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Bacterial drug resistance in meat animals: a review.  


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

Okolo, M I



Beta-lactamase gene in multi-drug-resistant clinical bacterial isolates from Egyptian food animal species  

Microsoft Academic Search

Resistance to antibiotics is a worldwide human and veterinary health problem. By disk diffusion method the antibiotic resistance activities of 8 antibiotics including amoxicillin clavulanic acid (AMC) in 43 clinical bacterial isolates (13 Escherichia coli; 13 Pseudomonas aeruginosa; 11 Staphylococcus aureus & 6 Klebsiella pneumoniae) was evaluated. That bacterial isolates were from avian, dromedary camel and ovine clinical samples. Multi-drug-resistant

Mona I. El-Enbaawy; Ausama A. Yousif


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

PubMed Central

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

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



[Factor analysis of outcomes during drug-resistant bacterial infection treatment].  


Factors related to poor outcome in drug-resistant bacterial infection treatment were analyzed based on surveys at 54 National Hospital Organization facilities. Results showed common etiological causes of Methicillin-resistant Staphylococcus aureus (MRSA) and Penicillin-resistant Streptococcus pneumoniae (PRSP). Specifically, the odds ratio in the elderly, aged 75 years and older, was 1.473 (p=0.006) for MRSA and 6.401 (p=0.0001) for PRSP. Among those undergoing tracheal intubation, the odds ratio was 1.767 (p=0.021) for MRSA and 4.185 (p=0.0001) for PRSP, showing that advanced age and tracheal intubation tended to aggravate disease. MRSA-specific causes were pneumonia with an odds ratio of 2.426 (p=0.0001) and sepsis with one of 1.417 (p=0.013). Causes specific to Multi-drug resistant Pseudomonas aeruginosa (MDRP) were Intravenous hyperalimentation (IVH) with an odds ratio of 2.078 (p=0.0001) and urinary-tract infection with one of 0.566 (p=0.027). The individual roles of these factors in poor outcomes must thus be clarified to develop preventive measures against them. PMID:22117376

Hiraki, Yoichi; Hiraike, Mikako; Hanada, Kiyonori; Misumi, Nobuhiro; Kawano, Fumio; Miyazaki, Hisayoshi



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

Microsoft Academic Search

Cancer cells rapidly evolve drug resistance through somatic evolution and, in order to continue growth in the metastatic phase, violate the organism-wide consensus of regulated growth and beneficial communal interactions. We suggest that there is a fundamental mechanistic connection between the rapid evolution of resistance to chemotherapy in cellular communities within malignant tissues and the rapid evolution of antibiotic resistance

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



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



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.

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



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

Microsoft Academic Search

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

Jyothi Padiadpu; Sumanta Mukherjee; Nagasuma Chandra



Bacterial resistance mechanism: what proteomics can elucidate.  


Antibiotics are important therapeutic agents commonly used for the control of bacterial infectious diseases; however, resistance to antibiotics has become a global public health problem. Therefore, effective therapy in the treatment of resistant bacteria is necessary and, to achieve this, a detailed understanding of mechanisms that underlie drug resistance must be sought. To fill the multiple gaps that remain in understanding bacterial resistance, proteomic tools have been used to study bacterial physiology in response to antibiotic stress. In general, the global analysis of changes in the protein composition of bacterial cells in response to treatment with antibiotic agents has made it possible to construct a database of proteins involved in the process of resistance to drugs with similar mechanisms of action. In the past few years, progress in using proteomic tools has provided the most realistic picture of the infective process, since these tools detect the end products of gene biosynthetic pathways, which may eventually determine a biological phenotype. In most bacterial species, alterations occur in energy and nitrogen metabolism regulation; glucan biosynthesis is up-regulated; amino acid, protein, and nucleotide synthesis is affected; and various proteins show a stress response after exposing these microorganisms to antibiotics. These issues have been useful in identifying targets for the development of novel antibiotics and also in understanding, at the molecular level, how bacteria resist antibiotics. PMID:23349550

Lima, Thais Bergamin; Pinto, Michelle Flaviane Soares; Ribeiro, Suzana Meira; de Lima, Loiane Alves; Viana, Juliana Cançado; Gomes Júnior, Nelson; Cândido, Elizabete de Souza; Dias, Simoni Campos; Franco, Octávio Luiz



Restoration of Drug-Resistant Bacteria to Sensitivity to Chemotherapeutic Drugs.  

National Technical Information Service (NTIS)

Bacterial diseases caused by drug-resistant organisms present major problems in military medicine. Clinical (foremost quinacrine) as well as experimental pharmaceuticals and dyes restored drug-resistant bacteria to sensitivity to chemotherapeutic drugs wh...

F. E. Hahn J. Ciak



[Multi-drug resistant bacteria and antibiotics].  


Antibiotics are still routinely prescribed, despite the increase in bacterial resistance to these drugs. To contain this public health problem, doctors need to be better trained and the general public better informed. PMID:23865247

Carlet, Jean


Drug Abuse Resistance  

NSDL National Science Digital Library

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

Koyle, Mrs.



Multi-drug-resistant gram-negative bacterial infection in surgical patients hospitalized in the ICU: a cohort study.  


We sought to identify risk factors for postoperative infections, caused by multi-drug-resistant gram-negative bacteria (MDR-GNB) in surgical patients. This was a retrospective cohort study among patients hospitalized in the intensive care unit (ICU) for more than 5 days, following general surgical operations. Comparison of patients who developed infection caused by MDR-GNB with the remainder of the cohort showed that every minute of operative time, use of special treatments during hospitalization (antineoplastic, immunosuppressive or immunomodulating therapies), every day of metronidazole, and every day of carbapenems use, increased patients' odds to acquire an infection caused by MDR-GNB by 0.7%, 8.9 times, 9%, and 9%, respectively [OR (95% CI): 1.007 (1.003-1.011), p?=?0.001; 8.9 (1.8-17.3), p?=?0.004; 1.09 (1.04-1.18), p?=?0.039; 1.09 (1.01-1.18), p?=?0.023, respectively]. The above were adjusted in the multivariable analysis for the confounder of time distribution of infections caused by MDR-GNB. Finally, the secondary comparison, with patients that did not develop any infection, showed that patients who had received antibiotics, within 3 months prior to admission, had 3.8 times higher odds to acquire an infection caused by MDR-GNB [OR (95% CI): 3.8 (1.07-13.2), p?=?0.002]. This study depicts certain, potentially modifiable, risk factors for postoperative infections in patients hospitalized in the ICU for more than 5 days. PMID:21796346

Alexiou, V G; Michalopoulos, A; Makris, G C; Peppas, G; Samonis, G; Falagas, M E



Antibiotic resistance of bacterial biofilms.  


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

Høiby, Niels; Bjarnsholt, Thomas; Givskov, Michael; Molin, Søren; Ciofu, Oana



Antimalarial drug resistance  

PubMed Central

Malaria, the most prevalent and most pernicious parasitic disease of humans, is estimated to kill between one and two million people, mainly children, each year. Resistance has emerged to all classes of antimalarial drugs except the artemisinins and is responsible for a recent increase in malaria-related mortality, particularly in Africa. The de novo emergence of resistance can be prevented by the use of antimalarial drug combinations. Artemisinin-derivative combinations are particularly effective, since they act rapidly and are well tolerated and highly effective. Widespread use of these drugs could roll back malaria.

White, Nicholas J.



Antiretroviral drug resistance testing.  


While antiretroviral drugs, those approved for clinical use and others under evaluation, attempt in lowering viral load and boost the host immune system, antiretroviral drug resistance acts as a major impediment in the management of human immune deficiency virus type-1 (HIV-1) infection. Antiretroviral drug resistance testing has become an important tool in the therapeutic management protocol of HIV-1 infection. The reliability and clinical utilities of genotypic and phenotypic assays have been demonstrated. Understanding of complexities of interpretation of genotyping assay, along with updating of lists of mutation and algorithms and determination of clinically relevant cut-offs for phenotypic assays are of paramount importance. The assay results are to be interpreted and applied by experienced HIV practitioners, after taking into consideration the clinical profile of the patient. This review sums up the methods of assay currently available for measuring resistance to antiretroviral drugs and outlines the clinical utility and limitations of these assays. PMID:16855319

Sen, Sourav; Tripathy, S P; Paranjape, R S


Antimicrobial utilization and bacterial resistance at three different hospitals  

Microsoft Academic Search

It has been generally recognized that the prevalence of bacterial resistance among bacteria is an unavoidable consequence of antibiotic use and is positively linked to the overall use of antibacterial drugs. The purpose of this study was to investigate the extent of antimicrobial usage and to evaluate the antimicrobial resistance at three different hospital settings in Croatia: a clinical hospital,

Miro Morovi?; Goran Pal?evski



Drug resistance in cancer  

Microsoft Academic Search

Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission

E Yagüe; S Raguz



Drug Resistance in Nematodes  

Microsoft Academic Search

Anthelmintic drugs remain the principal means of intervention for therapy and prophylaxis of nematode parasitic diseases in\\u000a humans and animals. Other than improvements in sanitation, there are no effective alternatives to chemical control of parasitic\\u000a nematodes. However, resistance to anthelmintics has become a major problem in veterinary medicine, threatens both agricultural\\u000a production and animal welfare, and there is increasing concern

Roger Prichard


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

PubMed Central

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



Host resistance assays including bacterial challenge models.  


Immunotoxicity testing is used to provide safety assessment with the major objective being the avoidance of unacceptable risk of infectious or neoplastic disease. To this end, immunotoxicity testing has employed a variety of host resistance challenge models for measuring both host resistance to disease as well as immune function. This chapter provides an overview of those viral, bacterial, fungal, and parasitic host resistance models that are most commonly used in safety assessment. It also describes in more detail the bacterial challenge models that are employed to address specific host resistance and immune function issues. PMID:19967508

Burleson, Florence G; Burleson, Gary R



Drug-resistant tuberculous meningitis.  


Drug-resistant tuberculosis, including drug-resistant tuberculous meningitis, is an emerging health problem in many countries. An association with Beijing strains and drug resistance-related mutations, such as mutations in katG and rpoB genes, has been found. The pathology, clinical features and neuroimaging characteristics of drug-resistant tuberculous meningitis are similar to drug-responsive tuberculous meningitis. Detection of mycobacteria in cerebrospinal fluid (CSF) by conventional methods (smear examination or culture) is often difficult. Nucleic acid amplification assays are better methods owing to their rapidity and high sensitivity. The Xpert MTB/RIF assay (Cepheid, CA, USA) is a fully-automated test that has also been found to be effective for CSF samples. Treatment of multidrug-resistant tuberculous meningitis depends on the drug susceptibility pattern of the isolate and/or the previous treatment history of the patient. Second-line drugs with good penetration of the CSF should be preferred. Isoniazid monoresistant disease requires addition of another drug with better CSF penetration. Drug-resistant tuberculous meningitis is associated with a high mortality. HIV infected patients with drug-resistant tuberculous meningitis have severe clinical manifestations with exceptionally high mortality. Prevention of tuberculosis is the key to reduce drug-resistant tuberculous meningitis. PMID:23750732

Garg, Ravindra K; Jain, Amita; Malhotra, Hardeep S; Agrawal, Avinash; Garg, Rajiv



Drug Resistance in HIV-1  

PubMed Central

Purpose of the review Changing antiretroviral regimens and the introduction of new antiretroviral drugs have altered drug resistance patterns in resistance human immunodeficiency virus type 1 (HIV-1). This review summarizes recent information on antiretroviral drug resistance. Recent findings As tenofovir and abacavir have replaced zidovudine and stavudine in antiretroviral regimens, thymidine analog resistance mutations have become less common in patients failing antiretroviral therapy in developed countries. Similarly, the near universal use of ritonavir-boosted protease inhibitors (PI) in place of unboosted PIs has made the selection of PI resistance mutations uncommon in patients failing a first- or second-line PI regimen. The challenge of treating patients with multidrug-resistant HIV-1 has largely been addressed by the advent of newer PIs, second-generation non-nucleoside reverse transcriptase inhibitors and drugs in novel classes, including integrase inhibitors and CCR5 antagonists. Resistance to these newer agents can emerge, however, resulting in the appearance of novel drug resistance mutations in the HIV-1 polymerase, integrase and envelope genes. Summary New drugs make possible the effective treatment of multidrug-resistant HIV-1, but the activity of these drugs may be limited by the appearance of novel drug resistance mutations.

Kuritzkes, Daniel R.



Resistance to antimicrobial drugs in Ghana  

PubMed Central

Background Antimicrobial drug resistance is a global issue that affects health, economic, and social development. The problem has been attributed to misuse of antimicrobial agents. Purpose To identify the agents of bacterial infection in Ghana, determine their antibiogram, and the possibility of setting up a surveillance program. Patients and methods A prospective quantitative study set in various hospitals including two teaching hospitals, seven regional hospitals, and two district hospitals in Ghana. A total of 5099 bacterial isolates from various clinical specimens were collected over a period of 1 year, including data related to the patients. Susceptibility of the isolates was determined by the Kirby–Bauer method. In addition, the minimum inhibitory concentration (MIC) of multidrug-resistant isolates of epidemiological significance was also determined using the E-test. Results A wide range of bacterial isolates were identified in both teaching and regional hospitals. High percentage of resistance was observed for tetracycline (82%), cotrimoxazole (73%), ampicillin (76%), and chloramphenicol (75%). Multidrug resistance was observed to a combination of ampicillin, tetracycline, chloramphenicol, and cotrimoxazole. On the other hand, a lower percentage of resistance was observed for ceftriaxone (6.3%), ciprofloxacin (11%), and amikacin (9.9%). Conclusion Generally, the prevalence of multidrug resistance was widespread among the various isolates. Some multidrug-resistant strains of Staphylococcus aureus, Salmonella typhi, and non-typhoidal Salmonella (NTS) had high MIC to cefuroxime (>256), gentamicin (>256), and ciprofloxacin (>32).

Newman, Mercy J; Frimpong, Enoch; Donkor, Eric S; Opintan, Japheth A; Asamoah-Adu, Alex



Phytochemicals for bacterial resistance--strengths, weaknesses and opportunities.  


This review covers some of the opportunities which currently exist to exploit plants for their natural products as templates for new antibacterial substances. This is a timely exercise given the continuing and developing problems of bacterial resistance, and in particular multidrug-resistance (MDR). Some of the challenges which are evident with bacterial resistance will be described and the strengths and weaknesses of plant natural products are highlighted. Opportunities to characterise antibacterial compounds from several key taxa are described with activity against methicillin-resistant STAPHYLOCOCCUS AUREUS (MRSA), MDR variants of this species and MYCOBACTERIUM TUBERCULOSIS (MTB). These pathogens continue to cause problems in terms of their eradication and spread and MTB strains which are extremely-drug resistant (XDR) promise to afford an additional challenge for clinicians. The review also covers plant natural products that modulate or modify bacterial resistance. Specific examples include plant-derived efflux pump inhibitors (EPIs) which inhibit bacterial antibiotic efflux mechanisms that are problematic due to their broadness in substrate specificity. A summary on future trends and directions in this fruitful and interesting area is also given. PMID:18446673

Gibbons, Simon



Development of aminoglycoside antibiotics effective against resistant bacterial strains.  


Aminoglycosides are important broad-spectrum antibiotics used in the therapy of many microbial infections. As the bacterial resistance to antibiotic therapy is appearing as an increasingly significant threat to public health, the development of aminoglycoside antibiotics with extended antibacterial spectrum and potency, devoid of nephro- and ototoxicity, and evading the resistance process returns to the focus of researchers. In this review, various developments brought to the aminoglycoside family of antibiotics effective against resistant bacteria have been described, focused on chemical modifications, drug-modifying enzyme inhibitors, and conformationally constrained analogs, as well as related antibacterial compounds, with the hope to provide information useful in rational design of novel antibiotics addressing bacterial resistance, and paving the way for new perspectives in antimicrobial therapy. PMID:20615188

Yang, Lin; Ye, Xin-Shan



Bacterial resistance: A sensitive issue  

Microsoft Academic Search

The development of antimicrobial agents has been a key achievement of modern medicine. However, their overuse has led to an increasing incidence of infections due to antibiotic-resistant microorganisms. Quantitative figures on the current economic and health impact of antimicrobial resistance are scant, but it is clearly a growing challenge that requires timely action. That action should be at the educational,

W. T. M. Jansen; J. T. van der Bruggen; J. Verhoef; A. C. Fluit



Novel antimicrobial peptides that exhibit activity against select agents and other drug resistant bacteria  

Microsoft Academic Search

One of the greatest challenges facing modern medicine is the evolution of drug resistant strains of bacteria. In addition to traditional methods of exposure to traditional bacterial organisms there is a growing concerned of the use of bacteria as bio-terrorism agents. To counter the evolution of drug resistant and potential bio-terrorism bacterial agents new antibiotic drugs must be developed. One

Divakaramenon Venugopal; David Klapper; Antoine H. Srouji; Jayendra B. Bhonsle; Richard Borschel; Allen Mueller; Amanda L. Russell; Brittany C. Williams; Rickey P. Hicks



Communicating trends in resistance using a drug resistance index.  


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

Laxminarayan, Ramanan; Klugman, Keith P



[Travellers and multi-drug resistance bacteria].  


The number of international travellers has increased. There is enormous diversity in medical backgrounds, purposes of travel, and travelling styles among travellers. Travellers are hospitalized abroad because of exotic and common diseases via medical tourism. This is one way of transporting and importing human bacteria between countries, including multi-drug resistant organisms. In developing countries, the antimicrobial resistance in Shigella sp. and Salmonella sp. have been a problem, because of this trend, the first choice of antibiotics has changed in some countries. Community acquired infections as well as hospital acquired infections with MRSA, multi-drug resistance (MDR) Pseudomonas aeruginosa, and ESBL have been a problem. This review will discuss the risk of MDR bacterial infectious diseases for travellers. PMID:22413540

Takeshita, Nozomi



Antibacterial Cleaning Products and Drug Resistance  

PubMed Central

We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug–resistant bacteria on hands of household members. Households (N = 224) were randomized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in homes. Antibacterial product use did not lead to a significant increase in antimicrobial drug resistance after 1 year (odds ratio 1.33, 95% confidence interval 0.74–2.41), nor did it have an effect on bacterial susceptibility to triclosan. However, more extensive and longer term use of triclosan might provide a suitable environment for emergence of resistant species. Further research on this issue is needed.

Marshall, Bonnie; Levy, Stuart B.; Della-Latta, Phyllis; Lin, Susan X.; Larson, Elaine



Resistant Bacterial Spore Coats and Their Breakdown During Germination.  

National Technical Information Service (NTIS)

The bacterial endospore is a uniquely resistant and highly differentiated form of bacterial cell. Its unique structure confers resistance to a variety of conditions such as heat, pressure, radiation, dehydration and chemicals. Nevertheless, it is able to ...

A. Moir R. Allan



Antimicrobial (Drug) Resistance  


... updates Order publications Skip Stay Connected Stay Connected Social media privacy policy and disclaimers. Volunteer for NIAID-funded ... Enterococci (VRE) Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) Gram-Negative ... Resistance —June 3, 2013 Media Availability: NIH Scientists Discover Promising Target to Block ...


Modeling physiological resistance in bacterial biofilms  

Microsoft Academic Search

A mathematical model of the action of antimicrobial agents on bacterial biofilms is presented. The model includes the fluid\\u000a dynamics in and around the biofilm, advective and diffusive transport of two chemical constituents and the mechanism of physiological\\u000a resistance. Although the mathematical model applies in three dimensions, we present two-dimensional simulations for arbitrary\\u000a biofilm domains and various dosing strategies. The

N. G. Cogan; Ricardo Cortez; Lisa Fauci



Colourful parrot feathers resist bacterial degradation.  


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



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.

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



Drug Resistance in Pulmonary Tuberculosis in Istanbul  

Microsoft Academic Search

Antituberculosis drug resistance, especially multidrug resistance, is a major factor threatening the success of tuberculosis control programs [1]. To date, no antituberculosis drug resistance surveys have been conducted in Turkey, although high resistance rates have been reported from various hospital-based studies [2, 3]. The aim of the present study was to determine the rate of drug resistance in patients with

Z. Kilicaslan; H. Albal; E. Kiyan; N. Aydemir; E. Seber



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

Microsoft Academic Search

At a time of the emergence of drug-resistant bacterial strains, the development of antimicrobial compounds with novel mechanisms of action is of considerable interest. Perhaps the most promising among these is a family of antibacterial peptides originally isolated from insects. These were shown to act in a stereospecific manner on an as-yet unidentified target bacterial protein. One of these peptides,




Drug Resistance: Genotype versus Phenotypeâ€\\  

Microsoft Academic Search

The Clowes award confers honor, encouragement, and opportunity. That opportunity allows me to review investigations of genetic mecha nisms and phenotypic consequences of drug resistance development in mammalian cells. In so doing I can identify and thank those individu als who, at an early stage in my career, provided inspiration and illumination. Before I begin, let me express appreciation to

June L. Biedler


Drug-Resistant Tuberculosis Transmission and Resistance Amplification within Families  

PubMed Central

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

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



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

PubMed Central

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

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



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



Microevolution of extensively drug-resistant tuberculosis in Russia.  


