded as one of the major challenges among health care-associated infections worldwide. Here, we report the draft genome sequence of an extensively drug-resistant (XDR) K. pneumoniae strain isolated in 2013 from Yunnan Province, China. PMID:25573939

Tan, Hong-Li; Wang, Yong; Cheng, Xue-Qin; Huang, Yan-Mei; Liu, Wei



Screening foods for processing-resistant bacterial spores and characterization of a pressure- and heat-resistant Bacillus licheniformis isolate.  


This study was carried out to isolate pressure- and heat-resistant indicator spores from selected food matrices (black pepper, red pepper, garlic, and potato peel). Food samples were processed under various thermal (90 to 105°C) and pressure (700 MPa) combination conditions, and surviving microorganisms were isolated. An isolate from red pepper powder, Bacillus licheniformis, was highly resistant to pressure-thermal treatments. Spores of the isolate in deionized water were subjected to the combination treatments of pressure (0.1 to 700 MPa) and heat (90 to 121°C). Compared with the thermal treatment, the combined pressure-thermal treatments considerably reduced the numbers of B. licheniformis spores to less than 1.0 log CFU/g at 700 MPa plus 105°C and at 300 to 700 MPa plus 121°C. The inactivation kinetic parameters of the isolated B. licheniformis spores were estimated using linear and nonlinear models. Within the range of the experimental conditions tested, the pressure sensitivity (zP) of the spores decreased with increasing temperature (up to 121°C), and the temperature sensitivity (zT) was maximum at atmospheric pressure (0.1 MPa). These results will be useful for developing a combined pressure-thermal inactivation kinetics database for various bacterial spores. PMID:24853517

Ahn, Juhee; Balasubramaniam, V M



Rates of emergence of HIV drug resistance in resource-limited settings: a systematic review  

PubMed Central

Background The increasing availability of anti-retroviral therapy (ART) has improved survival and quality of life for many infected with HIV, but can also engender drug resistance. This review summarizes the available information on drug-resistance in adults in resource-limited settings (RLSs). Methods The online databases PubMed and Google Scholar, pertinent conference abstracts, and references from relevant articles were searched for publications available before November 2011. Data collected after ART roll-out were reviewed. Results Seven studies fulfilled the criteria for the analysis of acquired drug resistance while 22 fulfilled the criteria for the analysis of transmitted drug resistance (TDR). Acquired resistance was detected in 7·2% of patients on ART for 6–11 months, compared to 11·1% at 12—23 months, 15·0% at 24–35 months, and 20·7% at ?36 months. Multi-class drug resistance also increased steadily with time on ART. The overall rate of TDR in all resource-limited countries studied was 6·6% (469/7063). Patients in countries in which ART had been available for ?5 years were 1.7 times more likely to have transmitted drug-resistance than those living in a country where ART had been available for <5 years (p<0·001). The reported prevalence of transmitted HIVDR was 5·7% (233/4069) in Africa, 7·6% (160/2094) in Asia, and 8·4% (76/900) in Brazil. Conclusions The emergence of drug resistance following access to antiretroviral therapy in RLSs resembles what was seen in resource-rich countries and highlights the need for virologic monitoring for drug failure, drug resistance testing, and alternative drug regimens that have proven beneficial in these resource-rich settings. PMID:23052978

Stadeli, Kathryn M



Cross-Resistance to Nitro Drugs and Implications for Treatment of Human African Trypanosomiasis? ?  

PubMed Central

The success of nifurtimox-eflornithine combination therapy (NECT) for the treatment of human African trypanosomiasis (HAT) has renewed interest in the potential of nitro drugs as chemotherapeutics. In order to study the implications of the more widespread use of nitro drugs against these parasites, we examined the in vivo and in vitro resistance potentials of nifurtimox and fexinidazole and its metabolites. Following selection in vitro by exposure to increasing concentrations of nifurtimox, Trypanosoma brucei brucei nifurtimox-resistant clones designated NfxR1 and NfxR2 were generated. Both cell lines were found to be 8-fold less sensitive to nifurtimox than parental cells and demonstrated cross-resistance to a number of other nitro drugs, most notably the clinical trial candidate fexinidazole (?27-fold more resistant than parental cells). Studies of mice confirmed that the generation of nifurtimox resistance in these parasites did not compromise virulence, and NfxR1 remained resistant to both nifurtimox and fexinidazole in vivo. In the case of fexinidazole, drug metabolism and pharmacokinetic studies indicate that the parent drug is rapidly metabolized to the sulfoxide and sulfone form of this compound. These metabolites retained trypanocidal activity but were less effective in nifurtimox-resistant lines. Significantly, trypanosomes selected for resistance to fexinidazole were 10-fold more resistant to nifurtimox than parental cells. This reciprocal cross-resistance has important implications for the therapeutic use of nifurtimox in a clinical setting and highlights a potential danger in the use of fexinidazole as a monotherapy. PMID:20439607

Sokolova, Antoaneta Y.; Wyllie, Susan; Patterson, Stephen; Oza, Sandra L.; Read, Kevin D.; Fairlamb, Alan H.



Molecular Approaches for Detection of the Multi-Drug Resistant Tuberculosis (MDR-TB) in Bangladesh  

PubMed Central

The principal obstacles in the treatment of tuberculosis (TB) are delayed and inaccurate diagnosis which often leads to the onset of the drug resistant TB cases. To avail the appropriate treatment of the patients and to hinder the transmission of drug-resistant TB, accurate and rapid detection of resistant isolates is critical. Present study was designed to demonstrate the efficacy of molecular techniques inclusive of line probe assay (LPA) and GeneXpert MTB/RIF methods for the detection of multi-drug resistant (MDR) TB. Sputum samples from 300 different categories of treated and new TB cases were tested for the detection of possible mutation in the resistance specific genes (rpoB, inhA and katG) through Genotype MTBDRplus assay or LPA and GeneXpert MTB/RIF tests. Culture based conventional drug susceptibility test (DST) was also carried out to measure the efficacy of the molecular methods employed. Among 300 samples, 191 (63.7%) and 193 (64.3%) cases were found to be resistant against rifampicin in LPA and GeneXpert methods, respectively; while 189 (63%) cases of rifampicin resistance were detected by conventional DST methods. On the other hand, 196 (65.3%) and 191 (63.7%) isolates showed isoniazid resistance as detected by LPA and conventional drug susceptibility test (DST), respectively. Among the drug resistant isolates (collectively 198 in LPA and 193 in conventional DST), 189 (95.6%) and 187 (96.9%) were considered to be MDR as examined by LPA and conventional DST, respectively. Category-II and -IV patients encountered higher frequency of drug resistance compared to those from category-I and new cases. Considering the higher sensitivity, specificity and accuracy along with the required time to results significantly shorter, our study supports the adoption of LPA and GeneXpert assay as efficient tools in detecting drug resistant TB in Bangladesh. PMID:24932706

Aurin, Tafsina Haque; Munshi, Saurab Kishore; Kamal, S. M. Mostofa; Rahman, Md. Mostafizur; Hossain, Md. Shamim; Marma, Thaythayhla; Rahman, Farjana; Noor, Rashed



Tetracycline Antibiotics: Mode of Action, Applications, Molecular Biology, and Epidemiology of Bacterial Resistance  

PubMed Central

Tetracyclines were discovered in the 1940s and exhibited activity against a wide range of microorganisms including gram-positive and gram-negative bacteria, chlamydiae, mycoplasmas, rickettsiae, and protozoan parasites. They are inexpensive antibiotics, which have been used extensively in the prophlylaxis and therapy of human and animal infections and also at subtherapeutic levels in animal feed as growth promoters. The first tetracycline-resistant bacterium, Shigella dysenteriae, was isolated in 1953. Tetracycline resistance now occurs in an increasing number of pathogenic, opportunistic, and commensal bacteria. The presence of tetracycline-resistant pathogens limits the use of these agents in treatment of disease. Tetracycline resistance is often due to the acquisition of new genes, which code for energy-dependent efflux of tetracyclines or for a protein that protects bacterial ribosomes from the action of tetracyclines. Many of these genes are associated with mobile plasmids or transposons and can be distinguished from each other using molecular methods including DNA-DNA hybridization with oligonucleotide probes and DNA sequencing. A limited number of bacteria acquire resistance by mutations, which alter the permeability of the outer membrane porins and/or lipopolysaccharides in the outer membrane, change the regulation of innate efflux systems, or alter the 16S rRNA. New tetracycline derivatives are being examined, although their role in treatment is not clear. Changing the use of tetracyclines in human and animal health as well as in food production is needed if we are to continue to use this class of broad-spectrum antimicrobials through the present century. PMID:11381101