Extensively drug-resistant (XDR) tuberculosis (TB), which is resistant to both first- and second-line antibiotics, is an escalating problem, particularly in the Russian Federation. Molecular fingerprinting of 2348 Mycobacterium tuberculosis isolates collected in Samara Oblast, Russia, revealed that 72% belonged to the Beijing lineage, a genotype associated with enhanced acquisition of drug resistance and increased virulence. Whole-genome sequencing of 34 Samaran isolates, plus 25 isolates representing global M. tuberculosis complex diversity, revealed that Beijing isolates originating in Eastern Europe formed a monophyletic group. Homoplasic polymorphisms within this clade were almost invariably associated with antibiotic resistance, indicating that the evolution of this population is primarily driven by drug therapy. Resistance genotypes showed a strong correlation with drug susceptibility phenotypes. A novel homoplasic mutation in rpoC, found only in isolates carrying a common rpoB rifampicin-resistance mutation, may play a role in fitness compensation. Most multidrug-resistant (MDR) isolates also had mutations in the promoter of a virulence gene, eis, which increase its expression and confer kanamycin resistance. Kanamycin therapy may thus select for mutants with increased virulence, helping preserve bacterial fitness and promoting transmission of drug-resistant TB strains. The East European clade was dominated by two MDR clusters, each disseminated across Samara. Polymorphisms conferring fluoroquinolone resistance were independently acquired multiple times within each cluster, indicating that XDR TB is currently not widely transmitted. PMID:22294518

Casali, Nicola; Nikolayevskyy, Vladyslav; Balabanova, Yanina; Ignatyeva, Olga; Kontsevaya, Irina; Harris, Simon R; Bentley, Stephen D; Parkhill, Julian; Nejentsev, Sergey; Hoffner, Sven E; Horstmann, Rolf D; Brown, Timothy; Drobniewski, Francis



Engineering antibiotic production and overcoming bacterial resistance.  


Progress in DNA technology, analytical methods and computational tools is leading to new developments in synthetic biology and metabolic engineering, enabling new ways to produce molecules of industrial and therapeutic interest. Here, we review recent progress in both antibiotic production and strategies to counteract bacterial resistance to antibiotics. Advances in sequencing and cloning are increasingly enabling the characterization of antibiotic biosynthesis pathways, and new systematic methods for de novo biosynthetic pathway prediction are allowing the exploration of the metabolic chemical space beyond metabolic engineering. Moreover, we survey the computer-assisted design of modular assembly lines in polyketide synthases and non-ribosomal peptide synthases for the development of tailor-made antibiotics. Nowadays, production of novel antibiotic can be tranferred into any chosen chassis by optimizing a host factory through specific strain modifications. These advances in metabolic engineering and synthetic biology are leading to novel strategies for engineering antimicrobial agents with desired specificities. PMID:21661120

Planson, Anne-Gaëlle; Carbonell, Pablo; Grigoras, Ioana; Faulon, Jean-Loup



Antimicrobial-resistance trends in bacterial isolates from companion-animal community practice in the UK  

Microsoft Academic Search

We conducted a longitudinal, retrospective investigation of antimicrobial resistance in bacterial isolates obtained from canine and feline clinical cases in veterinary community practice in UK (1989–1997). Individual-drug resistance was examined using isolates of Escherichia coli and Staphylococcus spp. as Gram-negative and Gram-positive indicator organisms, respectively. The annual prevalence of resistance was calculated for each organism to each of nine (for

E. H Normand; N. R Gibson; S. W. J Reid; S Carmichael; D. J Taylor



Bacterial and archaeal resistance to ionizing radiation  

NASA Astrophysics Data System (ADS)

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

Confalonieri, F.; Sommer, S.




Microsoft Academic Search

adaptation ? Abstract The widespread deployment of antimicrobial agents in medicine and agriculture is nearly always followed by the evolution of resistance to these agents in the pathogen. With the limited availability of antifungal drugs and the increasing incidence of opportunistic fungal infections, the emergence of drug resistance in fun- gal pathogens poses a serious public health concern. Antifungal drug

Leah E. Cowen; James B. Anderson; Linda M. Kohn



Selection of bacterial wilt-resistant tomato through tissue culture  

Microsoft Academic Search

Bacterial wilt-resistant plants were obtained using a tomato tissue culture system. A virulent strain ofPseudomonas solanacearum secreted some toxic substances into the culture medium. Leaf explant-derived callus tissues which were resistant to these toxic substances in the culture filtrate were selectedin vitro and regenerated into plants. These plants expressed bacterial wilt resistance at the early infection stage to suppress or

Hideyoshi Toyoda; Kunihiko Shimizu; Kazuyuki Chatani; Nobuhiro Kita; Yoshinori Matsuda; Seiji Ouchi



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

Microsoft Academic Search

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

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



Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development.  


New drug deployment strategies are imperative to address the problem of drug resistance, which is limiting the management of infectious diseases and cancers. We evolved resistance in Escherichia coli toward 23 drugs used clinically for treating bacterial infections and mapped the resulting collateral sensitivity and resistance profiles, revealing a complex collateral sensitivity network. On the basis of these data, we propose a new treatment framework-collateral sensitivity cycling-in which drugs with compatible collateral sensitivity profiles are used sequentially to treat infection and select against drug resistance development. We identified hundreds of such drug sets and demonstrated that the antibiotics gentamicin and cefuroxime can be deployed cyclically such that the treatment regimen selected against resistance to either drug. We then validated our findings with related bacterial pathogens. These results provide proof of principle for collateral sensitivity cycling as a sustainable treatment paradigm that may be generally applicable to infectious diseases and cancer. PMID:24068739

Imamovic, Lejla; Sommer, Morten O A



Impact of restricted amoxicillin\\/clavulanic acid use on Escherichia coli resistance—antibiotic DU90% profiles with bacterial resistance rates: a visual presentation  

Microsoft Academic Search

High use of amoxicillin\\/clavulanic acid (AMC) at the University Hospital Osijek (Croatia) contributed to high rates of resistance in Enterobacteriaceae, in particular Escherichia coli (50%). Thus, in order to decrease bacterial resistance, AMC use was restricted. We present results of the restriction on resistance amongst antibiotics accounting for 90% of antibiotic use [drug utilisation 90% (DU90%)]. Data were analysed on

Suzana Mimica Matanovic; Ulf Bergman; Dubravka Vukovic; Björn Wettermark; Vera Vlahovic-Palcevski



Evolution of antibiotic resistance at non-lethal drug concentrations.  


Human use of antimicrobials in the clinic, community and agricultural systems has driven selection for resistance in bacteria. Resistance can be selected at antibiotic concentrations that are either lethal or non-lethal, and here we argue that selection and enrichment for antibiotic resistant bacteria is often a consequence of weak, non-lethal selective pressures - caused by low levels of antibiotics - that operates on small differences in relative bacterial fitness. Such conditions may occur during antibiotic therapy or in anthropogenically drug-polluted natural environments. Non-lethal selection increases rates of mutant appearance and promotes enrichment of highly fit mutants and stable mutators. PMID:22516308

Andersson, Dan I; Hughes, Diarmaid



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.

Cortez, Karoll J.; Maldarelli, Frank



[Influence of carbapenem selection pressure on bacterial resistance].  


As a result of high resistance of bacterial pathogens to broad-spectrum penicillins and cephalosporins, carbapenems have been increa-singly used recently. The presented study aimed at analyzing the association between carbapenem consumption and resistance of selected Gramnegative pathogens to meropenem. Using linear regression analysis, a statistically significant association was found between carbapenem consumption and resistance of Pseudomonas aeruginosa. PMID:23945829

Kolá?, Milan; Htoutou Sedláková, Miroslava; Suchánková, Hana; Hanulík, Vojt?ch



Drug resistance in human pathogenic fungi  

Microsoft Academic Search

Since the therapy of the mycoses, particularly the systemic mycoses, is relatively long-term in nature, emergence of resistance to antifungal drugs during the treatment of period would be of considerable clinical importance. However, most reports of resistance to antifungal agents among human pathogenic fungi indicate that naturally-occurring resistance is very rare, and that the induction of resistant mutants or variants

K. Iwata



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

PubMed Central

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

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



Bacterial Toxin-Triggered Drug Release from Gold Nanoparticle-Stabilized Liposomes for the Treatment of Bacterial Infection  

PubMed Central

We report a new approach to selectively delivering antimicrobials to the sites of bacterial infections by utilizing bacterial toxins to activate drug release from gold nanoparticle-stabilized phospholipid liposomes. The binding of chitosan modified gold nanoparticles to the surface of liposomes can effectively prevent them from fusing with one another and from undesirable payload release in regular storage or physiological environments. However, once these protected liposomes “see” bacteria that secrete toxins, the toxins will insert into the liposome membranes and form pores, through which the encapsulated therapeutic agents are released. The released drugs subsequently impose antimicrobial effects on the toxin-secreting bacteria. Using methicillin-resistant Staphycoccus aureus (MRSA) as a model bacterium and vacomycin as a model anti-MRSA antibiotic, we demonstrate that the synthesized gold nanoparticle-stabilized liposomes can completely release the encapsulated vacomycin within 24 h in the presence of MRSA bacteria and lead to inhibition of MRSA growth as effective as an equal amount of vacomycin loaded liposomes (without nanoparticle stabilizers) and free vacomycin. This bacterial toxin enabled drug release from nanoparticle-stabilized liposomes provides a new, safe and effective approach for the treatment of bacterial infections. This technique can be broadly applied to treat a variety of infections caused by bacteria that secrete pore-forming toxins.

Pornpattananangkul, Dissaya; Zhang, Li; Olson, Sage; Aryal, Santosh; Obonyo, Marygorret; Vecchio, Kenneth; Huang, Chun-Ming; Zhang, Liangfang



Evolutionary paths to antibiotic resistance under dynamically sustained drug selection.  


Antibiotic resistance can evolve through the sequential accumulation of multiple mutations. To study such gradual evolution, we developed a selection device, the 'morbidostat', that continuously monitors bacterial growth and dynamically regulates drug concentrations, such that the evolving population is constantly challenged. We analyzed the evolution of resistance in Escherichia coli under selection with single drugs, including chloramphenicol, doxycycline and trimethoprim. Over a period of ?20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing of the evolved strains identified mutations both specific to resistance to a particular drug and shared in resistance to multiple drugs. Chloramphenicol and doxycycline resistance evolved smoothly through diverse combinations of mutations in genes involved in translation, transcription and transport. In contrast, trimethoprim resistance evolved in a stepwise manner, through mutations restricted to the gene encoding the enzyme dihydrofolate reductase (DHFR). Sequencing of DHFR over the time course of the experiment showed that parallel populations evolved similar mutations and acquired them in a similar order. PMID:22179135

Toprak, Erdal; Veres, Adrian; Michel, Jean-Baptiste; Chait, Remy; Hartl, Daniel L; Kishony, Roy



Marker-assisted Selection for Combining Resistance to Bacterial Spot and Bacterial Speck in Tomato  

Microsoft Academic Search

ADDITIONAL INDEX WORDS. Xanthomonas euvesicatoria, X. vesicatoria, X. perforans, X. gardneri, Pseudomonas syringae pv. tomato, plant breeding, DNA isolation method ABSTRACT. The lack of resistance to bacterial diseases increases both the fi nancial cost and environmental impact of tomato (Lycopersicon esculentum Mill.) production while reducing yield and quality. Because several bacterial diseases can be present in the same fi eld,

Wencai Yang; David M. Francis



Population Mobility, Globalization, and Antimicrobial Drug Resistance  

Microsoft Academic Search

Population mobility is a main factor in globalization of public health threats and risks, specifically distribution of antimicrobial drug-resistant organisms. Drug resistance is a major risk in healthcare settings and is emerging as a problem in community-acquired infections. Traditional health policy approaches have focused on diseases of global public health significance such as tuberculosis, yellow fever, and cholera; however, new

Douglas W. MacPherson; Brian D. Gushulak; William B. Baine; Shukal Bala; Paul O. Gubbins; Paul Holtom; Marisel Segarra-Newnham



Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme  

Microsoft Academic Search

The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-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 β-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian

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



Multi-drug resistant childhood tuberculosis.  


Emergence of drug resistant tuberculosis is one of the major challenges faced by health community globally. Tuberculosis is an important cause of morbidity and mortality among children in endemic areas, yet little is known regarding epidemiology of pediatric tuberculosis and even far lesser information is available about epidemiology, diagnosis, management and treatment outcome of drug resistant tuberculosis in children. Despite limited data and difficulties in its management, drug resistant tuberculosis can be successfully treated even in resource poor settings with proper use of existing technologies. A high index of suspicion and early drug susceptibility testing is the key to early diagnosis and good treatment outcome. Difficulties in establishing the diagnosis, drug toxicities and absence of pediatric formulations add challenges to the management of Pediatric MDR TB Cases. Active research is required to answer the unresolved issues of finding optimal diagnostic tools, treatment regimens and duration and chemoprophylaxis in pediatric drug resistant tuberculosis. PMID:21193973

Singh, Varinder; Kaur, Satnam



MicroRNA and drug resistance  

Microsoft Academic Search

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

J Ma; C Dong; C Ji




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...



Technology Transfer Automated Retrieval System (TEKTRAN)

Antimicrobial resistance has emerged as a global problem. Although it 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 resistance to a single antimicrobial was overcome by th...


Assessment of bacterial antibiotic resistance transfer in the gut.  


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



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.

Schj?rring, Susanne; Krogfelt, Karen A.



[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



Cancer drug resistance: an evolving paradigm.  


Resistance to chemotherapy and molecularly targeted therapies is a major problem facing current cancer research. The mechanisms of resistance to 'classical' cytotoxic chemotherapeutics and to therapies that are designed to be selective for specific molecular targets share many features, such as alterations in the drug target, activation of prosurvival pathways and ineffective induction of cell death. With the increasing arsenal of anticancer agents, improving preclinical models and the advent of powerful high-throughput screening techniques, there are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification. PMID:24060863

Holohan, Caitriona; Van Schaeybroeck, Sandra; Longley, Daniel B; Johnston, Patrick G



NOTE: Dielectrophoretic assay of bacterial resistance to antibiotics  

NASA Astrophysics Data System (ADS)

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

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



Innate and Induced Resistance Mechanisms of Bacterial Biofilms  

Microsoft Academic Search

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

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


Phenotypic Conversion of Drug-Resistant Bacteria to Drug Sensitivity  

Microsoft Academic Search

Plasmids that contain synthetic genes coding for small oligoribonucleotides called external guide sequences (EGSs) have been introduced into strains of Escherichia coli harboring antibiotic resistance genes. The EGSs direct RNase P to cleave the mRNAs transcribed from these genes thereby converting the phenotype of drug-resistant cells to drug sensitivity. Increasing the EGS-to-target mRNA ratio by changing gene copy number or

Cecilia Guerrier-Takada; Reza Salavati; Sidney Altman



Emerging pathogens: Dynamics, mutation and drug resistance  

SciTech Connect

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

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



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




Technology Transfer Automated Retrieval System (TEKTRAN)

Common bacterial blight (CBB) (Xanthomonas axonopodis pv. phaseoli) and halo blight (HB) (Pseudomonas savastanoi pv. phaseolicola) are serious seedborne diseases of dry beans. These diseases are widely distributed throughout the bean producing areas in South Africa and can cause severe yield and see...


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)



Evolutionary paths to antibiotic resistance under dynamically sustained drug stress  

PubMed Central

Antibiotic resistance can evolve through sequential accumulation of multiple mutations1. To study such gradual evolution, we developed a selection device, the morbidostat, which continuously monitors bacterial growth and dynamically regulates drug concentrations such that the evolving population is constantly challenged. We analyzed evolutionary trajectories of Escherichia coli populations towards resistance to chloramphenicol, doxycycline, and trimethoprim. Over a period of ~20 days, resistance levels increased dramatically, with parallel populations showing similar phenotypic trajectories. Whole-genome sequencing revealed both drug-specific and drug-general genetic changes. Chloramphenicol and doxycycline resistance evolved through diverse combinations of mutations in genes involved in translation, transcription, and transport2. In contrast, trimethoprim resistance evolved in a stepwise manner1,3, through mutations restricted to the target enzyme dihydrofolate reductase (DHFR)4,5. Sequencing DHFR over time revealed that parallel populations not only evolved similar mutations, but also acquired them in similar order6. Uncovering such recurrent genotypic pathways may help the spread of resistance.

Toprak, Erdal; Veres, Adrian; Michel, Jean-Baptiste; Chait, Remy; Hartl, Daniel L.; Kishony, Roy



Dielectrophoretic assay of bacterial resistance to antibiotics  

Microsoft Academic Search

The dielectrophoretic collection spectra of antibiotic-sensitive and antibiotic-resistant strains of Staphylococcus epidermidis have been determined. These indicate that in the absence of antibiotic treatment there is a strong similarity between the dielectric properties of sensitive and resistant strains, and that there is a significant difference between the sensitive strains before and after treatment with the antibiotic streptomycin after 24 h

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



Bacterial resistance and topical antimicrobial wash products  

Microsoft Academic Search

Current scientific evidence has not shown that a link exists between the use of topical antimicrobial formulations and antiseptic or antibiotic resistance. As a result of the extensive history and varied use of antiseptic products and ingredients, any selective pressure for antibiotic resistance that may be occurring or may be uncovered in the future because of antiseptic use would be

Rhonda D. Jones



Antibiotic resistant bacterial profiles of anaerobic swine lagoon effluent.  


Although land application of swine (Sus scrofa) 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 antibiotic resistance in swine lagoon bacteria from sow, nursery, and finisher farms in the southeastern United States. Effluents from 37 lagoons were assayed for the presence of Escherichia coli, Campylobacter, Listeria, and Salmonella. Antibiotic resistance profiles were determined by the Kirby-Bauer swab method for 12 antibiotics comprising eight classes. Statistical analyses indicated that farm type influenced the amount and type of resistance, with nurseries and sow farms ranking as most influential, perhaps due to use of more antibiotic treatments. Finisher farms tended to have the least amount of antibiotic class resistance, signaling an overall healthier market pig, and less therapeutic or prophylactic antibiotic use. Many bacterial isolates were resistant to penicillin, cephalosporin, and tetracycline class antibiotics, while nearly all were susceptible to quinolone antibiotics. It appeared that swine farm type had a significant association with the amount of resistance associated with bacterial genera sampled from the lagoons; nurseries contributed the largest amount of bacterial resistance. PMID:19875799

Brooks, J P; McLaughlin, M R



Overcoming Drug Resistance in Pancreatic Cancer  

PubMed Central

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

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



Expression of cytokeratin confers multiple drug resistance  

SciTech Connect

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

Bauman, P.A.; Dalton, W.S.; Anderson, J.M.; Cress, A.E. (Univ. of Arizona, Tucson, AZ (United States))



Drug Resistance Mutations in HIV1  

Microsoft Academic Search

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

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


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.

Fidler, D. P.



Chemical States of Bacterial Spores: Dry-Heat Resistance  

PubMed Central

Mature bacterial spores can be manipulated by chemical pretreatments between states sensitive and resistant to dry heat. The two chemical forms of the spore differ in dry-heat resistance by about an order of magnitude. Log survivor curves for each chemical state were approximately straight lines. The temperature dependence of dry-heat resistance for each chemical state was similar to that usually found for dry-heat resistance. A method of testing spore resistance to dry heat has been designed to minimize artifacts resulting from (i) change of chemical state during the test, (ii) effects of water vapor activity, (iii) incomplete recovery of spores from the test container and clumping of spores. Implications of the existence of different chemical resistance states for experimental strategy and testing of dry-heat resistance are discussed.

Alderton, Gordon; Snell, Neva



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


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



Challenges and Controversies in Defining Totally Drug-Resistant Tuberculosis  

PubMed Central

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

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



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.



CancerDR: Cancer Drug Resistance Database  

PubMed Central

Cancer therapies are limited by the development of drug resistance, and mutations in drug targets is one of the main reasons for developing acquired resistance. The adequate knowledge of these mutations in drug targets would help to design effective personalized therapies. Keeping this in mind, we have developed a database “CancerDR”, which provides information of 148 anti-cancer drugs, and their pharmacological profiling across 952 cancer cell lines. CancerDR provides comprehensive information about each drug target that includes; (i) sequence of natural variants, (ii) mutations, (iii) tertiary structure, and (iv) alignment profile of mutants/variants. A number of web-based tools have been integrated in CancerDR. This database will be very useful for identification of genetic alterations in genes encoding drug targets, and in turn the residues responsible for drug resistance. CancerDR allows user to identify promiscuous drug molecules that can kill wide range of cancer cells. CancerDR is freely accessible at

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



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.

Adhvaryu, Meghna; Vakharia, Bhasker



Drug-resistant tuberculosis: emerging treatment options.  


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



Bacterial resistance to heavy metals and metalloids  

Microsoft Academic Search

Bacteria have evolved various types of resistance mechanisms to toxic metals and metalloids including mercury, cadmium\\/zinc,\\u000a copper\\/silver and arsenic\\/antimony. Active efflux of the metal is a frequently utilized stratagem, lowering the intracellular\\u000a concentration to subtoxic levels. Reduction to a less toxic form or to a form recognized by an efflux system also occurs.\\u000a Sequestration of metals has also been observed.

Barry P. Rosen



Antibiotic Resistance of Bacterial Litter Isolates  

Microsoft Academic Search

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



Protein Oxidation: Key to Bacterial Desiccation Resistance?  

SciTech Connect

For extremely ionizing radiation resistant bacteria, survival has been attributed to protection of proteins from oxidative damage during irradiation, with the result that repair systems survive and function with far greater efficiency during recovery than in sensitive bacteria. Here we examined the relationship between survival of dry-climate soil bacteria and the level of cellular protein oxidation induced by desiccation. Bacteria were isolated from surface soils of the shrub-steppe of the U.S. Department of 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.

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



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



Drug-resistant tuberculosis: an insurmountable epidemic?  