Chopra, Ian; Roberts, Marilyn



Resistance and Susceptibility of Mice to Bacterial Infection: Histopathology of Listeriosis in Resistant and Susceptible Strains  

PubMed Central

C57BL/10 mice have previously been shown to be 100 times more resistant to intravenously injected Listeria monocytogenes than are BALB/c mice due to the action of a single gene, Lr. Differences in the histopathology of listeriosis in the two strains were sought. Of the tissues examined, only liver, spleen, blood, and thymus showed changes. In the liver, Listeria localized in Kupffer cells within 3 h of infection. By 24 h these cells became surrounded by neutrophilic polymorphonuclear leukocytes. After high doses of Listeria, the susceptible BALB/c mice showed many foci surrounded by few polymorphs, whereas in the resistant C57BL/10 mice there were relatively few foci surrounded by many polymorphs. By 4 days in sublethally infected mice the polymorphs in the liver of both strains were being replaced by monocytes and macrophages. Liver morphology returned to normal by 8 days postinfection. In the blood of both strains there was a rise in total lymphocyte numbers at 24 h, followed by a fall in T-lymphocytes and recovery at 5 days. C57BL/10 mice showed an early monocytic response in the blood, whereas BALB/c mice showed a polymorph leukocytosis. In the spleens of both C57BL/10 and BALB/c mice there was an early neutrophil response and red pulp hyperemia. This was followed by a dramatic lymphocyte depletion in the T-dependent periarteriolar regions in both strains beginning 2 days after infection. Absolute numbers of Thy-1+ cells in spleen cell suspensions also fell to 10% of normal, recovering 6 to 8 days postinfection. Surface immunoglobulin-positive B-lymphocytes and Thy-1?, immunoglobulin-negative “null” cells rose in both strains at days 4 to 5, returning to normal levels on days 10 to 12. Whether the null cells represent lymphocytes or other cell types remains unresolved. Thymus atrophy was seen in the BALB/c mice but not in C57BL/10 mice. ImagesFig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11 PMID:6785235

Mandel, Thomas E.; Cheers, Christina



Identification of qRBS1, a QTL involved in resistance to bacterial seedling rot in rice.  


Bacterial seedling rot (BSR), a destructive disease of rice (Oryza sativa L.), is caused by the bacterial pathogen Burkholderia glumae. To identify QTLs for resistance to BSR, we conducted a QTL analysis using chromosome segment substitution lines (CSSLs) derived from a cross between Nona Bokra (resistant) and Koshihikari (susceptible). Comparison of the levels of BSR in the CSSLs and their recurrent parent, Koshihikari, revealed that a region on chromosome 10 was associated with resistance. Further genetic analyses using an F5 population derived from a cross between a resistant CSSL and Koshihikari confirmed that a QTL for BSR resistance was located on the short arm of chromosome 10. The Nona Bokra allele was associated with resistance to BSR. Substitution mapping in the Koshihikari genetic background demonstrated that the QTL, here designated as qRBS1 (quantitative trait locus for RESISTANCE TO BACTERIAL SEEDLING ROT 1), was located in a 393-kb interval (based on the Nipponbare reference genome sequence) defined by simple sequence repeat markers RM24930 and RM24944. PMID:23797600

Mizobuchi, R; Sato, H; Fukuoka, S; Tsushima, S; Imbe, T; Yano, M



Multimodal neuroimaging in presurgical evaluation of drug-resistant epilepsy?  