Drug-resistant tuberculosis has brought back the spectre of pre-antibiotic days. WHO surveillance data from 2007 showed multi-drug-resistant tuberculosis (MDR-TB)-tubercle bacillus resistant to both isoniazid and rifampicin accounting for 4.8% of all new and subsequent cases of tuberculosis. India and China-the two most populated countries of the world, house the maximum number of drug-resistant tuberculosis cases. In eastern European and central Asian countries, more than 6% of new TB cases are MDR-TB, whereas the number is <3% in the countries of the western world. Extensively drug-resistant tuberculosis (XDR-TB) has emerged with the prospect of tuberculosis becoming an incurable disease. A surveillance spreading over the six continents showed 10% of MDR-TB cases were also XDR-TB. The fact that tuberculosis is the most common opportunistic infection among HIV-infected patients in developing countries makes the challenge almost insurmountable. The mortality of HIV and MDR-TB co-infected patients is exceedingly high. The absence of guidelines for treatment of drug-resistant tuberculosis and of infrastructure for delivery of DOT program and rapid laboratory diagnostic facilities, including drug susceptibility testing for both first and second-line drugs, and lack of trained human resource in most of the developing world account for the emergence and perpetuation of this menacing problem. WHO along with partnership with Green Light Committee and individual national governments has started DOT plus program to control this global epidemic. PMID:21127999

Chakroborty, Amitabha



Drug Resistance in African Trypanosomiasis  

Microsoft Academic Search

Human sleeping sickness has been with mankind from its earliest beginnings, and may actually have contributed to the evolutionary\\u000a split of the hominids from their primate relatives. Drugs against sleeping sickness were among the fi rst targets of the new\\u000a art and science of chemotherapy that was initiated by Paul Ehrlich and his collaborators at the turn of the last

Thomas Seebeck; Pascal Mäser


Minority Variants of Drug-Resistant HIV  

PubMed Central

Minor drug-resistant variants exist in every HIV-infected patient. Since these minority variants are usually present at very low levels, they cannot be detected and quantified using conventional genotypic and phenotypic tests. Recently, several assays have been developed to characterize these low-abundance drug-resistant variants in the large genetically complex population present in every HIV-infected individual. The most important issue is, what results generated by these assays can predict clinical or treatment outcomes and might guide patient management in clinical practice. Cutoff-values for the detection of these low-abundance viral variants that predict increased risk of treatment failure should be determined. These thresholds may be specific for each mutation and treatment regimen. In this review we summarize the attributes and limitations of the currently available detection assays and review the existing information about both acquired and transmitted drug resistant minority variants.

Gianella, Sara; Richman, Douglas D.



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.

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.



Drug Resistance Assays for Mycobacterium tuberculosis  

Microsoft Academic Search

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

Leonid Heifets; Gerard Cangelosi


Drug resistance confounding prion therapeutics.  


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



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

PubMed Central

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



TGF-?: An emerging player in drug resistance.  


The transforming growth factor ? (TGF-?) pathway acts as a double-edged sword in tumorigenesis. By constraining epithelial cell growth, TGF-? is a potent tumor suppressor. However, TGF-? also acts as a key player in the induction of epithelial-to-mesenchymal transition (EMT), thereby enhancing invasiveness and metastasis. Furthermore, TGF-? signaling has recently been correlated with resistance against both targeted and conventional anticancer agents. Here, we present data demonstrating a role for TGF-? in chemotherapy resistance in colorectal cancer (CRC). We discuss these results in the context of recent findings indicating TGF-? signaling as an emerging player in cancer drug resistance. PMID:23974105

Brunen, Diede; Willems, Stefan M; Kellner, Udo; Midgley, Rachel; Simon, Iris; Bernards, René



Mechanisms of Candida biofilm drug resistance.  


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

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



Death Receptor Ligands, in Particular TRAIL, to Overcome Drug Resistance  

Microsoft Academic Search

The efficacy of chemotherapeutic drugs is hampered by the occurrence of intrinsic and acquired drug resistance. A variety of mechanisms cause drug-resistance. A final common factor, however, is the reduced capacity of drug resistant cells to go into apoptosis following treatment with DNA damaging agents. This is due to defects in apoptotic pathways, for example, changes in p53. The presence

S. de Jong; T. Timmer; F. J. Heijenbrok; E. G. E. de Vries



Antibacterial Cleaning Products and Drug Resistance  

Microsoft Academic Search

We examined whether household use of antibacterial cleaning and hygiene products is an emerging risk factor for carriage of antimicrobial drug-resistant bacteria on hands of household members. Households (N = 224) were random- ized to use of antibacterial or nonantibacterial cleaning and hygiene products for 1 year. Logistic regression was used to assess the influence of antibacterial product use in

Allison E. Aiello; Bonnie Marshall; Stuart B. Levy; Phyllis Della-Latta; Susan X. Lin; Elaine Larson



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.

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



Tumour stem cells and drug resistance  

Microsoft Academic Search

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters

Tito Fojo; Susan Bates; Michael Dean



Countering amyloid polymorphism and drug resistance with minimal drug cocktails  

PubMed Central

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



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



Molecular Mechanisms of Bacterial Resistance to Antimicrobial Peptides  

Microsoft Academic Search

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

D. Kraus; A. Peschel


Update on tamper-resistant drug formulations.  


An expert panel convened in 2005 by the College on Problems of Drug Dependence (CPDD) to consider strategies to reduce the risk of prescription medication abuse concluded that drug formulation plays a significant role in determining risk of abuse. Efforts on the part of the pharmaceutical industry to develop drugs that deter abuse have focused primarily on opioid formulations resistant to common forms of tampering, most notably crushing or dissolving the tablet to accelerate release. Several opioid formulations developed to be tamper resistant have been approved, but the US Food and Drug Administration has not approved explicit label claims of abuse deterrence and has stated that any such claim will require substantial postmarketing data. Drug development efforts in this area raise questions about the relative impact of abuse-deterrent formulations, not only on individuals who might abuse a medication, but also on patients who are compliant with therapy. This review discusses progress since the 2005 CPDD meeting with an emphasis on opioids. Articles cited in the review were identified via a PubMed search covering the period between January 1, 2000, and October 5, 2011. Scientific work presented by the authors and their colleagues at meetings held through May 2012 also was included. Published literature suggests that development of abuse-deterrent products will require broad public health support and continued encouragement from regulatory authorities so that such products will become the expected standard of care for certain drug classes. PMID:23415386

Romach, M K; Schoedel, K A; Sellers, E M



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


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

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



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.



Bacterial resistances to toxic metal ions--a review.  


Bacterial plasmids encode resistance systems for toxic metal ions, including Ag+, AsO2-, AsO4(3-), Cd2+, Co2+, CrO4(2-), Cu2+, Hg2+, Ni2+, Pb2+, Sb3+, TeO3(2-), Tl+ and Zn2+. The function of most resistance systems is based on the energy-dependent efflux of toxic ions. Some of the efflux systems are ATPases and others are chemiosmotic cation/proton antiporters. The Cd(2+)-resistance ATPase of Gram-positive bacteria (CadA) is membrane cation pump homologous with other bacterial, animal and plant P-type ATPases. CadA has been labeled with 32P from [alpha-32P] ATP and drives ATP-dependent Cd2+ (and Zn2+) uptake by inside-out membrane vesicles (equivalent to efflux from whole cells). Recently, isolated genes defective in the human hereditary diseases of copper metabolism, namely Menkes syndrome and Wilson's disease, encode P-type ATPases that are more similar to bacterial CadA than to other ATPases from eukaryotes. The arsenic resistance efflux system transports arsenite [As(III)], alternatively using either a double-polypeptide (ArsA and ArsB) ATPase or a single-polypeptide (ArsB) functioning as a chemiosmotic transporter. The third gene in the arsenic resistance system, arsC, encodes an enzyme that converts intracellular arsenate [As(V)] to arsenite [As(III)], the substrate of the efflux system. The triple-polypeptide Czc (Cd2+, Zn2+ and Co2+) chemiosmotic efflux pump consists of inner membrane (CzcA), outer membrane (CzcC) and membrane-spanning (CzcB) proteins that together transport cations from the cytoplasm across the periplasmic space to the outside of the cell. PMID:8991852

Silver, S



Chemical communication of antibiotic resistance by a highly resistant subpopulation of bacterial cells.  


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

El-Halfawy, Omar M; Valvano, Miguel A



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

PubMed Central

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

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



Molecular mechanisms involved in bacterial speck disease resistance of tomato  

PubMed Central

An important recent advance in the field of plant-microbe interactions has been the cloning of genes that confer resistance to specific viruses, bacteria, fungi or nematodes. Disease resistance (R) genes encode proteins with predicted structural motifs consistent with them having roles in signal recognition and transduction. The future challenge is to understand how R gene products specifically perceive defence-eliciting signals from the pathogen and transduce those signals to pathways that lead to the activation of plant defence responses. In tomatoes, the Pto kinase (product of the Pto R gene) confers resistance to strains of the bacterial speck pathogen, Pseudomonas syringae pv. tomato, that carry the corresponding avirulence gene avrPto. Resistance to bacterial speck disease is initiated by a mechanism involving the physical interaction of the Pto kinase and the AvrPto protein. This recognition event initiates signalling events that lead to defence responses including an oxidative burst, the hypersensitive response and expression of pathogenesis-related genes. Pto-interacting (Pti) proteins have been identified that appear to act downstream of the Pto kinase and our current studies are directed at elucidating the roles of these components.

Gu, Y.-Q.



European recommendations on surveillance of antituberculosis drug resistance.  


Antituberculosis drug resistance, whose extent in Europe is not well documented, is a serious threat to tuberculosis control. The aim of the recent European recommendations on antituberculosis drug resistance surveillance, issued by a working group compos PMID:12631965

Schwoebel, V; Lambregts, C.S.B.; Moro, M.L.; Drobniewski, F; Hoffner, S.E.; Raviglione, M.C.; Rieder, H.L.



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.

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



A Reservoir of Drug-Resistant Pathogenic Bacteria in Asymptomatic Hosts  

Microsoft Academic Search

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

Gabriel G. Perron; Sylvain Quessy; Graham Bell; Dee A. Carter



4??-N-Demethylspiramycin Derivatives: Synthesis and Evaluation of Effectiveness against Drug-resistant Bacteria  

Microsoft Academic Search

18-Amino-4?-O-benzoyl-4??-N-demethyl-18-deoxospiramycins were designed and synthesized. Synthetic strategy involved selective demethylation of the dimethylamino group in forosamine, benzoylation of the hydroxyl group at the C4? position and reductive N-amination of the formyl group. Antibacterial characteristics of spiramycin derivatives were tested. The derivatives exhibited promising activity against drug-resistant bacterial strains.

Toshiaki Sunazuka; Hiroko Shudo; Kenichiro Nagai; Kiminari Yoshida; Yukie Yamaguchi; Hideaki Hanaki; Satoshi ?mura



Engaging resistant adolescents in drug abuse treatment  

Microsoft Academic Search

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

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



[Pharmacogenetic criteria of drug-resistant epilepsy].  


Pharmacogenetics, allows to improve our understanding of the mechanisms of action of AEDs and causes drug-resistence epilepsy. We found an association between farmakorezestentnistyu patient with epilepsy and the presence of a CC allele polymorphisms S3534T (rs1045642), S 1236T (rs 1128503) gene ABCB1 that encodes P-glycoprotein (hereafter P - glycoprotein rs1045642, P - glycoprotein rs1128503) and TT allelic polymorphism rs3812718 gene SCN1A, encoding a voltage-dependent sodium channels. PMID:23786015

Oros, M M



Recent trends in HIV-1 drug resistance.  


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

Siliciano, Janet D; Siliciano, Robert F



A Novel Transporter, Pfcrt, Confers Antimalarial Drug Resistance  

Microsoft Academic Search

The elucidation of the molecular details of drug resistance phenomena is a very active area of research that crosses many disciplinary boundaries. Drug resistance is due to altered drug-target interaction, and\\/or dysregulated signaling related to cell growth and death. Since many drugs need to rapidly diffuse into and within cells in order to find their targets, and since transmembrane ion

E. M. Howard; H. Zhang; P. D. Roepe



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


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

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



Drug resistance in cancer chemotherapy as an optimal control problem  

Microsoft Academic Search

We analyze non cell-cycle specific mathematical models for drug resistance in cancer chemotherapy. In each model developing drug resistance is inevitable and the issue is how to prolong its onset. Distinguishing between sensitive and resistant cells we consider a model which includes interactions of two killing agents which generate separate resistant populations. We formu- late an associated optimal control problem

Urszula Ledzewicz



Effect of Trimethoprim on the Occurrence of Drug-Resistant Coliform Bacteria in the Faecal Flora  

Microsoft Academic Search

The occurrence of drug-resistant coliform bacteria was studied in the faecal flora of 30 persons receiving for 3 weeks either trimethoprim alone, a combination of sulphamethoxazole and trimethoprim, or a combination of sulphamethox-ydiazine and sulphamethoxazole. Bacterial sensitivity was tested against trimethoprim, sulphamethoxazole-trimethoprim, sulphamethoxazole, and sulphaisodimidine. After treatment with trimethoprim alone, no increase in the occurrence of strains resistant to either

Auli Toivanen; Antero Kasanen; Hannu Sundquist; Paavo Toivanen



Sequential treatment of drug-resistant tumors with targeted minicells containing siRNA or a cytotoxic drug  

Microsoft Academic Search

The dose-limiting toxicity of chemotherapeutics, heterogeneity and drug resistance of cancer cells, and difficulties of targeted delivery to tumors all pose daunting challenges to effective cancer therapy. We report that small interfering RNA (siRNA) duplexes readily penetrate intact bacterially derived minicells previously shown to cause tumor stabilization and regression when packaged with chemotherapeutics. When targeted via antibodies to tumor-cell-surface receptors,

Jennifer A MacDiarmid; Nancy B Amaro-Mugridge; Jocelyn Madrid-Weiss; Ilya Sedliarou; Stefanie Wetzel; Kartini Kochar; Vatsala N Brahmbhatt; Leo Phillips; Scott T Pattison; Carlotta Petti; Bruce Stillman; Robert M Graham; Himanshu Brahmbhatt



In vitro antibacterial potential of Eugenia jambolana seed extracts against multidrug-resistant human bacterial pathogens.  


The present study was carried out to evaluate the possible in vitro antibacterial potential of extracts of Eugenia jambolana seeds against multidrug-resistant human bacterial pathogens. Agar well diffusion and microbroth dilution assay methods were used for antibacterial susceptibility testing. Kill-kinetics study was done to know the rate and extent of bacterial killing. Phytochemical analysis and TLC-bioautography were performed by colour tests to characterize the putative compounds responsible for this antibacterial activity. Cytotoxic potential was evaluated on human erythrocytes by haemolytic assay method and acute oral toxicity study was done in mice. The plant extracts demonstrated varying degrees of strain specific antibacterial activity against all the test isolates. Further, ethyl acetate fraction obtained from fractionation of most active ethanol extract showed maximum antibacterial effect against all the test isolates. Phytochemical analysis and TLC-bioautography of ethyl acetate fraction revealed that phenolics were the major active phytoconstituents. Ethyl acetate fraction also demonstrated no haemolytic activity on human erythrocytes and no gross behavioural changes as well as toxic symptoms were observed in mice at recommended dosage level. The results provide justification for the use of E. jambolana in folk medicine to treat various infectious diseases and may contribute to the development of novel antimicrobial agents for the treatment of infections caused by these drug-resistant bacterial pathogens. PMID:22444436

Bag, Anwesa; Bhattacharyya, Subir Kumar; Pal, Nishith Kumar; Chattopadhyay, Rabi Ranjan



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



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

PubMed Central

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

Fernandez, Lucia



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

Microsoft Academic Search

The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it.

Andrew S. Bell; Silvie Huijben; Krijn P. Paaijmans; Derek G. Sim; Brian H. K. Chan; William A. Nelson; Andrew F. Read



Rural Adolescent Perceptions of Alcohol and Other Drug Resistance.  

ERIC Educational Resources Information Center

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

Jenkins, Jeanne E.



Markers of drug resistance in relapsing colon cancer  

Microsoft Academic Search

Purpose: 5-Fluorouracil failure and drug resistance, which often occurs during chemotherapy, is still a great obstacle to the success of human colon cancer treatment. Thus, the comparative study of markers of drug resistance in cancer cells before and after chemotherapy may be extremely helpful in the selection of the appropriate chemotherapeutic drug in colon cancer patients who fail adjuvant treatment

A. Lazaris; N. Kavantzas; H. Zorzos; N. Tsavaris; P. Davaris



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

ERIC Educational Resources Information Center

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

Silva, Roberta K.


Drug and radiation resistance in spheroids: cell contact and kinetics  

Microsoft Academic Search

Cells from multicellular spheroids are often more resistant than monolayers to drugs and radiation. While explanations for resistance can be based on differences in cell cycle distribution, inability of the drug to penetrate the spheroid, or the presence of hypoxic cells, these mechanisms do not adequately explain resistance to all agents. Small spheroids (containing about 25–50 cells) exposed to ionizing

Peggy L. Olive; Ralph E. Durand



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


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

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



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



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

Federal Register 2010, 2011, 2012, 2013

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



Worldwide Emergence of Extensively Drug-resistant Tuberculosis  

PubMed Central

Mycobacterium tuberculosis strains that are resistant to an increasing number of second-line drugs used to treat multidrug-resistant tuberculosis (MDR-TB) are becoming a threat to public health worldwide. We surveyed the Network of Supranational Reference Laboratories for M. tuberculosis isolates that were resistant to second-line anti-TB drugs during 2000–2004. We defined extensively drug-resistant TB (XDR-TB) as MDR-TB with further resistance to ?3 of the 6 classes of second-line drugs. Of 23 eligible laboratories, 14 (61%) contributed data on 17,690 isolates, which reflected drug susceptibility results from 48 countries. Of 3,520 (19.9%) MDR-TB isolates, 347 (9.9%) met criteria for XDR-TB. Further investigation of population-based trends and expanded efforts to prevent drug resistance and effectively treat patients with MDR-TB are crucial for protection of public health and control of TB.

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



Clinical significance of drug resistance in human immunodeficiency virus.  


Antiretroviral drugs exert only limited activity against viruses that replicate persistently to high levels. Thus, drug-resistant viruses readily emerge. It has been difficult to assess the contribution of such drug resistance to the failure of treatment with drugs that have only limited effectiveness in the first place. The emergence of zidovudine-resistant human immunodeficiency virus is predictive of clinical disease progression, although the relationship of this event to treatment failure is particularly complicated. The relationship between drug resistance and the loss of activity of non-nucleoside reverse transcriptase inhibitors and protease inhibitors appears to be more straightforward. The optimal use of antiretroviral drugs and combination regimens requires an appreciation of the impact of drug resistance. PMID:8845446

Richman, D D



Drug Resistance of Coliform Bacteria in Hospital and City Sewage  

PubMed Central

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

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



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



An 'inside-the-box' approach to drug resistance.  


Drug resistance is a growing problem in medicine that demands creative solutions. In this issue, Schiffer and colleagues describe their novel approach to pinpointing hot spots of resistance, which might lead to new anti-HIV therapeutics. PMID:15489157

Stewart, Kent D; Kempf, Dale J



Drug interactions and the evolution of antibiotic resistance  

PubMed Central

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

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



Classification Tree Method for Bacterial Source Tracking with Antibiotic Resistance Analysis Data  

Microsoft Academic Search

Bacterial source tracking (BST) with antibiotic resistance analysis (ARA) has been conducted using various statistical classification models to identify sources of bacterial contami- nation of surface waters (3-5, 9-15). Isolates are obtained from fecal samples from known sources, such as humans, pets, live- stock, and wildlife, and are tested for antibiotic resistance against a panel of antibiotics at different concentrations.

Bertram Price; Elichia A. Venso; Mark F. Frana; Joshua Greenberg; Adam Ware; Lee Currey



Bacterial resistance to antisense peptide phosphorodiamidate morpholino oligomers.  


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

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



Resistance to antimalarial drugs: molecular, pharmacological and clinical considerations  

PubMed Central

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

Travassos, Mark A.; Laufer, Miriam K.



Engaging Resistant Adolescents in Drug Abuse Treatment  

PubMed Central

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

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



Beijing/W Genotype Mycobacterium tuberculosis and Drug Resistance  

PubMed Central

Beijing/W genotype Mycobacterium tuberculosis is widespread, may be increasing, and may have a predilection for drug resistance. Individual-level data on >29,000 patients from 49 studies in 35 countries were combined to assess the Beijing genotype’s prevalence worldwide, trends over time and with age, and associations with drug resistance. We found 4 patterns for Beijing/W genotype tuberculosis (TB): 1) endemic, not associated with drug resistance (high level in most of East Asia, lower level in parts of the United States); 2) epidemic, associated with drug resistance (high level in Cuba, the former Soviet Union, Vietnam, and South Africa, lower level in parts of Western Europe); 3) epidemic but drug sensitive (Malawi, Argentina); and 4) very low level or absent (parts of Europe, Africa). This study confirms that Beijing/W genotype TB is an emerging pathogen in several areas and a predominant endemic strain in others; it is frequently associated with drug resistance.



New approaches for understanding mechanisms of drug resistance in schistosomes.  


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

Greenberg, Robert M



New approaches for understanding mechanisms of drug resistance in schistosomes  

PubMed Central

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




The Effect of Antibiotic Drug Resistance on the Environment and its Impact on Public Health (Development of Drug Resistance).  

National Technical Information Service (NTIS)

The problem of drug resistance has arisen secondary to favorable selection pressures in an atmosphere of widespread usage of antibiotics. Resistance has been shown to be genetically or environmentally influenced and has been demonstrated to be transferabl...

E. T. Takafuji



Development of drug resistance in a murine mammary tumour.  