PubMed Central

Intracranial EEG (icEEG) monitoring is critical in epilepsy surgical planning, but it has limitations. The advances of neuroimaging have made it possible to reveal epileptic abnormalities that could not be identified previously and improve the localization of the seizure focus and the vital cortex. A frequently asked question in the field is whether non-invasive neuroimaging could replace invasive icEEG or reduce the need for icEEG in presurgical evaluation. This review considers promising neuroimaging techniques in epilepsy presurgical assessment in order to address this question. In addition, due to large variations in the accuracies of neuroimaging across epilepsy centers, multicenter neuroimaging studies are reviewed, and there is much need for randomized controlled trials (RCTs) to better reveal the utility of presurgical neuroimaging. The results of multiple studies indicate that non-invasive neuroimaging could not replace invasive icEEG in surgical planning especially in non-lesional or extratemporal lobe epilepsies, but it could reduce the need for icEEG in certain cases. With technical advances, multimodal neuroimaging may play a greater role in presurgical evaluation to reduce the costs and risks of epilepsy surgery, and provide surgical options for more patients with drug-resistant epilepsy. PMID:24282678

Zhang, Jing; Liu, Weifang; Chen, Hui; Xia, Hong; Zhou, Zhen; Mei, Shanshan; Liu, Qingzhu; Li, Yunlin



Drug-resistant chronic migraine: the Italian GON project.  


Chronic daily headache is a major problem due to severe disability and high socio-economic costs. In the last years, some trials have shown potential benefit from new therapeutic approach by occipital neurostimulation techniques, already applied with some success for the treatment of chronic cluster headache. Due to the extremely heterogeneous population suffering from refractory chronic daily headaches, we propose a national multicenter experimental study involving Italian ANIRCEF Headache Centres with the aim to evaluate the efficacy of occipital neurostimulation in a selected group representative for the drug-resistant chronic migraine. Patients with chronic migraine according to Manzoni's modified IHS criteria-2011, with or without medication overuse headache, will be selected. Duration of illness should be at least 2 years and pharmacological refractoriness defined strictly for experimental-surgical purposes as those patients who have properly tried without success almost all available classes of prophylactic medications. Those presenting with medication overuse should have tried at least two previous detoxification treatments. A full psychopathological assessment will be performed by a psychiatrist, to exclude mainly psychotic disorder, ongoing severe status of an affective disorder, severe post traumatic stress disorder. Headache characteristics and abortive treatments used will be reported daily on a predisposed diary during 3-month baseline and continuously through the post implant follow up, while disability and QoL scale (MIDAS, SF-12) will be completed baseline, 6 and 12 months after implant. PMID:22644167

Proietti Cecchini, A; Leone, M; Manzoni, G C; Torelli, P; Bussone, G



Characterization of copper-resistant bacteria and bacterial communities from copper-polluted agricultural soils of central Chile  

PubMed Central

Background Copper mining has led to Cu pollution in agricultural soils. In this report, the effects of Cu pollution on bacterial communities of agricultural soils from Valparaiso region, central Chile, were studied. Denaturing gradient gel electrophoresis (DGGE) of the 16S rRNA genes was used for the characterization of bacterial communities from Cu-polluted and non-polluted soils. Cu-resistant bacterial strains were isolated from Cu-polluted soils and characterized. Results DGGE showed a similar high number of bands and banding pattern of the bacterial communities from Cu-polluted and non-polluted soils. The presence of copA genes encoding the multi-copper oxidase that confers Cu-resistance in bacteria was detected by PCR in metagenomic DNA from the three Cu-polluted soils, but not in the non-polluted soil. The number of Cu-tolerant heterotrophic cultivable bacteria was significantly higher in Cu-polluted soils than in the non-polluted soil. Ninety two Cu-resistant bacterial strains were isolated from three Cu-polluted agricultural soils. Five isolated strains showed high resistance to copper (MIC ranged from 3.1 to 4.7 mM) and also resistance to other heavy metals. 16S rRNA gene sequence analyses indicate that these isolates belong to the genera Sphingomonas, Stenotrophomonas and Arthrobacter. The Sphingomonas sp. strains O12, A32 and A55 and Stenotrophomonas sp. C21 possess plasmids containing the Cu-resistance copA genes. Arthrobacter sp. O4 possesses the copA gene, but plasmids were not detected in this strain. The amino acid sequences of CopA from Sphingomonas isolates (O12, A32 and A55), Stenotrophomonas strain (C21) and Arthrobacter strain (O4) are closely related to CopA from Sphingomonas, Stenotrophomonas and Arthrobacter strains, respectively. Conclusions This study suggests that bacterial communities of agricultural soils from central Chile exposed to long-term Cu-pollution have been adapted by acquiring Cu genetic determinants. Five bacterial isolates showed high copper resistance and additional resistance to other heavy metals. Detection of copA gene in plasmids of four Cu-resistant isolates indicates that mobile genetic elements are involved in the spreading of Cu genetic determinants in polluted environments. PMID:22950448



Assessment of benzimidazole resistance in Haemonchus contortus in sheep flocks in Ontario, Canada: comparison of detection methods for drug resistance.  