PubMed Central

The development of resistance to melphalan, cis-platinum and cyclophosphamide has been examined in the MT murine mammary carcinoma. A gradual decrease in therapeutic response was detected using growth delay and clonogenic cell survival during repeated drug treatment. A slow rate of resistance development, a gradual change in the slope of the dose-survival curves and the inability of 180 mg kg-1 cyclophosphamide to bring about a reduction in tumour response at a faster rate than 60 mg kg-1 cyclophosphamide suggest that resistance development was not due to the selection of a pre-existing highly drug resistant sub-population of tumour cells. Partial drug-resistance is proposed as one possible reason for the apparent inconsistency between these data and existing models of drug-resistance development. The drug-resistant lines were characterized for karyotype, DNA content and cell volume, but only the cyclophosphamide-resistant line showed any significant difference from the wild-type tumour. Cross-resistance studies revealed some inconsistencies with previous reports. Also, resistance to cyclophosphamide developed more quickly in the line which was resistant to melphalan, than in the wild-type tumour, despite the initial appearance of little cross-resistance. This increased rate of resistance development may be important in salvage chemotherapy.

McMillan, T. J.; Stephens, T. C.; Steel, G. G.



Expression of Xa1, a bacterial blight-resistance gene in rice, is induced by bacterial inoculation  

PubMed Central

The Xa1 gene in rice confers resistance to Japanese race 1 of Xanthomonas oryzae pv. oryzae, the causal pathogen of bacterial blight (BB). We isolated the Xa1 gene by a map-based cloning strategy. The deduced amino acid sequence of the Xa1 gene product contains nucleotide binding sites (NBS) and a new type of leucine-rich repeats (LRR); thus, Xa1 is a member of the NBS-LRR class of plant disease-resistance genes, but quite different from Xa21, another BB-resistance gene isolated from rice. Interestingly, Xa1 gene expression was induced on inoculation with a bacterial pathogen and wound, unlike other isolated resistance genes in plants, which show constitutive expression. The induced expression may be involved in enhancement of resistance against the pathogen.

Yoshimura, Satomi; Yamanouchi, Utako; Katayose, Yuichi; Toki, Seiichi; Wang, Zi-Xuan; Kono, Izumi; Kurata, Nori; Yano, Masahiro; Iwata, Nobuo; Sasaki, Takuji



Drug resistance in leishmaniasis: current drug-delivery systems and future perspectives.  


Leishmaniasis is a complex of diseases with numerous clinical manifestations for instance harshness from skin lesions to severe disfigurement and chronic systemic infection in the liver and spleen. So far, the most classical leishmaniasis therapy, despite its documented toxicities, remains pentavalent antimonial compounds. The arvailable therapeutic modalities for leishmaniasis are overwhelmed with resistance to leishmaniasis therapy. Mechanisms of classical drug resistance are often related with the lower drug uptake, increased efflux, the faster drug metabolism, drug target modifications and over-expression of drug transporters. The high prevalence of leishmaniasis and the appearance of resistance to classical drugs reveal the demand to develop and explore novel, less toxic, low cost and more promising therapeutic modalities. The review describes the mechanisms of classical drug resistance and potential drug targets in Leishmania infection. Moreover, current drug-delivery systems and future perspectives towards Leishmaniasis treatment are also covered. PMID:24144417

Yasinzai, Masoom; Khan, Momin; Nadhman, Akhtar; Shahnaz, Gul



[Bioinformatics studies on drug resistance against anti-HIV-1 drugs].  


More than 20 drugs have been available for anti-HIV-1 treatment in Japan. Combination therapy with these drugs dramatically decreases in morbidity and mortality of AIDS. However, due to high mutation rate of HIV-1, treatment with ineffective drugs toward patients infected with HIV-1 causes accumulation of mutations in the virus, and emergence of drug resistant viruses. Thus, to achieve appropriate application of the drugs toward the respective patients living with HIV-1, methods for predicting the level of drug-resistance using viral sequence information has been developed on the basis of bioinformatics. Furthermore, ultra-deep sequencing by next-generation sequencer whose data analysis is also based on bioinformatics, or in silico structural modeling have been achieved to understand drug resistant mechanisms. In this review, I overview the bioinformatics studies about drug resistance against anti-HIV-1 drugs. PMID:21972554

Ode, Hirotaka



Novel antimicrobial peptides that exhibit activity against select agents and other drug resistant bacteria.  


One of the greatest challenges facing modern medicine is the evolution of drug resistant strains of bacteria. In addition to traditional methods of exposure to traditional bacterial organisms there is a growing concerned of the use of bacteria as bio-terrorism agents. To counter the evolution of drug resistant and potential bio-terrorism bacterial agents new antibiotic drugs must be developed. One potential source of new therapeutic agents that act via a novel mechanism of action are natural and synthetic antimicrobial peptides (AMPs). In our laboratories we have developed a series of AMPs incorporating the un-natural amino acids Tic-Oic to impart organism selectivity and potency while increasing metabolic stability. Herein the in vitro activity of these peptides, including ten new compounds, against eight potential bio-terrorism bacterial agents and three other bacterial strains is presented and discussed. These peptides exhibit a wide range of organism potency and selectivity. Calcein fluorescence leakage and circular dichroism studies were conducted to confirm that these peptides interact with zwitterionic and anionic liposomes. PMID:20558071

Venugopal, Divakaramenon; Klapper, David; Srouji, Antoine H; Bhonsle, Jayendra B; Borschel, Richard; Mueller, Allen; Russell, Amanda L; Williams, Brittany C; Hicks, Rickey P



Mapping Factors that Drive Drug Resistance (with a Focus on Resource-Limited Settings): A First Step Towards Better Informed Policy  

Microsoft Academic Search

Drug resistance is a global challenge, affecting multiple diseases and recognizing no borders. Resistance to the pharmacopeia available to treat AIDS, malaria, tuberculosis, and other bacterial infections is rising and threatens progress in global health. Up to 10% of treatment-naive HIV+ individuals in the industrialized world have been found to be infected by relatively fit strains of HIV with resistance

Alexandra Beith


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

Microsoft Academic Search

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

Segaran P. Pillai; Delbert M. Shankel



Pervasive Sign Epistasis between Conjugative Plasmids and Drug-Resistance Chromosomal Mutations  

Microsoft Academic Search

Multidrug-resistant bacteria arise mostly by the accumulation of plasmids and chromosomal mutations. Typically, these resistant determinants are costly to the bacterial cell. Yet, recently, it has been found that, in Escherichia coli bacterial cells, a mutation conferring resistance to an antibiotic can be advantageous to the bacterial cell if another antibiotic-resistance mutation is already present, a phenomenon called sign epistasis.

Rui F. Silva; Sílvia C. M. Mendonça; Luís M. Carvalho; Ana M. Reis; Isabel Gordo; Sandra Trindade; Francisco Dionisio



Genetic and Biochemical Studies of Drug Resistance in Pathogenic Bacteria.  

National Technical Information Service (NTIS)

Sixty strains of Pseudomonas aeruginosa were selected from clinical stock cultures and used as donors of drug resistance to examine the presence of R factors. They were highly resistant to one or more of six drugs including tetracycline(TC), chloramphenic...

S. Mitsuhashi



Hematoprotection by Transfer of Drug-Resistance Genes  

Microsoft Academic Search

Myelosuppression represents a major side effect of cytotoxic anti-cancer agents. Infection due to granulocytopenia and the risk of bleeding due to thrombocytopenia compromise the potential of curative and palliative chemotherapy. Considering the many chemotherapeutic agents for which drug resistance genes have been described, and the recent improvements in vector and transduction technology, it seems conceivable that drug resistance gene transfer

Michael Flasshove; Thomas Moritz; Walter Bardenheuer; Siegfried Seeber



Drug resistance in Giardia: clinical versus laboratory isolates  

Microsoft Academic Search

The advantages and limitations of determining mechanisms of drug resistance in Giardia duodenalis laboratory isolates, which have been generated in a number of ways, is weighed against the difficulty of analysing mechanisms in clinical isolates with a large diversity of genetic and expression capabilities. Using isogenic strains to follow changes in enzyme regulation involved in drug resistance, we have been

Peter Upcroft



[Managing multi-drug resistant bacteria in nursing homes].  


The application of standard and sometimes additional hygiene precautions also concerns nursing homes, in order to prevent the transmission of multi-drug resistant bacteria. If a resident is a carrier or infected by a multi-drug resistant bacteria, the care must be organised accordingly but geographic confinement is rarely adapted. PMID:23865248

Novakova, Ivana; Neveur, Magali


Tumor microenvironment and drug resistance in hematologic malignancies.  


Increasing evidence supports the role of the tumor microenvironment in conferring drug resistance as a major cause of relapse and incurability of cancers. The tumor microenvironment consists of normal stromal cells, extracellular matrix, and soluble factors such as cytokines and growth factors. Tumor-tumor cell interaction, tumor-stromal cell interaction, as well as tumor-ECM interaction, all contribute to direct cell contact mediated drug resistance. In addition, soluble factors produced in the tumor microenvironment provide further signals for tumor cell growth and survival. Environment mediated-drug resistance (EM-DR) could be considered as the totality of cell adhesion mediated drug resistance (CAM-DR) and soluble factor mediated drug resistance (SM-DR) produced by the tumor-host interaction. This review focuses on the EM-DR model system and signaling pathways involved in cell survival of hematological malignancies. PMID:16920238

Li, Zhi-Wei; Dalton, William S



Impact of restricted amoxicillin/clavulanic acid use on Escherichia coli resistance--antibiotic DU90% profiles with bacterial resistance rates: a visual presentation.  


High use of amoxicillin/clavulanic acid (AMC) at the University Hospital Osijek (Croatia) contributed to high rates of resistance in Enterobacteriaceae, in particular Escherichia coli (50%). Thus, in order to decrease bacterial resistance, AMC use was restricted. We present results of the restriction on resistance amongst antibiotics accounting for 90% of antibiotic use [drug utilisation 90% (DU90%)]. Data were analysed on antibiotic use and microbiological susceptibility of E. coli during two 9-month periods, before and after the restriction of AMC use. Drug use was presented as numbers of defined daily doses (DDDs) and DDDs/100 bed-days. Resistance of E. coli to antibiotics was presented as percentages of isolated strains in the DU90% segment. Use of AMC was 16 DDDs/100 bed-days or 30% of all antibiotics before the intervention. Use of AMC fell to 2 DDDs/100 bed-days or 4% after the intervention, and resistance of E. coli fell from 37% to 11%. In conclusion, restricted use of AMC resulted in a significant decrease of E. coli resistance. DU90% resistance profiles are simple and useful tools in highlighting problems in antibiotic use and resistance but may also be useful in long-term follow-up of antibiotic policy. PMID:20688486

Mimica Matanovic, Suzana; Bergman, Ulf; Vukovic, Dubravka; Wettermark, Björn; Vlahovic-Palcevski, Vera



Intraocular delivery of anti-infective drugs-bacterial, viral, fungal and parasitic.  


This article reviews the current literature about the use of intraocular drugs for treatment of bacterial, fungal, viral and protozoal intraocular infection. This route of administration has the advantage of delivering antimicrobials directly into the eye achieving a high therapeutic concentration above the MIC(90) of most pathogens and with minimal systemic side effects. It is usually well tolerated but carries a small risk of intraocular complications. Intraocular therapy is now the main therapeutic approach for treatment of bacterial endophthalmitis and has an important adjunctive role in the management of endogenous fungal endophthalmitis and viral retinitis. Intravitreal clindamycin therapy offers a recent additional strategy to treat ocular toxoplasmosis in patients who are intolerant or resistant to systemic treatment. Current researches is now focusing on new patents as well as on the use of intraocular lenses that incorporate antibiotics during cataract surgery and thus provide a sustained high antibiotic levels in the eye in the immediate postoperative period, not depending on patient's compliance. PMID:18221186

Sallam, Ahmed; Jayakumar, Subash; Lightman, Susan



Is Bacterial Fatty Acid Synthesis a Valid Target for Antibacterial Drug Discovery?  

PubMed Central

The emergence of resistance against most current drugs emphasizes the need to develop new approaches to control bacterial pathogens, particularly Staphylococcus aureus. Bacterial fatty acid synthesis is one such target that is being actively pursued by several research groups to develop anti-Staphylococcal agents. Recently, the wisdom of this approach has been challenged based on the ability of a Gram-positive bacterium to incorporate extracellular fatty acids and thus circumvent the inhibition of de novo fatty acid synthesis. The generality of this conclusion has been challenged, and there is enough diversity in the enzymes and regulation of fatty acid synthesis in bacteria to conclude that there isn’t a single organism that can be considered typical and representative of bacteria as a whole. We are left without a clear resolution to this ongoing debate and await new basic research to define the pathways for fatty acid uptake and that determine the biochemical and genetic mechanisms for the regulation of fatty acid synthesis in Gram-positive bacteria. These crucial experiments will determine whether diversity in the control of this important pathway accounts for the apparently different responses of Gram-positive bacteria to the inhibition of de novo fatty acid synthesis in presence of extracellular fatty acid supplements.

Parsons, Joshua B.; Rock, Charles O.



Tumour endothelial cells acquire drug resistance in a tumour microenvironment.  


Tumour growth is dependent on angiogenesis, and tumour blood vessels are recognized as an important target for cancer therapy. Tumour endothelial cells (TECs) are the main targets of anti-angiogenic therapy. Unlike the traditionally held view, some TECs may be genetically abnormal and might acquire drug resistance. Therefore, we investigated the drug resistance of TECs and the mechanism by which it is acquired. TECs show resistance to paclitaxel through greater mRNA expression of multidrug resistance 1, which encodes P-glycoprotein, as compared with normal endothelial cells. We found that high levels of vascular endothelial growth factor in tumour-conditioned medium may be responsible for upregulated P-glycoprotein expression. This is a novel mechanism for the acquisition of drug resistance by TECs in a tumour microenvironment. This review focuses on the possibility that TECs can acquire drug resistance. PMID:23293323

Hida, Kyoko; Akiyama, Kosuke; Ohga, Noritaka; Maishi, Nako; Hida, Yasuhiro



Monopoly pricing of an antibiotic subject to bacterial resistance.  


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

Herrmann, Markus



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.

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



Transport Mechanisms of Resistance to Drugs and Toxic Metals  

Microsoft Academic Search

This chapter discusses the types of transport systems that confer resistance to antibiotics, antimicrobial drugs, and toxic\\u000a metals. A number of these are discussed in detail in other chapters, so here we focus on the ways in which microorganisms\\u000a have evolved to use transporters to evade the toxic effects of drugs and metals.\\u000a \\u000a Resistance to therapeutic drugs and toxic metals

Adrian R. Walmsley; Barry P. Rosen


Protein Interactome Analysis for Countering Pathogen Drug Resistance  

Microsoft Academic Search

Drug-resistant varieties of pathogens are now a recognized global threat. Insights into the routes for drug resistance in\\u000a these pathogens are critical for developing more effective antibacterial drugs. A systems-level analysis of the genes, proteins,\\u000a and interactions involved is an important step to gaining such insights. This paper discusses some of the computational challenges\\u000a that must be surmounted to enable

Limsoon Wong; Guimei Liu



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.

Lin, Jessica T.; Juliano, Jonathan J.



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.



Mycobacterium tuberculosis interactome analysis unravels potential pathways to drug resistance  

Microsoft Academic Search

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

Karthik Raman; Nagasuma Chandra



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


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

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



Cancer stem cells and drug resistance: the potential of nanomedicine  

PubMed Central

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

Vinogradov, Serguei; Wei, Xin



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



HIV Drug Resistance and the importance of adherence  

NSDL National Science Digital Library

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



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



Antimalarial Drugs Clear Resistant Parasites from Partially Immune Hosts  

Microsoft Academic Search

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




Antitubercular Drug Resistance in Four Healthcare Facilities in North India  

PubMed Central

Tuberculosis (TB) is a major public-health problem in India, having the highest number of incident and multidrug-resistant (MDR) TB cases. The study was carried out to appraise the prevalence of first-line anti-TB drug resistance in Mycobacterium tuberculosis (MTB) and its patterns among different types of TB patients from different settings in a province of North India. Of 3,704 clinical specimens, 345 (9.3%) were culture-positive, and drug-susceptibility testing was carried out for 301 MTB strains. A high level of primary and acquired drug resistance of MTB was observed in the region studied, with weighted mean of 10.5% and 28.08%, 12.81% and 29.72%, 17.12% and 29.94%, 11.97% and 27.84%, and 10.74% and 23.54% for rifampicin, isoniazid, streptomycin, ethambutol-resistant and MDR cases respectively. Drug resistance was significantly higher in pulmonary (p=0.014) and acquired drug-resistant TB cases (p<0.001). Any drug resistance (p=0.002) and MDR TB were significantly (p=0.009) associated with HIV-seropositive cases. An urgent plan is needed to continuously monitor the transmission trends of drug-resistant strains, especially MDR-TB strains, in the region.

Gupta, Anamika; Mathuria, Jitendra Prasad; Singh, Surya Kumar; Gulati, Anil Kumar



Race-specificity of plant resistance to bacterial spot disease determined by repetitive motifs in a bacterial avirulence protein  

Microsoft Academic Search

ELUCIDATION of the genetic and molecular basis of plant disease resistance is a major objective in the investigation of plant-micro-bial interactions. Xanthomonas campestris pathovar vesicatoria (Xcv), the causal agent of bacterial spot disease of pepper and tomato, has been developed as a model host-pathogen system to study the genetic interactions that specify the expression of plant disease resistance1-6. Several plant

Karin Herbers; Jutta Conrads-Strauch; Ulla Bonas



Chromosome mediated gene transfer of drug resistance to mitoxantrone.  


The anthracenedione, mitoxantrone, frequently selects for a unique drug resistance phenotype that is not mediated by either MDR 1, MRP, or altered DNA topoisomerase II. In this study, we demonstrate that mitoxantrone resistance is likely to be multifactorial with at least one resistance mechanism being the result of a dominant genetic event. This finding was demonstrated by conducting chromosome transfer experiments from human breast cancer cell lines that were either sensitive (MCF7/S) or resistant to mitoxantrone (MCF7/Mitox). Chromosomes transferred from MCF7/Mitox cells into CHO-K1 cells resulted in the isolation of multiple clones resistant to mitoxantrone. In contrast, chromosomes transferred from the drug sensitive MCF7/S, parent cell line did not confer drug resistance in the rodent CHO-K1 recipient cell line. Both Alu-PCR analysis and Southern blot analysis demonstrated human DNA in the CHO-K1 cells receiving chromosomes from the MCF7/Mitox cells. Unlike the MCF7/Mitox cell line, the drug resistant, CHO-K1 chromosome transferrant clones did not have a decrease in total drug accumulation. We conclude that chromosome transfer from the MCF7/Mitox cell line into CHO-K1 cells, confers a non-transport mediated mechanism of drug resistance that is a dominant genetic event. These studies provide evidence of the genetic multifactorial nature of multidrug resistance in cells selected with mitoxantrone in-vitro. PMID:9615755

Hazlehurst, L A; Gros, P; Dalton, W S


A bacterial antibiotic-resistance gene that complements the human multidrug-resistance P-glycoprotein gene  

Microsoft Academic Search

Bacteria have developed many fascinating antibiotic-resistance mechanisms,. A protein in Lactococcus lactis, LmrA, mediates antibiotic resistance by extruding amphiphilic compounds from the inner leaflet of the cytoplasmic membrane,. Unlike other known bacterial multidrug-resistance proteins, LmrA is an ATP-binding cassette (ABC) transporter. The human multidrug-resistance P-glycoprotein, encoded by the MDR1 gene, is also an ABC transporter, overexpression of which is one

Hendrik W. van Veen; Richard Callaghan; Loredana Soceneantu; Alessandro Sardini; Wil N. Konings; Christopher F. Higgins



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

Microsoft Academic Search

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

Hiromichi Yamazaki; Sunao Kikuchi; Tsuguo Hoshina; Takeshi Kimura



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


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

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



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.

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



[New tuberculosis drugs in resistant and multiresistant tuberculosis].  


Drug-resistant tuberculosis is a globally emerging problem with a rising incidence. According to the WHO in 2008, 17% of strains of Mycobacterium tuberculosis, in untreated cases were resistant to at least one drug and 3.6% were resistant to rifampicin and isoniazid, which is called multidrug-resistant tuberculosis. The problem is greater in patients previously treated and in some countries, where rates of multidrug resistance reach 60%. Approximately 5% of multidrug-resistant tuberculosis patients are also resistant to any fluoroquinolone and at least one injectable drug, being called extensively drug-resistant tuberculosis. The treatment of these forms of tuberculosis requires the use of second-line drugs, which causes higher cost, higher toxicity and a longer duration of treatment. There is a need for new compounds with efficacy and safety profiles better than those currently used to treat these forms of tuberculosis. In the last decade different drugs have being reassessed and appeared, which are at different stages of development. PMID:23540388

Ramírez Lapausa, Marta; Pascual Pareja, José Francisco; Noguerado Asensio, Arturo



Genotypic Testing for Human Immunodeficiency Virus Type 1 Drug Resistance  

PubMed Central

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

Shafer, Robert W.



What is the mechanism for persistent coexistence of drug-susceptible and drug-resistant strains of Streptococcus pneumoniae?  