In 2011, a field study was conducted to assess drug resistance of gastro-intestinal nematodes in sheep flocks in Ontario, Canada. Benzimidazole resistance in Haemonchus contortus was assessed by genetic analysis of eggs; measurement of resistant allele percentages at codons 167, 198 and 200 in the ?-tubulin gene was determined on pools of H. contortus eggs using pyrosequencing. Susceptibility to benzimidazoles in gastro-intestinal nematodes was also determined using a Faecal Egg Count Reduction Test (FECRT) and a Larval Development Assay (LDA). In total, 16 farms were assessed with the genetic test. Based on resistant allele frequencies, all of the farms (16/16) tested had benzimidazole resistance in H. contortus; the overall percentage of benzimidazole-resistant H. contortus (estimated prior to treatment using the Hardy-Weinberg formula) was 68.5%. The FECRT and LDA were performed on 11 and 13 farms, respectively. Resistance to fenbendazole was detected on 100% (11/11) of the farms where the FECRT was performed. The LDA revealed the presence of thiabendazole resistance in H. contortus in 92% (12/13) of the farms. Estimated percentages of resistant parasites in H. contortus populations obtained with the two biological tests and the genetic test were compared. The results of the genetic test were in agreement with the biological tests and confirmed that benzimidazole resistance in H. contortus is present in Ontario sheep flocks. Differences between the different methods of drug resistance detection are discussed in terms of cost, time and sampling. PMID:23993632

Barrere, V; Falzon, L C; Shakya, K P; Menzies, P I; Peregrine, A S; Prichard, R K



Methicillin-resistant Staphylococcus aureus screening by online immunometric monitoring of bacterial growth under selective pressure.  


Rapid, high-throughput screening tools are needed to contain the spread of hospital-acquired methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains. Most techniques used in current clinical practice still require time-consuming culture for primary isolation of the microbe. We present a new phenotypic assay for MRSA screening. The technique employs a two-photon excited fluorescence (TPX) detection technology with S. aureus-specific antibodies that allows the online monitoring of bacterial growth in a single separation-free process. Different progressions of fluorescence signals are recorded for methicillin-susceptible and -resistant strains when the growth of S. aureus is monitored in the presence of cefoxitin. The performance of the new technique was evaluated with 20 MRSA strains, 6 methicillin-susceptible S. aureus strains, and 7 coagulase-negative staphylococcal strains and two different monoclonal S. aureus-specific antibodies. When either of these antibodies was used, the sensitivity and the specificity of the TPX assay were 100%. All strains were correctly classified within 8 to 12 h, and up to 70 samples were simultaneously analyzed on a single 96-well microtiter plate. As a phenotypic method, the TPX assay is suited for screening purposes. The final definition of methicillin resistance in any S. aureus strain should be based on the presence of the mecA gene. The main benefit afforded by the initial use of the TPX methodology lies in its low cost and applicability to high-throughput analysis. PMID:19752281

Stenholm, Teppo; Hakanen, Antti J; Vaarno, Jonne; Pihlasalo, Sari; Terho, Perttu; Hänninen, Pekka E; Vuopio-Varkila, Jaana; Huovinen, Pentti; Kotilainen, Pirkko



Resistance to a bacterial parasite in the crustacean Daphnia magna shows Mendelian segregation with dominance.  


The influence of host and parasite genetic background on infection outcome is a topic of great interest because of its pertinence to theoretical issues in evolutionary biology. In the present study, we use a classical genetics approach to examine the mode of inheritance of infection outcome in the crustacean Daphnia magna when exposed to the bacterial parasite Pasteuria ramosa. In contrast to previous studies in this system, we use a clone of P. ramosa, not field isolates, which allows for a more definitive interpretation of results. We test parental, F1, F2, backcross and selfed parental clones (total 284 genotypes) for susceptibility against a clone of P. ramosa using two different methods, infection trials and the recently developed attachment test. We find that D. magna clones reliably exhibit either complete resistance or complete susceptibility to P. ramosa clone C1 and that resistance is dominant, and inherited in a pattern consistent with Mendelian segregation of a single-locus with two alleles. The finding of a single host locus controlling susceptibility to P. ramosa suggests that the previously observed genotype-genotype interactions in this system have a simple genetic basis. This has important implications for the outcome of host-parasite co-evolution. Our results add to the growing body of evidence that resistance to parasites in invertebrates is mostly coded by one or few loci with dominance. PMID:22167056

Luijckx, P; Fienberg, H; Duneau, D; Ebert, D



Resistance to a bacterial parasite in the crustacean Daphnia magna shows Mendelian segregation with dominance  

PubMed Central

The influence of host and parasite genetic background on infection outcome is a topic of great interest because of its pertinence to theoretical issues in evolutionary biology. In the present study, we use a classical genetics approach to examine the mode of inheritance of infection outcome in the crustacean Daphnia magna when exposed to the bacterial parasite Pasteuria ramosa. In contrast to previous studies in this system, we use a clone of P. ramosa, not field isolates, which allows for a more definitive interpretation of results. We test parental, F1, F2, backcross and selfed parental clones (total 284 genotypes) for susceptibility against a clone of P. ramosa using two different methods, infection trials and the recently developed attachment test. We find that D. magna clones reliably exhibit either complete resistance or complete susceptibility to P. ramosa clone C1 and that resistance is dominant, and inherited in a pattern consistent with Mendelian segregation of a single-locus with two alleles. The finding of a single host locus controlling susceptibility to P. ramosa suggests that the previously observed genotype–genotype interactions in this system have a simple genetic basis. This has important implications for the outcome of host–parasite co-evolution. Our results add to the growing body of evidence that resistance to parasites in invertebrates is mostly coded by one or few loci with dominance. PMID:22167056

Luijckx, P; Fienberg, H; Duneau, D; Ebert, D



Priming cancer cells for drug resistance: role of the fibroblast niche  

PubMed Central

Conventional and targeted chemotherapies remain integral strategies to treat solid tumors. Despite the large number of anti-cancer drugs available, chemotherapy does not completely eradicate disease. Disease recurrence and the growth of drug resistant tumors remain significant problems in anti-cancer treatment. To develop more effective treatment strategies, it is important to understand the underlying cellular and molecular mechanisms of drug resistance. It is generally accepted that cancer cells do not function alone, but evolve through interactions with the surrounding tumor microenvironment. As key cellular components of the tumor microenvironment, fibroblasts regulate the growth and progression of many solid tumors. Emerging studies demonstrate that fibroblasts secrete a multitude of factors that enable cancer cells to become drug resistant. This review will explore how fibroblast secretion of soluble factors act on cancer cells to enhance cancer cell survival and cancer stem cell renewal, contributing to the development of drug resistant cancer. PMID:25045348

FANG, Wei Bin; YAO, Min; CHENG, Nikki



Cost-effectiveness of Newer Antiretroviral Drugs in Treatment-Experienced Patients with Multi-drug Resistant HIV Disease  

PubMed Central

Objective Newer antiretroviral drugs provide substantial benefits but are expensive. We determined the cost-effectiveness of using antiretroviral drugs in combination for patients with multi-drug resistant HIV disease. Design We built a cohort state-transition model representing treatment-experienced patients with low CD4 counts, high viral load levels, and multi-drug resistant virus. We estimated the effectiveness of newer drugs (those approved in 2005 or later) from published randomized trials. We estimated other parameters from a randomized trial and from the literature. The model had a lifetime time horizon and used the perspective of an ideal insurer in the United States. The interventions were combination antiretroviral therapy, consisting of two newer drugs and one conventional drug, compared to three conventional drugs. Outcome measures were life-years, quality-adjusted life-years (QALYs), costs, and incremental cost-effectiveness. Results Substituting newer antiretroviral drugs increased expected survival by 3.9 years in advanced HIV disease. The incremental cost-effectiveness ratio of newer, compared to conventional, antiretroviral drugs was $75,556/QALY gained. Sensitivity analyses showed that substituting only one newer antiretroviral drug cost $54,559 to $68,732/QALY, depending on assumptions about efficacy. Substituting three newer drugs cost $105,956 to $117,477/QALY. Cost-effectiveness ratios were higher if conventional drugs were not discontinued. Conclusions In treatment-experienced patients with advanced HIV disease, use of newer antiretroviral agents can be cost effective, given a cost-effectiveness threshold in the range of $50,000 to $75,000 per QALY gained. Newer antiretroviral agents should be used in carefully selected patients for whom less expensive options are clearly inferior. PMID:24129369