PubMed Central

The rise of antimicrobial resistance in many pathogens presents a major challenge to the treatment and control of infectious diseases. Furthermore, the observation that drug-resistant strains have risen to substantial prevalence but have not replaced drug-susceptible strains despite continuing (and even growing) selective pressure by antimicrobial use presents an important problem for those who study the dynamics of infectious diseases. While simple competition models predict the exclusion of one strain in favour of whichever is ‘fitter’, or has a higher reproduction number, we argue that in the case of Streptococcus pneumoniae there has been persistent coexistence of drug-sensitive and drug-resistant strains, with neither approaching 100 per cent prevalence. We have previously proposed that models seeking to understand the origins of coexistence should not incorporate implicit mechanisms that build in stable coexistence ‘for free’. Here, we construct a series of such ‘structurally neutral’ models that incorporate various features of bacterial spread and host heterogeneity that have been proposed as mechanisms that may promote coexistence. We ask to what extent coexistence is a typical outcome in each. We find that while coexistence is possible in each of the models we consider, it is relatively rare, with two exceptions: (i) allowing simultaneous dual transmission of sensitive and resistant strains lets coexistence become a typical outcome, as does (ii) modelling each strain as competing more strongly with itself than with the other strain, i.e. self-immunity greater than cross-immunity. We conclude that while treatment and contact heterogeneity can promote coexistence to some extent, the in-host interactions between strains, particularly the interplay between coinfection, multiple infection and immunity, play a crucial role in the long-term population dynamics of pathogens with drug resistance.

Colijn, Caroline; Cohen, Ted; Fraser, Christophe; Hanage, William; Goldstein, Edward; Givon-Lavi, Noga; Dagan, Ron; Lipsitch, Marc



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

Code of Federal Regulations, 2010 CFR for predicting drug resistance/susceptibility based on...genomic mutations that confer resistance to specific antiretroviral drugs, as an...Document: In Vitro HIV Drug Resistance Genotype Assay.â See §...



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

Code of Federal Regulations, 2010 CFR for predicting drug resistance/susceptibility based on...genomic mutations that confer resistance to specific antiretroviral drugs, as an...Document: In Vitro HIV Drug Resistance Genotype Assay.â See §...



Methods, microarray, and kits for detection of drug resistance genes in gram-negative bacteria  

US Patent & Trademark Office Database

The present invention provides kits and microarrays containing primer pairs for amplifying drug resistance genes and/or probes for detection of drug resistance genes. Also provided are methods of detecting drug resistance genes using kits and microarrays described herein.



History of Drug-Resistant Microbes  

Microsoft Academic Search

Resistance to antimicrobial agents has been recognized since the dawn of the antibiotic era. Paul Ehrlich, the father of modern\\u000a chemotherapy, observed that, during treatment of trypanosome infections, organisms sometimes emerged that were resistant to\\u000a the agent being used. Resistance was specifi c in the sense that a fuchsin dye-resistant strain was still susceptible to an\\u000a arsenic compound, while a

George A. Jacoby



Technology Transfer Automated Retrieval System (TEKTRAN)

Common bacterial blight caused by Xanthomonas axonopodis pv. phaseoli is a serious seedborne disease limiting common bean production worldwide. Genetic resistance is the most important component of integrated strategies including planting pathogen-free seed, crop rotation, and chemical applications,...


DNA origami as a carrier for circumvention of drug resistance.  


Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was non-covalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer. PMID:22803823

Jiang, Qiao; Song, Chen; Nangreave, Jeanette; Liu, Xiaowei; Lin, Lin; Qiu, Dengli; Wang, Zhen-Gang; Zou, Guozhang; Liang, Xingjie; Yan, Hao; Ding, Baoquan



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

PubMed Central

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

Seo, Yumi



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

Technology Transfer Automated Retrieval System (TEKTRAN)

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


Sustainable control of pea bacterial blight : approaches for durable genetic resistance and biocontrol by endophytic bacteria  

Microsoft Academic Search

Key-words: bacterial blight, biological control, biodiversity, endophytic bacteria, L-form, pea, PDRl retrotransposon, Pisum sativum, Pisum abyssinicum, Pseudomonas syringae pv. pisi, race specific resistance, race non-specific resistance, Spanish landraces.<\\/font>Pea bacterial blight (Pseudomonas syringae pv. pisi) occurs worldwide and can cause severe damage under cool and wet conditions particularly at the seedling stage in wintersown crops. Seven Ps. syr. pv. pisi races

M. Elvira-Recuenco



Survival probability of drug resistant mutants in malaria parasites.  

PubMed Central

This study predicts the ultimate probability of survival of a newly arisen drug resistant mutant in a population of malaria parasites, with a view to understanding what conditions favour the evolution of drug resistance. Using branching process theory and a population genetics transmission model, the probabilities of survival of one- and two-locus new mutants are calculated as functions of the degree of drug pressure, the mean and variation in transmission rate, and the degree of natural selection against the mutant. Probability of survival increases approximately linearly with drug pressure, the slope of the line increasing with mean transmission rate. Thus increased drug pressure, especially in combination with high transmission rates, strongly favours the evolution of drug resistance. These conclusions also hold for the case of multiple drug resistance where it is coded for by two unlinked loci: the greater effective recombination breakdown in high transmission areas is counteracted by greater effective selection so that the net effect of higher transmission rates is to favour the evolution of multiple drug resistance. High variability in transmission rate and natural selection against the mutants are unfavourable to mutant survival, though these are relatively weak forces.

Mackinnon, M J



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


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

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



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.

Martinez, Jose L.; Baquero, Fernando



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.

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



Identification of QTL associated with resistance to bacterial spot race T4 in tomato  

Microsoft Academic Search

Bacterial spot of tomato (Solanum lycopersicum L.), caused by several Xanthomonas sp., is a serious but difficult disease to control by chemical means. Development of resistance has been hindered by emergence\\u000a of races virulent to tomato, by the quantitative inheritance of resistance, and by a low correlation between seedling assays\\u000a and resistance in the field. Resistance to multiple races, including

Samuel F. HuttonJay; Jay W. Scott; Wencai Yang; Sung-Chur Sim; David M. Francis; Jeffrey B. Jones



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

PubMed Central

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

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



Heterogeneous distribution of Plasmodium falciparum drug resistance haplotypes in subsets of the host population  

Microsoft Academic Search

BACKGROUND: The emergence of drug resistance is a major problem in malaria control. For mathematical modelling of the transmission and spread of drug resistance the determinant parameters need to be identified and measured. The underlying hypothesis is that mutations associated with drug resistance incur fitness costs to the parasite in absence of drug pressure. The distribution of drug resistance haplotypes

Sonja Schoepflin; Jutta Marfurt; Mary Goroti; Moses Baisor; Ivo Mueller; Ingrid Felger



Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia  

PubMed Central

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

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



Drug Resistance Among Pathogenic Bacteria from Animals in Ontario  

PubMed Central

Prevalence of antimicrobial drug resistance among over 3000 clinical isolates of animal pathogens in Ontario during 1971-72 has been studied. A high number of multiple resistance patterns is prevalent among members of Enterobacteriaceae, especially Escherichia coli and Salmonella typhimurium. The most common resistance pattern among bovine strains was against not less than six drugs in common use. Among different animal species the bovine population was found to be the source of a high percentage of chloramphenicol resistant E. coli and S. typhimurium organisms. All the isolates resistant to this drug were in addition resistant to three or more other antibiotics of established therapeutic value. All the multiple resistant isolates of S. typhimurium tested had R factors and they transferred most of the resistance determinants including that for chloramphenicol to a recipient E. coli in vitro. Penicillin resistance among Staphylococcus aureus of bovine mammary origin did not appear to be high. Antimicrobial drug susceptibility patterns of staphylococci, streptococci and Corynebacterium sp indicate effective in vitro activity with many antimicrobial agents.

Hariharan, H.; Barnum, D. A.; Mitchell, W. R.



Aggressive Chemotherapy and the Selection of Drug Resistant Pathogens  

PubMed Central

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

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



Drug efflux pump deficiency and drug target resistance masking in growing bacteria  

PubMed Central

Recent experiments have shown that drug efflux pump deficiency not only increases the susceptibility of pathogens to antibiotics, but also seems to “mask” the effects of mutations, that decrease the affinities of drugs to their intracellular targets, on the growth rates of drug-exposed bacteria. That is, in the presence of drugs, the growth rates of drug-exposed WT and target mutated strains are the same in a drug efflux pump deficient background, but the mutants grow faster than WT in a drug efflux pump proficient background. Here, we explain the mechanism of target resistance masking and show that it occurs in response to drug efflux pump inhibition among pathogens with high-affinity drug binding targets, low cell-membrane drug-permeability and insignificant intracellular drug degradation. We demonstrate that target resistance masking is fundamentally linked to growth-bistability, i.e., the existence of 2 different steady state growth rates for one and the same drug concentration in the growth medium. We speculate that target resistance masking provides a hitherto unknown mechanism for slowing down the evolution of target resistance among pathogens.

Fange, David; Nilsson, Karin; Tenson, Tanel; Ehrenberg, Mans



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.

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



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

PubMed Central

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

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



Stochastic model of an influenza epidemic with drug resistance  

Microsoft Academic Search

A continuous-time Markov chain (CTMC) model is formulated for an influenza epidemic with drug resistance. This stochastic model is based on an influenza epidemic model, expressed in terms of a system of ordinary differential equations (ODE), developed by Stilianakis, N.I., Perelson, A.S., Hayden, F.G., [1998. Emergence of drug resistance during an influenza epidemic: insights from a mathematical model. J. Inf.

Yaji Xu; Linda J. S. Allen; Alan S. Perelson



Complex genetics of drug resistance in Mycobacterium tuberculosis.  


Three new studies have used whole-genome sequencing of M. tuberculosis to demonstrate unexpected complexity in the modern evolution of drug-resistant tuberculosis, and a fourth study suggests a close evolutionary relationship between the pathogen and its human host over a period of 70,000 years. Collectively, the observations in these studies suggest that future strategies to tackle drug-resistant tuberculosis must integrate host genetics with detailed strain epidemiology. PMID:24071843

Warner, Digby F; Mizrahi, Valerie



Competitive release of drug resistance following drug treatment of mixed Plasmodium chabaudi infections  

PubMed Central

Background Malaria infections are often genetically diverse, potentially leading to competition between co-infecting strains. Such competition is of key importance in the spread of drug resistance. Methods The effects of drug treatment on within-host competition were studied using the rodent malaria Plasmodium chabaudi. Mice were infected simultaneously with a drug-resistant and a drug-sensitive clone and were then either drug-treated or left untreated. Transmission was assessed by feeding mice to Anopheles stephensi mosquitoes. Results In the absence of drugs, the sensitive clone competitively suppressed the resistant clone; this resulted in lower asexual parasite densities and also reduced transmission to the mosquito vector. Drug treatment, however, allowed the resistant clone to fill the ecological space emptied by the removal of the sensitive clone, allowing it to transmit as well as it would have done in the absence of competition. Conclusion These results show that under drug pressure, resistant strains can have two advantages: (1) they survive better than sensitive strains and (2) they can exploit the opportunities presented by the removal of their competitors. When mixed infections are common, such effects could increase the spread of drug resistance.

de Roode, Jacobus C; Culleton, Richard; Bell, Andrew S; Read, Andrew F



Targeting Imperfect Vaccines against Drug-Resistance Determinants: A Strategy for Countering the Rise of Drug Resistance  

PubMed Central

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

Joice, Regina; Lipsitch, Marc



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

PubMed Central

Treatment of drug-resistant tuberculosis is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for drug-resistant tuberculosis are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving World Health 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.

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



Divergence in Fitness and Evolution of Drug Resistance in Experimental Populations of Candida albicans  

Microsoft Academic Search

The dissemination and persistence of drug-resistant organisms in nature depends on the relative fitness of sensitive and resistant genotypes. While resistant genotypes are expected to be at an advantage compared to less resistant genotypes in the presence of drug, resistance may incur a cost; resistant genotypes may be at a disadvantage in the absence of drug. We measured the fitness




Aptamers that recognize drug-resistant HIV-1 reverse transcriptase  

PubMed Central

Drug-resistant variants of HIV-1 reverse transcriptase (RT) are also known to be resistant to anti-RT RNA aptamers. In order to be able to develop diagnostics and therapies that can focus on otherwise drug-resistant viruses, we have isolated two aptamers against a well-known, drug-resistant HIV-1 RT, Mutant 3 (M3) from the multidrug-resistant HIV-1 RT panel. One aptamer, M302, bound M3 but showed no significant affinity for wild-type (WT) HIV-1 RT, while another aptamer, 12.01, bound to both M3 and WT HIV-1 RTs. In contrast to all previously selected anti-RT aptamers, neither of these aptamers showed observable inhibition of either polymerase or RNase H activities. Aptamers M302 and 12.01 competed with one another for binding to M3, but they did not compete with a pseudoknot aptamer for binding to the template/primer cleft of WT HIV-1 RT. These results represent the surprising identification of an additional RNA-binding epitope on the surface of HIV-1 RT. M3 and WT HIV-1 RTs could be distinguished using an aptamer-based microarray. By probing protein conformation as a correlate to drug resistance we introduce an additional and useful measure for determining HIV-1 drug resistance.

Li, Na; Wang, Yuxuan; Pothukuchy, Arti; Syrett, Angel; Husain, Naeem; Gopalakrisha, Siddharth; Kosaraju, Pradeepa; Ellington, Andrew D.



HIV antiviral drug resistance: patient comprehension  

Microsoft Academic Search

A patient's understanding and use of healthcare information can affect their decisions regarding treatment. Better patient understanding about HIV resistance may improve adherence to therapy, decrease population viral load and extend the use of first-line HIV therapies. We examined knowledge of developing HIV resistance and explored treatment outcomes in a cohort of HIV+ persons on highly active antiretroviral therapy (HAART).

C. Sarai Racey; Wendy Zhang; Eirikka K. Brandson; Kimberly A. Fernandes; Despina Tzemis; P. Richard Harrigan; Julio S. G. Montaner; Rolando Barrios; Junine Toy; Robert S. Hogg



World Antimalarial Resistance Network I: Clinical efficacy of antimalarial drugs  

Microsoft Academic Search

The proliferation of antimalarial drug trials in the last ten years provides the opportunity to launch a concerted global surveillance effort to monitor antimalarial drug efficacy. The diversity of clinical study designs and analytical methods undermines the current ability to achieve this. The proposed World Antimalarial Resistance Network (WARN) aims to establish a comprehensive clinical database from which standardised estimates

Ric N Price; Grant Dorsey; Elizabeth A Ashley; Karen I Barnes; J Kevin Baird; Umberto d'Alessandro; Philippe J Guerin; Miriam K Laufer; Inbarani Naidoo; François Nosten; Piero Olliaro; Christopher V Plowe; Pascal Ringwald; Carol H Sibley; Kasia Stepniewska; Nicholas J White



Glutathione-associated Enzymes in Anticancer Drug Resistance1  

Microsoft Academic Search

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

Kenneth D. Tew



Identification of Pyruvate Kinase in Methicillin-Resistant Staphylococcus aureus as a Novel Antimicrobial Drug Target?  

PubMed Central

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

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



Drug resistance, predictive markers and pharmacogenomics in colorectal cancer  

Microsoft Academic Search

Resistance to chemotherapy limits the effectiveness of current cancer therapies, including those used to treat colorectal cancer, which is the second most common cause of cancer death in Europe and the United States. 5-Fluorouracil-based chemotherapy regimens are the standard treatment for colorectal cancer in both the adjuvant and advanced disease settings. Drug resistance is thought to cause treatment failure in

Daniel B Longley; Wendy L. Allen; Patrick G. Johnston



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.


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.



The interplay between drug resistance and fitness in malaria parasites.  


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

Rosenthal, Philip J



Bacteremic Pneumonia Caused by Extensively Drug-Resistant Streptococcus pneumoniae  

PubMed Central

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

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



Drug-resistant bacteria: responding to the infectious disease crisis  

Microsoft Academic Search

The 1990s have been a period of growing anxiety about the emergence of antibiotic-resistant bacteria. Public health, society and the research community must respond quickly to safeguard existing drugs and develop new ones to prevent resistance overwhelming healthcare systems worldwide.

David B. Jack



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



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


The possible role of chemotherapy in antiangiogenic drug resistance.  


The use of antiangiogenic drugs for cancer treatment was welcomed because of the hypothesis that they would be much less likely to lose their therapeutic activity as a result of tumor-acquired resistance over time. Unfortunately, the clinical experience has shown that acquired resistance to antiangiogenic therapeutic strategies is possible since many patients whose tumors initially respond to drugs such as bevacizumab (a monoclonal antibody against VEGF), sorafenib, or sunitinib (tyrosine kinase inhibitors targeting VEGF receptors and PDGF receptors) or metronomic chemotherapy (e.g. low dose cyclophosphamide) become nonresponsive, often within months of therapy initiation. Indeed, the role of associated antineoplastic chemotherapy in antiangiogenic resistance seems to be ignored by the previous studies and the real part played by these drugs has to be written yet. The studies undertaken on antiangiogenic resistance mainly involved mechanisms directly related to the antiangiogenic drugs alone and as such lead one to ask whether the acquired resistance to angiogenesis pathway-targeting might also be mediated by the chemotherapeutic drugs usually associated (at least into the clinic) with these types of drugs. The proposed hypothesis is concerning the possibility that the acquired resistance to antiangiogenic therapy could be actively and heavily modulated by the choice of the associated chemotherapeutic drug. The chemotherapeutic compounds may delay or accelerate the process through the induction, upregulation or downregulation of pro-angiogenic or anti-angiogenic factors or their receptors in the tumor, endothelial and other type of cells of the tumor microenvironment. In conclusion, the consequences of our hypothesis could be promptly translated into the preclinical studies and verified in clinical trials, involving cancer patients resistant to chemotherapy plus antiangiogenic drug schedules. PMID:22365648

Bocci, Guido; Loupakis, Fotios



Acquisition of Drug Resistance and Dependence by Prions  

PubMed Central

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

Oelschlegel, Anja M.; Weissmann, Charles



Molecular epidemiology of drug-resistant Salmonella Typhimurium in Spain  

Microsoft Academic Search

SUMMARY One hundred and forty-seven Salmonella serotype Typhimurium strains isolated in three provinces in the midwest of Spain were studied. Of these, 93.6% were drug resistant. There were two predominant resistance phenotypes: 43 isolates (29.3%) were resistant to amoxicillin, tet- racyclines, chloramphenicol, streptomycin and sulphamethoxazole and 27 isolates (18.4%) to amoxicillin, amoxicillin\\/clavulanic acid, tetracy- clines, chloramphenicol, streptomycin and sulphamethoxazole. Randomly

N. Delgado Ronda; J. L. Muñoz Bellido; M. I. García García; R. Ibáñez Pérez; S. Muñoz Criado; R. Serrano Heranz; M. C. Sáenz González; J. A. García Rodríguez




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...


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

Microsoft Academic Search

The spread of pathogens in the environment due to human activities (pathogen pollution) may be involved in the emergence of many diseases in humans, livestock and wildlife. When manure from medicated livestock and urban effluents is spread onto agricultural land, both residues of antibiotics and bacteria carrying antibiotic resistance may be introduced into the environment. The transmission of bacterial resistance

Guillermo Blanco; Jesús A. Lemus; Javier Grande



Occurrence of bacterial resistance to arsenite, copper, and selenite in adverse habitats  

SciTech Connect

The effects of metal pollution on biotic communities has been extensively studied, particularly in the areas of ecotoxicology and species composition effects. Impact studies on bacterial communities have focused on adaptation via resistance mechanisms or biogeochemical cycling alterations. It has been shown that microbial communities in polluted environments are frequently resistant to higher levels of organics and metals than those in unimpacted areas. Increases in bacterial resistance to metals and metalloids has been attributed to selection and molecular mechanisms, such as gene transfer via plasmids. Relatively few natural environments have been surveyed for metal resistant bacterial populations, with most studies measuring mercury, lead or zinc resistance. Thus, the incidence of naturally-occurring and pollutant-related microbial resistance is poorly defined, as are the environmental factors which influence resistance. Elevated levels of arsenic, copper, and selenium have caused environmental impacts which are linked to agricultural, industrial, and municipal activities. The present study reports the incidence of aerobic heterotrophic bacterial resistance to arsenite, selenite and copper in a variety of habitats in the United States. These included soil, water, and sediments with know copper, arsenic, or selenium pollution, as well as control sites.

Burton, G.A. Jr.



Enhanced bacterial clearance and sepsis resistance in caspase-12-deficient mice  

Microsoft Academic Search

Caspases function in both apoptosis and inflammatory cytokine processing and thereby have a role in resistance to sepsis. Here we describe a novel role for a caspase in dampening responses to bacterial infection. We show that in mice, gene-targeted deletion of caspase-12 renders animals resistant to peritonitis and septic shock. The resulting survival advantage was conferred by the ability of

Maya Saleh; John C. Mathison; Melissa K. Wolinski; Steve J. Bensinger; Patrick Fitzgerald; Nathalie Droin; Richard J. Ulevitch; Douglas R. Green; Donald W. Nicholson



Bacterial resistance to disinfectants containing quaternary ammonium compounds  

Microsoft Academic Search

Quaternary ammonium compounds (QAC) are widely used as disinfectants in both medical and food environments. Microbial contaminants are, therefore, regularly exposed to their action and the isolation from clinical and food sources of resistant bacteria continues to be reported in many countries. Resistance to QAC in clinical strains of staphylococci is encoded by one of at least three resistance genes,

G. Sundheim; S. Langsrud; E. Heir; A. L. Holck



Antimicrobial Resistance & Drug Development FDA/IDSA ...  

Center for Drug Evaluation (CDER)

... Chuck Bonapace, Pharm.D. George L. Drusano, MD. Dennis M. Grasela, Pharm.D., Ph.D. Frank Pelsor, Pharm.D. Harmut Derendorf, Ph.D. ... More results from


Therapeutic Implications of Hepatitis C virus Resistance to Antiviral Drugs  

PubMed Central

Treatment of chronic hepatitis C is currently based on a combination of pegylated interferon-o! and ribavirin. Neither drug exerts direct selective pressure on viral functions, meaning that interferon-a/ribavirin treatment failure is not due to selection of interferon-a- or ribavirin-resistant viral variants. Several novel antiviral approaches are currently in preclinical or clinical development, and most target viral enzymes and functions, such as hepatitis C virus protease and polymerase. These new drugs all potentially select resistant viral variants both in vitro and in vivo, and resistance is therefore likely to become an important issue in clinical practice.