Bayoumi, Ahmed M.; Barnett, Paul G.; Joyce, Vilija R.; Griffin, Susan C.; Sun, Huiying; Bansback, Nick J.; Holodniy, Mark; Sanders, Gillian; Brown, Sheldon T.; Kyriakides, Tassos C.; Angus, Brian; Cameron, D. William; Anis, Aslam H.; Sculpher, Mark; Owens, Douglas K.



Emergence and Spread of Extensively and Totally Drug-Resistant Tuberculosis, South Africa  

PubMed Central

Factors driving the increase in drug-resistant tuberculosis (TB) in the Eastern Cape Province, South Africa, are not understood. A convenience sample of 309 drug-susceptible and 342 multidrug-resistant (MDR) TB isolates, collected July 2008–July 2009, were characterized by spoligotyping, DNA fingerprinting, insertion site mapping, and targeted DNA sequencing. Analysis of molecular-based data showed diverse genetic backgrounds among drug-sensitive and MDR TB sensu stricto isolates in contrast to restricted genetic backgrounds among pre–extensively drug-resistant (pre-XDR) TB and XDR TB isolates. Second-line drug resistance was significantly associated with the atypical Beijing genotype. DNA fingerprinting and sequencing demonstrated that the pre-XDR and XDR atypical Beijing isolates evolved from a common progenitor; 85% and 92%, respectively, were clustered, indicating transmission. Ninety-three percent of atypical XDR Beijing isolates had mutations that confer resistance to 10 anti-TB drugs, and some isolates also were resistant to para-aminosalicylic acid. These findings suggest the emergence of totally drug-resistant TB. PMID:23622714

Klopper, Marisa; Hayes, Cindy; Gey van Pittius, Nicolaas Claudius; Streicher, Elizabeth Maria; Müller, Borna; Sirgel, Frederick Adriaan; Chabula-Nxiweni, Mamisa; Hoosain, Ebrahim; Coetzee, Gerrit; David van Helden, Paul; Victor, Thomas Calldo; Trollip, André Phillip



Thioredoxin 1 upregulates FOXO1 transcriptional activity in drug resistance in ovarian cancer cells.  


Drug resistance is the major cause of failure of cancer chemotherapy in ovarian cancer. However, the molecular mechanisms on the regulation of drug resistance are not fully understood. Here we showed that Trx1 and FOXO1 were involved in paclitaxel (PTX)-induced drug resistance in ovarian cancer A2780 cells. PTX induced reactive oxygen species (ROS) and resulted in Trx1 and FOXO1 nuclear translocation. We further found that Trx1 bound to FOXO1 and enhanced FOXO1 transcriptional activity; however Trx1 C69S mutant which is barely detected in the nucleus downregulated Trx1-FOXO1 interaction and Trx1-induced FOXO1 transcriptional activation. Silencing of FOXO1 abrogated Trx1-induced drug resistance. Trx1 increased FOXO1-induced drug resistance, while Trx1 C69S mutant completely abolished the regulation of FOXO1-mediated drug resistance by Trx1. These findings provided a novel mechanism on Trx1/FOXO1 signaling in drug resistance in ovarian cancer cells. PMID:25483711

Wang, Jianlin; Yang, Hao; Li, Wenjie; Xu, Huibi; Yang, Xiangliang; Gan, Lu



Gender Differences in Preferred Drug Resistance Strategies of Rural Native Hawaiian Youth  

PubMed Central

This study examined the gender differences in preferred strategies used to resist drugs and alcohol for rural Native Hawaiian youth. Seventy-four youth (60% female) within eight different middle/intermediate or high schools participated in 15 different focus groups as part of a pilot/feasibility drug prevention study funded by the National Institute on Drug Abuse. Consistent with relational-cultural theory, qualitative findings indicated how female youth participants favored drug resistance strategies that maintained relational connectedness with the drug offerer, and how they considered the long-term relational consequences of different drug resistance strategies. Implications of these findings for indigenous- and gender-specific prevention are discussed. PMID:24511181

Okamoto, Scott K.; Helm, Susana; McClain, Latoya L.; Pel, Suzanne; Hayashida, Janai K. P.; Hill, Amber P.