Reversal of Multidrug Resistance by Synthetic and Natural Compounds in Drug-Resistant MCF7 Cell Lines  

Microsoft Academic Search

Background: Ineffectiveness of anticancer drugs is frequently observed in cancer chemotherapy. The resistance of tumor cells to various cytotoxic drugs is defined as multidrug resistance (MDR). The purpose of this study is to investigate the potential reversal effect of some synthetic and natural chemicals on drug-resistant MCF-7 cell lines. The effects of potential MDR modulators combined with some anticancer drugs

Meltem Demirel Kars; Ufuk Gunduz; Jozsef Molnar



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


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

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



Mechanism of EGER-related cancer drug resistance.  


Drug resistance in cancer arises from a complex range of biochemical and molecular events, which ultimately result in tumor cell survival. Identifying key genes and signal pathways involved in the molecular mechanisms of drug resistance is essential for establishment of new drug targets for preventing further resistance development and spreading. Epidermal growth factor receptor (EGFR) was the first growth factor receptor proposed as a target for cancer therapy. Significant progress in studying EGFR gene expression and mutation has been made in understanding the molecular events involved in EGFR-targeted agents. Recently, some individual chromosomal features such as EGFR copy number variation were demonstrated as new aspects related to drug sensitivity. Identifying these functional regulators of drug resistance will benefit therapeutic decision-making. In this study, we describe an extensive investigation of the published literature on mutation, amplification, and expression of EGFR and its downstream signaling that directly contribute to EGFR inhibitor resistance, including the gene status of KRAS, BRAF, PIK3CA, PTEN, MEK, and AKT on response to therapy. Analysis of these gene signatures identified reveals general modes of action of multicomponent therapies and the mechanisms of specific drug combinations, highlights the potential value of molecular interaction profiles in the discovery of novel therapies, and provides more information for personalized cancer medicine. PMID:21822122

Wei, Xiaona



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.

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



Convergence and coevolution of hepatitis B virus drug resistance.  


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



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.

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



Investigational new drugs for the treatment of resistant pneumococcal infections.  


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

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



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.

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



The Reversal of Drug-Resistance in Tumors Using a Drug-Carrying Nanoparticular System  

PubMed Central

Medical applications of nanoparticular systems have attracted considerable attention because of their potential use in therapeutic targeting of disease tissues and their lower level of toxicity against healthy tissue, relative to traditional pharmaceutical drugs. The use of nanoparticular systems has been shown to overcome the limitations of most anticancer drugs in clinical applications. In particular, the improved performance of smarted nanoparticular system for solving the drug resistance problems that typically interrupt tumor treatment has provided a promising strategy for successful tumor chemotherapy. This review highlights recent studies that have examined the therapeutic effect of nanoparticular systems on drug-resistant tumors and presents insight on how they work.

Oh, Kyung Taek; Baik, Hye Jung; Lee, A Hyeong; Oh, Young Taik; Youn, Yu Seok; Lee, Eun Seong



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



Drug-resistant tuberculosis: controversies and challenges in pediatrics.  


Tuberculosis remains one of the top two causes of death caused by a single infectious disease worldwide, despite curative therapy. Children with tuberculosis are especially difficult to detect, since acid fast bacilli smears and cultures are usually negative and clinical signs are nonspecific or lacking. Multidrug-resistant tuberculosis, or tuberculosis resistant to at least isoniazid and rifampin, has emerged in most areas of the world over the past 20 years. Treatment of multidrug-resistant tuberculosis is more expensive and difficult. The second-line tuberculosis medications required for treatment are more toxic and less efficacious than standard treatment. These medications are not readily available in many areas of the world where drug resistance is most common. Fluoroquinolones are one of the most promising classes of second-line medications, but are not generally recommended for use in children. Ethambutol is recommended in the initial treatment of tuberculosis in children treated in areas where there is a risk of drug-resistant disease and the susceptibility of the source case is not known. Some experts have been hesitant to use ethambutol due to the risk of visual impairment associated with the drug and the difficulties in monitoring vision in young children. Pediatric drug formulations are not available for most antituberculosis medications, even the first-line tuberculosis drugs. Treatment of children exposed, infected or ill with multidrug-resistant tuberculosis is reviewed with special emphasis on second-line drugs, including recommended dosage, available formulations and necessary monitoring. While new cases of multidrug-resistant tuberculosis have decreased in most developed countries over the past 10 years, cases continue to increase in many developing countries and among immigrants from high-risk areas. Tuberculosis and multidrug-resistant tuberculosis are serious threats requiring worldwide strategies to control and treat. Better diagnostic tests, medications, public health strategies and vaccines will all be needed to eliminate tuberculosis. PMID:16307511

Smith, Kim Connelly; Seaworth, Barbara J



Regulatory opportunities to encourage technology solutions to antibacterial drug resistance.  


Regulatory agencies play a critical role in the licensing of new antimicrobial agents. To address the pivotal role played by regulatory agencies, particularly in the context of a paucity of new drugs active against bacteria resistant to currently available drugs, the BSAC formed the 'Urgent Need' Working Party to address the regeneration of antibacterial drug discovery and development. The Working Party identified a number of issues, including: increased application of pharmacokinetic/pharmacodynamic principles to expedite drug development; the need to prioritize licensing of drugs (including 'orphan' drugs) active in life-threatening infections; and expansion of the use of surrogate markers and rapid point of care diagnostics to facilitate drug development. PMID:21700629

Finch, Roger



Establishing drug resistance in microorganisms by mass spectrometry.  


A rapid method to determine drug resistance in bacteria based on mass spectrometry is presented. In it, a mass spectrum of an intact microorganism grown in drug-containing stable isotope-labeled media is compared with a mass spectrum of the intact microorganism grown in non-labeled media without the drug present. Drug resistance is determined by predicting characteristic mass shifts of one or more microorganism biomarkers using bioinformatics algorithms. Observing such characteristic mass shifts indicates that the microorganism is viable even in the presence of the drug, thus incorporating the isotopic label into characteristic biomarker molecules. The performance of the method is illustrated on the example of intact E. coli, grown in control (unlabeled) and (13)C-labeled media, and analyzed by MALDI TOF MS. Algorithms for data analysis are presented as well. PMID:23568030

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



New Developments in Antiepileptic Drug Resistance: An Integrative View  

PubMed Central

Current theories on drug resistance in epilepsy include the drug transporter hypothesis, the drug target hypothesis, and a novel approach called the inherent severity model of epilepsy, which posits that the severity of the disease determines its relative response to medication. Valuable as each of these hypotheses is, none is currently a stand-alone theory that is able to convincingly explain drug resistance in human epilepsy. As a consequence, it may be of interest to update and integrate the various hypotheses of drug resistance and to explore possible links to the severity of epilepsy. The observation that a high frequency of seizures prior to onset of treatment is a prognostic signal of increased severity and future drug failure suggests that common neurobiological factors may underlie both disease severity and pharmacoresistance. Such a link has been proposed for depression; however, the evidence for a direct mechanistic link, genetic or otherwise, between drug response and disease severity of human epilepsy is still elusive. Although emerging data from experimental studies suggest that alterations in GABAA receptors may present one example of a mechanistic link, clearly more work is needed to explore whether common neurobiological factors may underlie both epilepsy severity and drug failure.

Schmidt, Dieter; Loscher, Wolfgang



MDR1-Mediated Drug Resistance in Candida dubliniensis  

PubMed Central

Candida dubliniensis is a recently described opportunistic fungal pathogen that is closely related to Candida albicans. Candida dubliniensis readily develops resistance to the azole antifungal agent fluconazole, both in vitro and in infected patients, and this resistance is usually associated with upregulation of the CdMDR1 gene, encoding a multidrug efflux pump of the major facilitator superfamily. To determine the role of CdMDR1 in drug resistance in C. dubliniensis, we constructed an mdr1 null mutant from the fluconazole-resistant clinical isolate CM2, which overexpressed the CdMDR1 gene. Sequential deletion of both CdMDR1 alleles was performed by the MPAR-flipping method, which is based on the repeated use of a dominant mycophenolic acid resistance marker for selection of integrative transformants and its subsequent deletion from the genome by FLP-mediated, site-specific recombination. In comparison with its parental strain, the mdr1 mutant showed decreased resistance to fluconazole but not to the related drug ketoconazole. In addition, we found that CdMDR1 confers resistance to the structurally unrelated drugs 4-nitroquinoline-N-oxide, cerulenin, and brefeldin A, since the enhanced resistance to these compounds of the parent strain CM2 compared with the matched susceptible isolate CM1 was abolished in the mdr1 mutant. In contrast, CdMDR1 inactivation did not cause increased susceptibility to amorolfine, terbinafine, fluphenazine, and benomyl, although overexpression of CdMDR1 in a hypersusceptible Saccharomyces cerevisiae strain had previously been shown to confer resistance to these compounds. The effect of CdMDR1 inactivation was identical to that seen in two similarly constructed C. albicans mdr1 mutants. Therefore, despite species-specific differences in the amino acid sequences of the Mdr1 proteins, overexpression of CaMDR1 and CdMDR1 in clinical C. albicans and C. dubliniensis strains seems to confer the same drug resistance profile in both species.

Wirsching, Stephanie; Moran, Gary P.; Sullivan, Derek J.; Coleman, David C.; Morschhauser, Joachim



Research Highlights: Helping Adolescents Resist Drugs.  

National Technical Information Service (NTIS)

Project ALERT departs boldly from prevention models of the 196Os and 197Os, which emphasized informing adolescents about the long-term consequences of drug use or building their decisionmaking skills. Instead, Project ALERT is based on the theory that ado...



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


... Enterococci (VRE) Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) Gram-negative Bacteria Research Skip Website Tools Website Tools Print this page Get email updates Order publications Skip Stay Connected Stay Connected Social media privacy policy and disclaimers. Research Feature Read about ...


Antimicrobial (Drug) Resistance: Vancomycin-Resistant Enterococci (VRE)  


... Asked Questions Multidrug-Resistant Neisseria gonorrhoeae (Gonorrhea) Gram-negative Bacteria Research Skip Website Tools Website Tools Print this page Get email updates Order publications Skip Stay Connected Stay Connected Social media privacy policy and disclaimers. Volunteer for NIAID-funded ...


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

PubMed Central

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

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



Evaluating Antibiograms To Monitor Drug Resistance  

Microsoft Academic Search

We used hospital antibiograms to assess predominant pathogens and their patterns of in vitro antimicrobial resist- ance in central Illinois, USA. We found a lack of information about national guidelines for in vitro antimicrobial suscepti- bility testing and differences in interpretation among labora- tories in the region. A number of databases are available in the United States to monitor antimicrobial

Mohamed El-Azizi; Adnan Mushtaq; Cheryl Drake; Jerry Lawhorn; Joan Barenfanger; Steven Verhulst; Nancy Khardori


Bacterial disinfectant resistance—a challenge for the food industry  

Microsoft Academic Search

The focus on hygiene in the food industry has resulted in an increasing use of chemical disinfection and it has been speculated that this will impose a selective pressure and contribute to the emergence of disinfectant-resistant microorganisms. The frequency of strains with a low-level resistance to quaternary ammonium compounds (QAC) is relatively high for Listeria monocytogenes (10%), Staphylococcus spp. (13%)

Solveig Langsrud; Maan Singh Sidhu; Even Heir; Askild L. Holck



Bacterial gene amplification: implications for the evolution of antibiotic resistance  

Microsoft Academic Search

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

Linus Sandegren; Dan I. Andersson



Management of Multi-Drug Resistant Enterococcal Infections.  


Abstract Enterococci are organisms with a remarkable ability to adapt to the environment and acquire antibiotic resistance determinants. The evolution of antimicrobial resistance in these organisms poses enormous challenges for clinicians when faced with patients affected with severe infections. The increased prevalence and dissemination of multi-drug resistant Enterococcus faecium worldwide has resulted in a major decrease in therapeutic options, since the majority of E. faecium isolates are now resistant to ampicillin, vancomycin and exhibit high-level resistance to aminoglycosides, three of the traditionally most useful anti-enterococcal antibiotics. Newer antibiotics such as linezolid, daptomycin and tigecycline have good in vitro activity against enterococcal isolates but their clinical use may be limited in certain clinical scenarios due to reduced rates of success, possible underdosing for enterococci and low serum levels, respectively, and also by the emergence of resistance. The experimental agent oritavancin may offer some hope for the treatment of vancomycin-resistant enterococci but clinical data are still lacking. Thus, optimal therapies for the treatment of multi-drug resistant enterococcal infections continue to be based on empirical observations and extrapolations from in vitro and animal data. Clinical studies evaluating new strategies, including combination therapies to treat severe vancomycin-resistant E. faecium infections are urgently needed. PMID:20345469

Arias, Cesar A; Contreras, German A; Murray, Barbara E



Development of bacterial resistance to several biocides and effects on antibiotic susceptibility  

Microsoft Academic Search

The aims of this study were to investigate the development of bacterial resistance to eugenol, thymol, trichlorocarbanalide (TCC), didecyldimethylammonium chloride (DDDMAC) and C10-16-alkyldimethyl, N-oxides (ADMAO) and subsequent effects on antibiotic susceptibility. An agar minimum inhibitory concentration (MIC) method was used to assess the activity of the biocides against standard bacterial strains and laboratory mutants. A range of techniques including disk

S. E Walsh; J.-Y Maillard; A. D Russell; C. E Catrenich; D. L Charbonneau; R. G Bartolo



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

Microsoft Academic Search

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

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



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

PubMed Central

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

Pepper, John W



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

PubMed Central

The evolution of drug resistant Plasmodium parasites is a major challenge to effective malaria control. In theory, competitive interactions between sensitive parasites and resistant parasites within infections are a major determinant of the rate at which parasite evolution undermines drug efficacy. Competitive suppression of resistant parasites in untreated hosts slows the spread of resistance; competitive release following treatment enhances it. Here we report that for the murine model Plasmodium chabaudi, co-infection with drug-sensitive parasites can prevent the transmission of initially rare resistant parasites to mosquitoes. Removal of drug-sensitive parasites following chemotherapy enabled resistant parasites to transmit to mosquitoes as successfully as sensitive parasites in the absence of treatment. We also show that the genetic composition of gametocyte populations in host venous blood accurately reflects the genetic composition of gametocytes taken up by mosquitoes. Our data demonstrate that, at least for this mouse model, aggressive chemotherapy leads to very effective transmission of highly resistant parasites that are present in an infection, the very parasites which undermine the long term efficacy of front-line drugs.

Bell, Andrew S.; Huijben, Silvie; Paaijmans, Krijn P.; Sim, Derek G.; Chan, Brian H. K.; Nelson, William A.; Read, Andrew F.



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



Efficacy of OH-CATH30 and Its Analogs against Drug-Resistant Bacteria In Vitro and in Mouse Models  

PubMed Central

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 (LD50) 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.

Li, Sheng-An



New drugs for methicillin-resistant Staphylococcus aureus: an update.  


Methicillin-resistant Staphylococcus aureus (MRSA) remains a leading cause of bacterial infections worldwide, with a dwindling repertoire of effective antimicrobials active against it. This review aims to provide an update on novel anti-MRSA molecules currently under pre-clinical and clinical development, with emphasis on their mechanism of action. This review is limited to molecules that target the pathogen directly and does not detail immunomodulatory anti-infectives. PMID:23429643

Kumar, Krishan; Chopra, Sidharth



Bacterial panicle blight resistance QTL in rice (Oryza sativa L.) and their association with resistance to other diseases  

Technology Transfer Automated Retrieval System (TEKTRAN)

Bacterial panicle blight (BPB) of rice (Oryza sativa L.) occurs when the bacterium Burkholderia glumae infects and colonizes emerging and flowering panicles, causing kernels to abort. To identify quantitative trait loci (QTL) for BPB resistance, a population of 300 recombinant inbred lines (RILs) d...


Drug Resistance Caused by Reversion Mutation  

Microsoft Academic Search

Cells carrying mutated BRCA1 or BRCA2 genes are defective in DNA repair by homologous recombination and, as a consequence, are highly sensitive to inhibitors of poly (ADP-ribose) polymerase (PARP).This provides the basis for a novel ''synthetic lethal'' approach to cancer therapy.We have recently shown that this sensitivity can be reversed, and resistance to PARP inhibition can be acquired by deletion

Alan Ashworth



Bacterial resistance and antibiotic use in the emergency department.  


Antibiotic resistance among bacteria that are commonly encountered in the pediatric emergency department is a fact of nature. New antibiotics will provide some help, but probably only temporarily. Vaccine strategies seem to provide the best answer to resistance, and many physicians eagerly await the conjugated pneumococcal vaccines, which we can only hope to be as successful as the H. influenzae type b vaccines. Vaccines against other resistant organisms are likely further off. At this point, a major goal must be to limit the prevalence of antibiotic resistance. In considering this goal, two complementary strategies are key. The first is to avoid antibiotics in situations in which they are unlikely to provide benefit, such as for colds, URIs, and bronchitis. The second is to use narrow-spectrum antibiotics as much as possible to minimize selective pressure. Emerging evidence shows that these strategies can be effective. In a day-care center in Omaha, Nebraska, Boken et al showed that nasopharyngeal carriage of highly resistant S. pneumoniae decreased dramatically among attendees when antibiotic use decreased. In Iceland, a nationwide campaign that resulted in decreased antibiotic use was followed by a decrease in the incidence of penicillin-resistant pneumococcal infections from 20.0% to 16.9% and a decrease in the rate of carriage of resistant pneumococci among day-care-center attendees from 49% to 15%. In Finland, erythromycin resistance in Group A streptococci recovered from pharyngeal and pus samples had reached 13% in 1990. National guidelines that recommended a reduction in the use of erythromycin and other macrolide antibiotics in the treatment of outpatients with respiratory and skin infections were instituted, and by 1996, macrolide antibiotic consumption had decreased by 50%, with a similar 50% decrease in frequency of erythromycin-resistant isolates. In the absence of such national strategies, it is incumbent on physicians treating infections on a daily basis in the emergency department to consider carefully the judicious use of antibiotics. PMID:10629677

Bennett, J; St Geme, J W



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

PubMed Central

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

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



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

PubMed Central

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

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



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

PubMed Central

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

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



Antifungal Drug Resistance: Clinical Relevance and Impact of Antifungal Drug Use  

Microsoft Academic Search

Antifungal drug resistance significantly impacts treatment outcomes in patients with invasive fungal infections (IFIs). Although\\u000a primary (intrinsic) resistance may occur independent of previous therapy, prior concomitant antifungal exposure increases\\u000a the risk for secondary (acquired) resistance and subsequent colonization or infection with less-susceptible pathogens. Among\\u000a various pathogen-antifungal combinations, this effect has been best studied clinically with azole exposure and the risk

Richard H. Drew; Mary L. Townsend



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.

Corpet, D E



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.

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; Hue, Stephane; 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



Persistence of HIV-1 Transmitted Drug Resistance Mutations.  


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



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


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

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



Clinical status and implications of antimalarial drug resistance  

Microsoft Academic Search

Africa carries the greatest burden of disease caused by Plasmodium falciparum, and we can expect this burden to rise in the near future, mainly because of drug resistance. Although effective drugs are available (such as artemether–lumefantrine, mefloquine, atovaquone–proguanil and halofantrine) they are uniformly too expensive for routine use. Affordable options include chloroquine plus sulfadoxine–pyrimethamine (SP), amodiaquine (alone or in combination

Peter A. Winstanley; Steven A. Ward; Robert W. Snow



Multi-drug resistant non-typhi salmonellae in Kenya  

Microsoft Academic Search

Two methods of plasmid characterization, restriction digest patterns and incompatibility grouping, were used to study self-transmissible multi-drug resistance among non-typhi salmonellae (NTS). Resistance to ampicillin and other commonly applied \\/Mactams was evaluated by iso-electric focusing and disc inactivation. Of the NTS isolated from blood, 75% were Salmonella typhimurium but those included several different phage types. Over 47% of isolates were

S. Kariaki; C. Gilks; J. Corkill; J. Kimari; A. Benea; P. Waiyaki; C. A. Hart



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


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

Zuniga, Ramiro; Nguyen, Tam



Bacterial hypermutation: clinical implications.  


Heritable hypermutation in bacteria is mainly due to alterations in the methyl-directed mismatch repair (MMR) system. MMR-deficient strains have been described from several bacterial species, and all of the strains exhibit increased mutation frequency and recombination, which are important mechanisms for acquired drug resistance in bacteria. Antibiotics select for drug-resistant strains and refine resistance determinants on plasmids, thus stimulating DNA recombination via the MMR system. Antibiotics can also act as indirect promoters of antibiotic resistance by inducing the SOS system and certain error-prone DNA polymerases. These alterations have clinical consequences in that efficacious treatment of bacterial infections requires high doses of antibiotics and/or a combination of different classes of antimicrobial agents. There are currently few new drugs with low endogenous resistance potential, and the development of such drugs merits further research. PMID:21349992

Jolivet-Gougeon, Anne; Kovacs, Bela; Le Gall-David, Sandrine; Le Bars, Hervé; Bousarghin, Latifa; Bonnaure-Mallet, Martine; Lobel, Bernard; Guillé, François; Soussy, Claude-James; Tenke, Peter



Rational drug redesign to overcome drug resistance in cancer therapy: imatinib moving target.  


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

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



World Antimalarial Resistance Network (WARN) III: Molecular markers for drug resistant malaria  

Microsoft Academic Search

Molecular markers for drug resistant malaria represent public health tools of great but mostly unrealized potential value. A key reason for the failure of molecular resistance markers to live up to their potential is that data on the their prevalence is scattered in disparate databases with no linkage to the clinical, in vitro and pharmacokinetic data that are needed to

Christopher V Plowe; Cally Roper; John W Barnwell; Christian T Happi; Hema H Joshi; Wilfred Mbacham; Steven R Meshnick; Kefas Mugittu; Inbarani Naidoo; Ric N Price; Robert W Shafer; Carol H Sibley; Colin J Sutherland; Peter A Zimmerman; Philip J Rosenthal



Drug resistant Shigella flexneri in & around Dibrugarh, north-east India  

PubMed Central

Background & objectives: Shigella flexneri is the most common species of Shigella causing diarrhoea and dysentery in Asia including India. Multidrug resistance in Shigella species has been reported worldwide and there is rising concern regarding development of fluoroquinolone resistance. This study was undertaken to find out the resistance pattern of Sh. flexneri, the commonest shigella isolated in Dibrugarh, north east India, including detection of fluoroquinolone resistance and extended spectrum beta lactamases. Methods: Stool samples collected from patients of diarrhoea and dysentery were tested for bacterial enteropathogens. Strains of Shigella species were confirmed by biochemical tests. Speciation was done using commercially available polyvalent antiserum. Antimicrobial susceptibility test was performed by Kirby Bauer disc diffusion method against 18 different antibiotics. Extended spectrum beta lactamase (ESBL) detection was done by disc approximation test as well as combination disc method and minimum inhibitory concentrations (MIC) of different antibiotics were also measured. Results: Multidrug resistance in Sh. flexneri was found to be common (90.2%) and the commonest phenotypic multi-drug resistance profile was ampicillin-tetracycline-co-trimoxazole-nalidixic acid. High resistance to nalidixic acid was detected in 90.3 per cent isolates (MIC >240 ?g/ml) and ciprofloxacin resistance was seen emerging in this region (11.2%, MIC >4 ?g/ml). Present of ESBL was phenotypically confirmed in two cases. Besides the fluoroquinolones, chloramphenicol, piperacillin-tazobactum and the third generation cephalosporins were effective in 87-100 per cent of the isolates. Interpretation & conclusions: Our study showed high resistance (MIC >240 ?g/ml) against nalidixic acid in Sh. flexneri isolates. Ciprofloxacin resistance is also emerging in this region. Shigellosis due to ESBL carrying Shigella can become a serious threat to public health. Guidelines for therapy should be monitored and modified based on regional reports of resistance to antimicrobial agents.

Nath, Reema; Saikia, Lahari; Choudhury, Gargi; Sharma, Daisy



Examination of Bacterial Resistance to Exogenous Nitric Oxide  

PubMed Central

While much research has been directed to harnessing the antimicrobial properties of exogenous NO, the possibility of bacteria developing resistance to such therapy has not been thoroughly studied. Herein, we evaluate potential NO resistance using spontaneous and serial passage mutagenesis assays. Specifically, Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Staphylococcus epidermidis, Escherichia coli, and Pseudomonas aeruginosa were systematically exposed to NO-releasing 75mol% MPTMS-TEOS nitrosothiol particles at or below minimum inhibitory concentration (MIC) levels. In the spontaneous mutagenesis assay, bacteria that survived exposure to lethal concentrations of NO showed no increase in MIC. Similarly, no increase in MIC was observed in the serial passage mutagenesis assay after exposure of these species to sub-inhibitory concentrations of NO through 20 d.

Privett, Benjamin J.; Broadnax, Angela D.; Bauman, Susanne J.; Riccio, Daniel A.; Schoenfisch, Mark H.



Overexpression of Multidrug Resistance-associated Protein (MRP) Increases Resistance to Natural Product Drugs I  

Microsoft Academic Search

Amplification of the gene encoding multidrug resistance-associated pro- tein (MRP) and overexpression of its cognate mRNA have been detected in multidrug-resistant cell lines derived from several different tumor types. To establish whether or not the increase in MRP is responsible for drug resistance in these cell lines, we have transfected HeLa cells with MRP expression vectors. The transfectants display an

Caroline E. Grant; Gunnar Valdimarsson; David R. Hipfner; Kurt C. AImquist; Susan P. C. Cole; Roger G. Deeley



Predictive value of multidrug resistance proteins and cellular drug resistance in childhood relapsed acute lymphoblastic leukemia  

Microsoft Academic Search

Purpose  Cellular resistance in childhood acute leukemias might be related to profile and function of multidrug resistance proteins\\u000a and apoptosis regulating proteins. The aims of the study were: (1) analysis of expression of MRP1, PGP1, LRP, BCL-2 and p53\\u000a proteins; (2) correlation with ex vivo drug resistance, and (3) analysis of their prognostic impact on clinical outcome in childhood acute lymphoblastic

Jan Styczynski; Mariusz Wysocki; Robert Debski; Krzysztof Czyzewski; Beata Kolodziej; Beata Rafinska; Malgorzata Kubicka; Sylwia Koltan; Andrzej Koltan; Monika Pogorzala; Andrzej Kurylak; Dorota Olszewska-Slonina; Walentyna Balwierz; Edyta Juraszewska; Maria Wieczorek; Igor Olejnik; Maryna Krawczuk-Rybak; Marta Kuzmicz; Jerzy Kowalczyk; Jolanta Stefaniak; Wanda Badowska; Danuta Sonta-Jakimczyk; Tomasz Szczepanski; Michal Matysiak; Iwona Malinowska; Elzbieta Stanczak



Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa  

PubMed Central

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

Upcroft, Peter; Upcroft, Jacqueline A.



Bacterial sensitivity to UV light as a model for ionizing radiation resistance  

Microsoft Academic Search

Summary Six bacterial isolates from the U.S. DOE Subsurface Science Program and three reference bacteria were tested for resistance to UV light and gamma radiation. The subsurface isolates included three aerobic, pigmented, Gram positive bacteria and three microaerophilic, non-pigmented, Gram negative bacteria. Deinococcus radiodurans was the most resistant bacterium to both types of radiation, with a D37 value of 4.0

A ARRANGE; Tommy J. Phelps; R EBENOIT; Anthony V. Palumbo; David C. White



The "multi" of drug resistance explained by oscillating drug transporters, drug-membrane physical interactions and spatial dimensionality.  


Multi-drug resistance (MDR) can be explained by a drug handling-type activity. In this context it is also necessary to consider the multi-specificity between drugs and drug transporters in order to explain MDR. Accordingly, the efficiency of drug efflux in MDR has always been a conceptual problem in biochemistry. Indeed, how one protein can expel, from cells, hundreds of compounds with high specificity is still controversial today. To safeguard the notion of biochemical specificity, many studies have suggested alternative mechanisms to Pgp-mediated drug resistance, which do not involve the handling of drugs. However, none of these studies have definitively ruled out the possibility concept of drug handling. Thus, until now it was not possible to imagine MDR without drug-transporter affinity or specificity. However, drug-transporter affinity is not always needed to generate what appears to be a very efficient chemical reaction. Indeed, based on the fact that bi-dimensional diffusion properties (i.e. diffusion in the membrane) are paramount to explain drug pumping-mediated MDR, it is possible to suggest how specific mathematical properties of random motions can be used to construct a model of Pgp-MDR, providing that Pgp oscillates between open/drug-accepting and closed/drug-expelling conformations. This different viewpoint highlights the fact that the multi-specificity of drug transporters and the "vacuum cleaner" hypothesis may actually be two sides of the same coin, both explained by the diffusion properties of drugs in the membrane. After retrieving basic results, predictions will be highlighted. Finally, the coherence of this model in the context of cancer biology will be discussed further. PMID:21336588

Rauch, Cyril



Mechanisms by which mammalian cells acquire resistance to drugs that affect microtubule  

Microsoft Academic Search

The development of resistance in mammalian cells to toxic drugs is a significant clinical problem, especially in cancer chemotherapy where drug-resistant tumor cells often prove to be refractory to treatment. In this article, we review some of the basic mechanisms of drug resistance from the perspective of a single cell bathed in medium Containing the drug. These mecha- nisms may




5-Nitroimidazole Drugs Effective against Metronidazole-Resistant Trichomonas vaginalis and Giardia duodenalis  

PubMed Central

Metronidazole (Mz)-resistant Giardia and Trichomonas were inhibited by 1 of 30 new 5-nitroimidazole drugs. Another five drugs were effective against some but not all of the Mz-resistant parasites. This study provides the incentive for the continued design of 5-nitroimidazole drugs to bypass cross-resistance among established 5-nitromidazole antiparasitic drugs.

Upcroft, Jacqueline A.; Dunn, Linda A.; Wright, Janelle M.; Benakli, Kamel; Upcroft, Peter; Vanelle, Patrice



Antiretroviral Drug Resistance Mutations Sustain or Enhance CTL Recognition of Common HIV1 Pol Epitopes  

Microsoft Academic Search

Antiretroviral drug resistance and escape from CTL are major obstacles to effective control of HIV replication. To investigate the possibility of combining drug and immune-based selective pressures against HIV, we studied the effects of antiretroviral drug resistance mutations on CTL recognition of five HIV-1 Pol epitopes presented by common HLA molecules. We found that these common drug resistance mutations sustain

Rosemarie D. Mason; M. Ian Bowmer; Constance M. Howley; Maureen Gallant; Jennifer C. E. Myers; Michael D. Grant


"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.



Treatment of antiretroviral-drug-resistant HIV-1 infection.  


Drug-resistant HIV-1 is a cause of growing clinical and public-health concern. In many patients, combination antiretroviral therapy fails to achieve complete viral suppression (virological failure). Continuing viral replication during therapy leads to the accumulation of drug-resistance mutations, resulting in increased viral load and a greater risk of disease progression. Patients with drug-resistant HIV-1 infection have three therapeutic options: a change to a salvage regimen with the aim of fully suppressing viral replication; interruption of therapy; or continuation of a partially effective regimen. The first strategy is preferred for most patients failing their first or perhaps their second regimen. However, the best approach remains unclear for patients who have failed multiple treatment regimens and who have limited options for complete viral suppression. The management of such patients requires a careful understanding of the pathogenesis of drug-resistant HIV-1, the clinical consequences of virological failure, the potential benefits and limitations of diagnostic assays, and the likelihood that agents in development will be effective. PMID:14683662

Deeks, Steven G



Drug Abuse Resistance Education Program (DARE). Evaluation Report.  

ERIC Educational Resources Information Center

|This paper presents an evaluation of the Drug Abuse Resistance Education (DARE) Program, an integral part of the fifth grade curriculum in 84 elementary schools in the Broward County (Florida) Public Schools. During the 1992-93 school year, nearly 12,000 fifth grade students attended DARE classes taught by 43 trained law enforcement officers.…

Blasik, Katherine A.; Belsito, Roseanne


"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.



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



Drug-resistant tuberculosis: time for visionary political leadership.  


Two decades ago, WHO declared tuberculosis a global emergency, and invested in the highly cost-effective directly observed treatment short-course programme to control the epidemic. At that time, most strains of Mycobacterium tuberculosis were susceptible to first-line tuberculosis drugs, and drug resistance was not a major issue. However, in 2013, tuberculosis remains a major public health concern worldwide, with prevalence of multidrug-resistant (MDR) tuberculosis rising. WHO estimates roughly 630?000 cases of MDR tuberculosis worldwide, with great variation in the frequency of MDR tuberculosis between countries. In the past 8 years, extensively drug-resistant (XDR) tuberculosis has emerged, and has been reported in 84 countries, heralding the possibility of virtually untreatable tuberculosis. Increased population movement, the continuing HIV pandemic, and the rise in MDR tuberculosis pose formidable challenges to the global control of tuberculosis. We provide an overview of the global burden of drug-resistant disease; discuss the social, health service, management, and control issues that fuel and sustain the epidemic; and suggest specific recommendations for important next steps. Visionary political leadership is needed to curb the rise of MDR and XDR tuberculosis worldwide, through sustained funding and the implementation of global and regional action plans. PMID:23531391

Abubakar, Ibrahim; Zignol, Matteo; Falzon, Dennis; Raviglione, Mario; Ditiu, Lucica; Masham, Susan; Adetifa, Ifedayo; Ford, Nathan; Cox, Helen; Lawn, Stephen D; Marais, Ben J; McHugh, Timothy D; Mwaba, Peter; Bates, Matthew; Lipman, Marc; Zijenah, Lynn; Logan, Simon; McNerney, Ruth; Zumla, Adam; Sarda, Krishna; Nahid, Payam; Hoelscher, Michael; Pletschette, Michel; Memish, Ziad A; Kim, Peter; Hafner, Richard; Cole, Stewart; Migliori, Giovanni Battista; Maeurer, Markus; Schito, Marco; Zumla, Alimuddin



Alcohol and Other Drug Resistance Strategies Employed by Rural Adolescents  

ERIC Educational Resources Information Center

|This study seeks to identify how rural adolescents make health decisions and utilize communication strategies to resist influence attempts in offers of alcohol, tobacco, and other drugs (ATOD). Semi-structured interviews were conducted with 113 adolescents from rural school districts to solicit information on ATOD norms, past ATOD experiences,…

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



Excess Mortality Associated with Antimicrobial Drug-Resistant Salmonella Typhimurium  

Microsoft Academic Search

In a matched cohort study, we determined the death rates associated with drug resistance in Salmonella Typhimurium. We linked data from the Danish Surveillance Registry for Enteric Pathogens with the Civil Registration System and the Danish National Discharge Registry. By survival analysis, the 2-year death rates were compared with a matched sample of the general Danish population, after the data

Morten Helms; Pernille Vastrup; Peter Gerner-Smidt; Kåre Mølbak


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

Microsoft Academic Search

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

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



Antiplatelet drug 'resistance'. Part 2: laboratory resistance to antiplatelet drugs—fact or artifact?  

Microsoft Academic Search

Many patients experience recurrent ischemic events despite optimal antiplatelet therapy. This has generated much interest in finding a laboratory test of platelet function to identify such patients, who have been termed 'nonresponders' or antiplatelet 'resistant'. Laboratory tests of platelet function have identified 'resistance' in 5–60% of patients taking aspirin and 4–30% of those taking clopidogrel. However, these tests of 'resistance'

Joseph M. Sweeny; Valentin Fuster; Diana A. Gorog



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

PubMed Central

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

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



Antibiotic resistance, antimicrobial residues and bacterial community composition in urban wastewater.  


This study was based on the hypothesis that the occurrence of antimicrobial residues and antibiotic resistant bacteria in the sewage could be correlated with the structure and composition of the bacterial community and the antibiotic resistance loads of the final effluent. Raw and treated wastewater composite samples were collected from an urban treatment plant over 14 sampling dates. Samples were characterized for the i) occurrence of tetracyclines, penicillins, sulfonamides, quinolones, triclosan, arsenic, cadmium, lead, chromium and mercury; ii) antibiotic resistance percentages for tetracycline, sulfamethoxazole, ciprofloxacin and amoxicillin and iii) 16S rRNA gene-DGGE patterns. The data of corresponding samples, taking into account the hydraulic residence time, was analyzed using multivariate analysis. Variations on the bacterial community structure of the final effluent were significantly correlated with the occurrence of tetracyclines, penicillins, sulfonamides, quinolones and triclosan in the raw inflow. Members of the class Epsilonproteobacteria presented positive correlations with those antimicrobials, whereas negative correlations were observed with Beta and Gammaproteobacteria and Firmicutes. Antibiotic resistance percentages presented different trends of variation in heterotrophs/enterobacteria and in enterococci, varied over time and after wastewater treatment. Antibiotic resistance was positively correlated with the occurrence of tetracyclines residues and high temperature. A relationship between antibiotic residues, bacterial community structure and composition and antibiotic resistance is demonstrated. Further studies, involving more wastewater treatment plants may help to elucidate this complex relationship. PMID:23375783

Novo, Ana; André, Sandra; Viana, Paula; Nunes, Olga C; Manaia, Célia M



[Bacterial resistance to antibiotics in the Czech Republic. The Working Group for Monitoring Resistance in the Czech Republic].  


In 1991 the authors made an investigation on the resistance of clinically important bacteria. Seventeen antibiotic centres in the Czech Republic participated in the investigation. The resistance to antibiotics of 32,567 strains of twelve bacterial species isolated from hospitalized patients depends on 1. the type of bacteria and antibiotics, 2. the source (specimen of pathological material) and 3. the locality (hospital). The resistance of Staphylococcus aureus to oxacillin with the exception of one hospital is not more than 6%, in rare instances also resistance to vancomycin was encountered. The frequency of resistance of gram-negative rods to so-called reserve antibiotics (cephalosporins of the third generation, quinolones and amikacin) depends markedly on the type of bacteria, being highest in typical causal agents of hospital infections--Enterobacter cloacae, Serratia marcescens, Providencia rettgeri and Pseudomonas aeruginosa. With the exception of cephalosporins the resistance of gram-negative rods and Pseudomonas aeruginosa isolated from urine is much greater than in strains from other clinical materials. The frequency of resistance in faculty hospitals which concentrate patients with more serious diseases is high, the highest resistance was, however, recorded in the North Bohemian area--in pneumococci against penicillin (13%) and in haemophili against ampicillin (17%). Every hospital is a closed ecological niche with a typical bacterial population and resistance rate. A competent estimate of an adequate and probably effective antibiotic for immediate initiation of treatment of an urgent infection can thus be made only by somebody with close and steady knowledge of the state of resistance in a given hospital. PMID:8111828

Urbásková, P; Schindler, J



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

PubMed Central

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

Shenoi, Sheela; Friedland, Gerald



Antibiotic Resistant Bacteria in Mud of Shrimp Farming Ponds and Bacterial Degradation of Antibiotic  

Microsoft Academic Search

An investigation was conducted to determine the occurrence, resistant efficiency of bacteria collected from four shrimp farming zones, Vunh Tau (VT), Nha Trang (NT), Da Nang (DN) and Hue (HU) of Viet Nam against five commonly applied antibiotics (sulphamethoxazole (SMX), trimethoprim (TMP), norfloxacin (NFC), amoxillin (AXC) and streptomycin (SMC)) and bacterial degradation of antibiotic. Mud samples were employed to examine

Jatindra Nath Bhakta; Yukihiro Munekage


Gamete Selection for Resistance to Common and Halo Bacterial Blights in Dry Bean Intergene Pool Populations  

Microsoft Academic Search

The common (caused by Xanthomonas campestris pv. phaseoli (Smith) Dye (Xcp) and X. campestris pv. phaseoli var. fuscans (Xcpf)) and halo bacterial blights (caused by Pseudomonas syringae pv. phase- olicola (Burkh.) Young et al. (Psp)) are seed-borne diseases that cause severe yield losses in dry and snap bean (Phaseolus vulgaris L.) worldwide. Use of cultivars resistant to these diseases is

M. Carmen Asensio-S.-Manzanera; Carmen Asensio; Shree P. Singh




Technology Transfer Automated Retrieval System (TEKTRAN)

The Agricultural Research Service, U.S. Department of Agriculture, and the Idaho Agricultural Experiment Station announce the release of USDK-CBB-15 dark red kidney (Phaseolus vulgaris L.) germplasm line with a high level of resistance to common bacterial blight caused by Xanthomonas axonopodis pv. ...


Drug Resistance Towards Etoposide and Cisplatin in Human Melanoma Cells is Associated with Drug-Dependent Apoptosis Deficiency  

Microsoft Academic Search

Anticancer drugs kill susceptible cells through induction of apoptosis. Alterations of apoptotic pathways in drug-resistant tumor cells leading to apoptosis deficiency might represent a potent mechanism conferring drug resistance. We have assessed the effect of etoposide and cisplatin on the apoptotic pathways of the drug-sensitive human melanoma cell line MeWo as well as its etoposide- and cisplatin-resistant sublines (MeWoEto01, MeWoEto1,

Heike Helmbach; Monika A. Kern; Evelyn Rossmann; Kristina Renz; Christine Kissel; Brigitte Gschwendt; Dirk Schadendorf



Epigenetic modulation of the biophysical properties of drug-resistant cell lipids to restore drug transport and endocytic functions.  


In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane's biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug 5-aza-2'-deoxycytidine (decitabine) significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance. PMID:22817326

Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod



Epigenetic Modulation of the Biophysical Properties of Drug-Resistant Cell Lipids to Restore Drug Transport and Endocytic Functions  

PubMed Central

In our recent studies exploring the biophysical characteristics of resistant cell lipids, and the role they play in drug transport, we demonstrated the difference of drug-resistant breast cancer cells from drug-sensitive cells in lipid composition and biophysical properties, suggesting that cancer cells acquire a drug-resistant phenotype through the alteration of lipid synthesis to inhibit intracellular drug transport to protect from cytotoxic effect. In cancer cells, epigenetic changes (e.g., DNA hypermethylation) are essential to maintain this drug-resistant phenotype. Thus, altered lipid synthesis may be linked to epigenetic mechanisms of drug resistance. We hypothesize that reversing DNA hypermethylation in resistant cells with an epigenetic drug could alter lipid synthesis, changing the cell membrane’s biophysical properties to facilitate drug delivery to overcome drug resistance. Herein we show that treating drug-resistant breast cancer cells (MCF-7/ADR) with the epigenetic drug, 5-aza-2?-deoxycytidine (decitabine), significantly alters cell lipid composition and biophysical properties, causing the resistant cells to acquire biophysical characteristics similar to those of sensitive cell (MCF-7) lipids. Following decitabine treatment, resistant cells demonstrated increased sphingomyelinase activity, resulting in a decreased sphingomyelin level that influenced lipid domain structures, increased membrane fluidity, and reduced P-glycoprotein expression. Changes in the biophysical characteristics of resistant cell lipids facilitated doxorubicin transport and restored endocytic function for drug delivery with a lipid-encapsulated form of doxorubicin, enhancing the drug efficacy. In conclusion, we have established a new mechanism for efficacy of an epigenetic drug, mediated through changes in lipid composition and biophysical properties, in reversing cancer drug resistance.