Drug resistance in Trypanosoma brucei spp., the causative agents of sleeping sickness in man and nagana in cattle  

Microsoft Academic Search

Drug resistance in pathogenic trypanosomes threatens successful control of fatal sleeping sickness in man and hinders economic livestock production in sub-Saharan Africa. We report on the occurrence and development of drug resistance, and discuss the genetic basis of such resistance in Trypanosoma brucei. Understanding these mechanisms at the molecular level will enable improved management of existing drugs and provide valuable

Enock Matovu; Thomas Seebeck; John C. K. Enyaru; Ronald Kaminsky



Optimization of the Bacterial Cytochrome P450 BM3 System for the Production of Human Drug Metabolites  

PubMed Central

Drug metabolism in human liver is a process involving many different enzymes. Among them, a number of cytochromes P450 isoforms catalyze the oxidation of most of the drugs commercially available. Each P450 isoform acts on more than one drug, and one drug may be oxidized by more than one enzyme. As a result, multiple products may be obtained from the same drug, and as the metabolites can be biologically active and may cause adverse drug reactions (ADRs), the metabolic profile of a new drug has to be known before this can be commercialized. Therefore, the metabolites of a certain drug must be identified, synthesized and tested for toxicity. Their synthesis must be in sufficient quantities to be used for metabolic tests. This review focuses on the progresses done in the field of the optimization of a bacterial self-sufficient and efficient cytochrome P450, P450 BM3 from Bacillus megaterium, used for the production of metabolites of human enzymes. The progress made in the improvement of its catalytic performance towards drugs, the substitution of the costly NADPH cofactor and its immobilization and scale-up of the process for industrial application are reported. PMID:23443101

Di Nardo, Giovanna; Gilardi, Gianfranco



Effects of melatonin on oxidative stress, and resistance to bacterial, parasitic, and viral infections: a review.  


Melatonin, a hormone secreted by the pineal gland, works directly and indirectly as a free radical scavenger. Its other physiological or pharmacological activities could be dependent or independent of receptors located in different cells, organs, and tissues. In addition to its role in promoting sleep and circadian rhythms regulation, it has important immunomodulatory, antioxidant, and neuroprotective effects suggesting that this indole must be considered as a therapeutic alternative against infections. The aim of this review is to describe the effects of melatonin on oxidative stress and the resistance to bacterial (Klebsiella pneumoniae, Helicobacter pylori, Mycobacterium tuberculosis, and Clostridium perfringens), viral (Venezuelan equine encephalomyelitis virus and respiratory syncytial virus), and parasitic (Plasmodium spp., Entamoeba histolytica, Trypanosoma cruzi, Toxoplasma gondii, and Opisthorchis viverrini) infections. PMID:24811367

Vielma, José Ramón; Bonilla, Ernesto; Chacín-Bonilla, Leonor; Mora, Marylú; Medina-Leendertz, Shirley; Bravo, Yanauri



Development of robust biocompatible silicone with high resistance to protein adsorption and bacterial adhesion.  


A new biocompatible silicone comprising a carboxybetaine (CB) ester analogue, 3-methacryloxypropyltris(trimethylsiloxy)silane (TRIS) and an organic silicone macromer (bis-?,?-(methacryloxypropyl) polydimethylsiloxane) has been developed using photo-polymerisation. Following interfacial hydrolysis of the CB ester, the resulting zwitterionic material became significantly more hydrophilic and exhibited high resistance to both non-specific protein adsorption and bacterial adhesion. Moreover, the stability of these non-fouling properties was dramatically improved by using a slow and controlled rate of ester hydrolysis of the original protective hydrophobic matrix. The subsequent ability to maintain the original optical and mechanical properties of the bare silicone following surface activation makes this material an ideal candidate for preparing contact lenses and other medical devices. PMID:21300187

Lin, Weifeng; Zhang, Juan; Wang, Zhen; Chen, Shengfu