Vijayaraghavalu, Sivakumar; Peetla, Chiranjeevi; Lu, Shan; Labhasetwar, Vinod



Validating the Vitality Strategy for Fighting Drug Resistance  

PubMed Central

The current challenge in designing effective drugs against HIV-1 is to find novel candidates with high potency, but with a lower susceptibility to mutations associated with drug resistance. Trying to address this challenge we developed in our previous study1 a novel computational strategy for fighting drug resistance by predicting the likely moves of the virus through constraints on binding and catalysis. This has been based on calculating the vitality values (defined as the ratio ((Kikcat/KM)mutant/ (Kikcat/KM)wild-type) and using it as guide for the moves of the virus. The corresponding calculations of the binding affinity, Ki, were based on using the semi-macroscopic version of the protein dipole Langevin dipole (PDLD/S) in its linear response approximation (LRA) in its ? version (PDLD/S-LRA/?). We, also, calculate the proteolytic efficiency, kcat/KM, by evaluating the transition state (TS) binding free energies using the PDLD/S-LRA/? method. Here we provide an extensive validation of our strategy by calculating the vitality of six existing clinical and experimental drug candidates. It is found that the computationally determined vitalities correlate reasonably well with those derived from the corresponding experimental data. This indicates that the calculated vitality may be used to identify mutations that would be most effective for the survival of the virus. Thus, it should be possible to use our approach in screening for mutations that would provide the most effective resistance to any proposed antiviral drug. This ability should be very useful in guiding the design of drug molecules that will lead to the slowest resistance.

Singh, Nidhi; Frushicheva, Maria P.; Warshel, Arieh



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.



Transcriptional Analyses of Antifungal Drug Resistance in Candida albicans  

PubMed Central

Oral infections with the pathogenic yeast Candida albicans are one of the most frequent and earliest opportunistic infections in human immunodeficiency virus-infected patients. The widespread use of azole antifungal drugs has led to the development of drug-resistant isolates. Several molecular mechanisms that contribute to drug resistance have been identified, including increased mRNA levels for two types of efflux pump genes: the ATP binding cassette transporter CDRs (CDR1 and CDR2) and the major facilitator MDR1. Using Northern blot analyses, the expression patterns of these genes have been determined during logarithmic and stationary phases of cell growth and during growth in different carbon sources in a set of matched susceptible and fluconazole-resistant isolates that have been characterized previously. MDR1, CDR1, and CDR2 are expressed early during logarithmic growth, CDR4 is expressed late during logarithmic growth, and CDR1 is preferentially expressed in stationary-phase cells. There is a small decrease in expression of these genes when the cells are grown in carbon sources other than glucose. While increased mRNA levels of efflux pump genes are commonly associated with azole resistance, the causes of increased mRNA levels have not yet been resolved. Southern blot analysis demonstrates that the increased mRNA levels in these isolates are not the result of gene amplification. Nuclear run-on assays show that MDR1 and CDR mRNAs are transcriptionally overexpressed in the resistant isolate, suggesting that the antifungal drug resistance in this series is associated with the promoter and trans-acting factors of the CDR1, CDR2, and MDR1 genes.

Lyons, Chris N.; White, Theodore C.



Variation in stress responses within a bacterial species and the indirect costs of stress resistance.  


Bacteria can exhibit high levels of resistance to one or more environmental stresses such as temperature, osmolarity, radiation, pH, starvation, as well as resistance to noxious chemicals and antibiotics. Yet evolution has not optimized stress resistance in all bacteria to all stresses. Even within a species like Escherichia coli, stress resistance is not constant between strains, suggesting that selection for stress resistance is under counterselection in some environments. The tradeoffs associated with stress resistance in E. coli are due to more than the direct cost of resistance mechanisms. A significant indirect cost is that high stress resistance is associated with a reduced ability to compete for poor growth substrates like acetate or even good substrates like glucose at suboptimal concentrations. High stress resistance also decreases the ability to use inorganic nutrients like phosphate. This tradeoff between self-preservation and nutritional competence, called the SPANC balance, is likely to be the major selective influence in natural populations. Another cost of high stress resistance in E. coli is an elevated mutation rate and the increased generation of deleterious mutations. Directional adaptations in SPANC balance and mutation rate are environment-dependent. The most common variations in SPANC are due to polymorphisms in the levels of global regulators RpoS and ppGpp between different strains. High levels favor stress resistance, and low levels allow better nutrition. The intimate association of RpoS/ppGpp with stress resistance and SPANC balancing influences numerous cellular processes and bacterial properties, including virulence. PMID:17483210

Ferenci, Thomas; Spira, Beny



Vancomycin-resistant Gram-positive bacterial endophthalmitis: epidemiology, treatment options, and outcomes  

PubMed Central

Background The purpose of this study is to evaluate the microbiological profile and treatment outcomes of vancomycin-resistant Gram-positive bacterial endophthalmitis. Medical records of all patients with Gram-positive bacterial endophthalmitis resistant to vancomycin presenting between 1 January 2005 and 31 December 2010 were reviewed in this noncomparative, consecutive, retrospective case series. Favorable outcome was defined as a best-corrected visual acuity of ?20/200. Results Out of 682 culture-positive endophthalmitis isolates, 448/682 (65.6%) were associated with Gram-positive bacteria. In vitro resistance to vancomycin was noted in 7/448 (1.56%). Three cases were posttraumatic, three were postoperative, and one was endogenous in origin. Four Bacillus isolates, two Staphylococcus isolates, and an Enterococcus isolate were resistant. Isolates resistant to vancomycin were sensitive in vitro to ciprofloxacin in 6/7 (86%) patients. Presenting visual acuity was light perception in all seven cases. Favorable outcome was achieved in only 1/7 (14.3%) cases. Conclusions Vancomycin-resistant endophthalmitis is uncommon and usually associated with poor visual outcome. Bacillus sp. is the most frequent Gram-positive bacteria resistant to vancomycin. Fluoroquinolones like ciprofloxacin may be considered as a useful alternative in vancomycin-resistant endophthalmitis.



Development of bacterial resistance to several biocides and effects on antibiotic susceptibility.  


The aims of this study were to investigate the development of bacterial resistance to eugenol, thymol, trichlorocarbanalide (TCC), didecyldimethylammonium chloride (DDDMAC) and C10-16-alkyldimethyl, N-oxides (ADMAO) and subsequent effects on antibiotic susceptibility. An agar minimum inhibitory concentration (MIC) method was used to assess the activity of the biocides against standard bacterial strains and laboratory mutants. A range of techniques including disk diffusion and gradient plate experiments were used to attempt to develop bacterial 'resistance' or tolerance to the biocides. The mutants produced were examined for cross-resistance to the other biocides and to antibiotics via disk diffusion and gradient plate MIC methods. Outer membrane proteins of the mutants were extracted and examined using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). Escherichia coli triclosan-resistant mutants were not cross-resistant to eugenol, thymol, TCC, DDDMAC and ADMAO. Mutants with elevated MICs to DDDMAC (E. coli and Pseudomonas aeruginosa), thymol (E. coli) and eugenol (E. coli) were isolated, but all remained sensitive to higher concentrations of the agents. Bacteria with elevated MICs to TCC and ADMAO were not obtained. Some low-level cross-resistance between DDDMAC, eugenol and thymol was observed with the E. coli gradient plate mutants, as well as reduced susceptibility to antibiotics, most notably chloramphenicol. The lack of cross-resistance of the triclosan mutants suggested that the mode of action of triclosan is not shared with the other biocides studied. SDS-PAGE results indicated that the DDDMAC P. aeruginosa mutant had a reduced amount (or absence) of one outer membrane protein in comparison with the standard strain. In conclusion, under laboratory conditions, bacterial exposure to thymol, eugenol and DDDMAC can lead to reduced susceptibility between selected biocidal agents and antibiotics, more specifically, chloramphenicol. However, further studies are required to determine if this is of clinical significance. PMID:14529633

Walsh, S E; Maillard, J-Y; Russell, A D; Catrenich, C E; Charbonneau, D L; Bartolo, R G



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



Beta-androstenes and resistance to viral and bacterial infections.  


This report illustrates that the beta-androstenes are indeed able to upregulate the host immune response to a level that enables the host to resist lethal infection by viruses or bacteria. These agents consist of a subgroup of steroids, which also mediates a rapid recovery of hematopoietic precursor cells after whole-body lethal radiation injury. In vivo, the androstenes increase the levels of the Th1 cytokines such as IL-2, IL-3, and IFN. Similar to hydrocortisone, they suppress inflammation, but without immune suppression, and have a role in the maintenance of the Th1/Th2 balance and immune homeostasis. PMID:19212128

Loria, Roger M



Molecular Basis for Drug Resistance in HIV-1 Protease  

PubMed Central

HIV-1 protease is one of the major antiviral targets in the treatment of patients infected with HIV-1. The nine FDA approved HIV-1 protease inhibitors were developed with extensive use of structure-based drug design, thus the atomic details of how the inhibitors bind are well characterized. From this structural understanding the molecular basis for drug resistance in HIV-1 protease can be elucidated. Selected mutations in response to therapy and diversity between clades in HIV-1 protease have altered the shape of the active site, potentially altered the dynamics and even altered the sequence of the cleavage sites in the Gag polyprotein. All of these interdependent changes act in synergy to confer drug resistance while simultaneously maintaining the fitness of the virus. New strategies, such as incorporation of the substrate envelope constraint to design robust inhibitors that incorporate details of HIV-1 protease’s function and decrease the probability of drug resistance, are necessary to continue to effectively target this key protein in HIV-1 life cycle.

Ali, Akbar; Bandaranayake, Rajintha M.; Cai, Yufeng; King, Nancy M.; Kolli, Madhavi; Mittal, Seema; Murzycki, Jennifer F.; Nalam, Madhavi N.L.; Nalivaika, Ellen A.; Ozen, Aysegul; Prabu-Jeyabalan, Moses M.; Thayer, Kelly; Schiffer, Celia A.



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

PubMed Central

Introduction The science of information systems, management, and interpretation plays an important part in the continuity of care of patients. This is becoming more evident in the treatment of human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS), the leading cause of death in sub-Saharan Africa. The high replication rates, selective pressure, and initial infection by resistant strains of HIV infer that drug resistance will inevitably become an important health care concern. This paper describes proposed research with the aim of developing a physician-administered, arti?cial intelligence-based decision support system tool to facilitate the management of patients on antiretroviral therapy. Methods This tool will consist of (1) an artificial intelligence computer program that will determine HIV drug resistance information from genomic analysis; (2) a machine-learning algorithm that can predict future CD4 count information given a genomic sequence; and (3) the integration of these tools into an electronic medical record for storage and management. Conclusion The aim of the project is to create an electronic tool that assists clinicians in managing and interpreting patient information in order to determine the optimal therapy for drug-resistant HIV patients.

Mars, Maurice



Spread of Drug-Resistant Pulmonary Tuberculosis in Estonia  

PubMed Central

Restriction fragment length polymorphism (RFLP) analysis of 209 Mycobacterium tuberculosis clinical isolates obtained from newly detected pulmonary tuberculosis patients (151 male and 58 female; mean age, 41 years) in Estonia during 1994 showed that 61 isolates (29%) belonged to a genetically closely related group of isolates, family A, with a predominant IS6110 banding pattern. These strains shared the majority of their IS6110 DNA-containing restriction fragments, representing a predominant banding pattern (similarity, >65%). This family A comprised 12 clusters of identical isolates, and the largest cluster comprised 10 strains. The majority (87.5%) of all multidrug-resistant (MDR) isolates, 67.2% of all isolates with any drug resistance, but only 12% of the fully susceptible isolates of M. tuberculosis belonged to family A. These strains were confirmed by spoligotyping as members of the Beijing genotype family. The spread of Beijing genotype MDR M. tuberculosis strains was also frequently seen in 1997 to 1999. The members of this homogenous group of drug-resistant M. tuberculosis strains have contributed substantially to the continual emergence of drug-resistant tuberculosis all over Estonia.

Kruuner, Annika; Hoffner, Sven E.; Sillastu, Heinart; Danilovits, Manfred; Levina, Klavdia; Svenson, Stefan B.; Ghebremichael, Solomon; Koivula, Tuija; Kallenius, Gunilla



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.



Systematic Review of the Performance of Rapid Rifampicin Resistance Testing for Drug-Resistant Tuberculosis  

PubMed Central

Introduction Rapid tests for rifampicin resistance may be useful for identifying isolates at high risk of drug resistance, including multidrug-resistant TB (MDR-TB). However, choice of diagnostic test and prevalence of rifampicin resistance may both impact a diagnostic strategy for identifying drug resistant-TB. We performed a systematic review to evaluate the performance of WHO-endorsed rapid tests for rifampicin resistance detection. Methods We searched MEDLINE, Embase and the Cochrane Library through January 1, 2012. For each rapid test, we determined pooled sensitivity and specificity estimates using a hierarchical random effects model. Predictive values of the tests were determined at different prevalence rates of rifampicin resistance and MDR-TB. Results We identified 60 publications involving six different tests (INNO-LiPA Rif. TB assay, Genotype MTBDR assay, Genotype MTBDRplus assay, Colorimetric Redox Indicator (CRI) assay, Nitrate Reductase Assay (NRA) and MODS tests): for all tests, negative predictive values were high when rifampicin resistance prevalence was ? 30%. However, positive predictive values were considerably reduced for the INNO-LiPA Rif. TB assay, the MTBDRplus assay and MODS when rifampicin resistance prevalence was < 5%. Limitations In many studies, it was unclear whether patient selection or index test performance could have introduced bias. In addition, we were unable to evaluate critical concentration thresholds for the colorimetric tests. Discussion Rapid tests for rifampicin resistance alone cannot accurately predict rifampicin resistance or MDR-TB in areas with a low prevalence of rifampicin resistance. However, in areas with a high prevalence of rifampicin resistance and MDR-TB, these tests may be a valuable component of an MDR-TB management strategy.

Arentz, Matthew; Sorensen, Bess; Horne, David J.; Walson, Judd L.



Transfer of Drug Resistance to Myxococcus from Bacteria Carrying Drug-resistance Factors  

Microsoft Academic Search

SUMMARY Resistance to chloramphenicol was successfully transferred from strains of Escherichia coli carrying R factors representative of compatibility groups F, W, S and N to strains of Myxococcus xanthus and M. fulvus. Resistance to kanamycin was transferred from an R factor in group S, and to neomycin from an R factor of group P. Myxobacterial strains differed in their capacity

J. H. Parish



Thioridazine: an old neuroleptic effective against totally drug resistant tuberculosis.  


Globally, tuberculosis infections continue to increase their resistance to antibiotics. Multidrug resistant tuberculosis infections (MDR TB) have progressed to extensively drug resistance status (XDR TB) and the latter have evolved in some parts of the world to totally drug resistant (TDR TB) infections. MDR TB is difficult to treat successfully, and when therapy is ineffective, a single case can cost almost $500,000. When the infection is XDR TB therapy is mostly unsuccessful and is accompanied with high mortality. TDR TB-a yet to be defined infection, is resistant to all forms of therapy and mortality is almost certain. We have, over a period of 14 years, studied thioridazine (TZ) an old neuroleptic that we have shown to: i) have in vitro activity against all antibiotic resistant forms of Mycobacterium tuberculosis; ii) have activity against intracellular Mycobacterium tuberculosis regardless of its antibiotic resistance status; iii) cure the infected mouse of an antibiotic susceptible and MDR TB infections; and, iv) when used in combination with antibiotics used for therapy of tuberculosis, would render the organism significantly more susceptible. These studies have guided our Argentinian colleagues to treat successfully XDR TB infections with thioridazine in combination with three antibiotics to which the infection was initially resistant. This mini review will describe our further work and the mechanisms by which TZ alone and in combination with antibiotics cures an XDR TB infection and why it is expected to cure TDR TB infections as well. The concepts presented are totally new and because they focus on the activation of killing by non-killing macrophages where Mycobacterium tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic resistant status, effective therapy of any antibiotic resistant TB infection is possible. Because TZ is cheap and therefore affordable to any economically disadvantaged country, and will produce no harm when appropriate measures are taken, it is the ideal drug for immediate use in countries that have high frequencies of MDR, XDR and TDR TB infections. PMID:22985923

Amaral, Leonard



Host resistance to an intragastric infection with Listeria monocytogenes in mice depends on cellular immunity and intestinal bacterial flora.  

PubMed Central

Suckling and adult mice were infected intragastrically with different doses of viable Listeria monocytogenes. The 50% lethal dose for the intragastric infection was 10(3.7) CFU for suckling mice, while adult mice were highly resistant and the 50% lethal dose was more than 10(9.3) CFU. When adult mice were infected intragastrically with 5 x 10(8) CFU of L. monocytogenes, no mice died. However, 35% of adult mice died when they were treated with cyclosporin A 1 day before infection. Although mice did not die when treated with an L. monocytogenes-resistant broad-spectrum cephalosporin, sodium cefbuperazone, before and during infection, the number of L. monocytogenes bacteria increased in the feces. The sodium cefbuperazone treatment of mice resulted in superinfection, i.e., a marked decrease of Escherichia coli and an increase of Enterococcus spp. in the intestines. Furthermore, host resistance against the intragastric infection markedly decreased when the mice were treated with both drugs. The growth of L. monocytogenes was augmented in the spleens, mesenteric lymph nodes, Peyer's patches, and feces, and the mortality of the mice was 65%. These results suggest that both cellular immunity and the intestinal bacterial flora are required for host resistance against oral L. monocytogenes infection.

Okamoto, M; Nakane, A; Minagawa, T



Fibroblasts contribute to melanoma tumour growth and drug resistance  

PubMed Central

The role of tumour-stromal interactions in progression is generally well accepted but their role in initiation or treatment is less well understood. It is now generally agreed that rather than consisting solely of malignant cells, tumours consist of a complex dynamic mixture of cancer cells, host fibroblasts, endothelial cells, and immune cells that interact with each other and micro-environmental factors to drive tumour progression. We are particularly interested in stromal cells (for example fibroblasts) and stromal factors (for example fibronectin) as important players in tumour progression since they have also been implicated in drug resistance. Here we develop an integrated approach to understand the role of such stromal cells and factors in the growth and maintenance of tumours as well as their potential impact on treatment resistance, specifically in application to melanoma. Using a suite of experimental assays we show that melanoma cells can stimulate the recruitment of fibroblasts and activate them, resulting in melanoma cell growth by providing both structural (extra-cellular matrix proteins) and chemical support (growth factors). Motivated by these experimental results we construct a compartment model and use it to investigate the roles of both stromal activation and tumour aggressiveness in melanoma growth and progression. We utilise this model to investigate the role fibroblasts might play in melanoma treatment resistance and the clinically observed flare phenomena that is seen when a patient, who appears resistant to a targeted drug, is removed from that treatment. Our model makes the unexpected prediction that targeted therapies may actually hasten tumour progression once resistance has occurred. If confirmed experimentally, this provocative prediction may bring important new insights into how drug resistance could be managed clinically.

Flach, Edward H.; Rebecca, Vito W.; Herlyn, Meenhard; Smalley, Keiran S. M.; Anderson, Alexander R. A.



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


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

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



Recent highlights in antimalarial drug resistance and chemotherapy research  

PubMed Central

This review summarizes recent investigations into antimalarial drug resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of antimalarial chemotherapy and priorities moving forward.

Fidock, David A.; Eastman, Richard T.; Ward, Stephen A.; Meshnick, Steven R.



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

PubMed Central

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

Martinez, Jose L.




PubMed Central

Unanesthetized immature albino rabbits exposed to 2 hours of severe but reversible hemorrhagic shock induced with aseptic precautions by multiple cardiac bleedings exhibited no increase in susceptibility to single intravenous injections of 200 µg./kg. E. coli endotoxin administered 4 hours post retransfusion, a quantity of endotoxin that was found to be the largest dose uniformly non-lethal to normal rabbits. Paired and randomly selected rabbits treated identically except for the additional procedure of a femoral arterial cutdown and ligation (without aseptic precautions) exhibited increases in susceptibility to the same endotoxin of several hundredfold. This effect could not be attributed to the femoral cutdown and arterial ligation alone since such trauma when coupled with sham cardiac bleedings failed to increase susceptibility to 200 µg./kg. of endotoxin. These data appear valid since sham cardiac bleedings produced no detectable impairment of myocardial contractility, while 2 hours of hemorrhagic shock at 50 mm. Hg with the Lamson reservoir technique caused an increase in endotoxin susceptibility comparable to that seen when cardiac bleedings were combined with a non-sterile femoral arterial cutdown and ligation. The mechanisms increasing the susceptibility to E. coli endotoxin were investigated. It was found that (a) rabbit femoral skeletal muscle is normally contaminated with clostridia, (b) the use of aseptic femoral wounding precautions exerted some suggestive protective influence, (c) the use of aseptic wounding precautions combined with immediate topical sulfanilamide and wound closure exerted a significant protective influence, and (d) prophylactic polyvalent gas gangrene antitoxin protected in a manner not demonstrable when diphtheria antitoxin was employed as a control. These observations suggest that clostridial wound infection is one mechanism whereby a femoral arterial cutdown lowers endotoxin resistance of the rabbit following hemorrhagic shock. It is, however, not the only mechanism since the ligation of a femoral artery during hemorrhagic shock led to edema following retransfusion equivalent to a mean of approximately 30 per cent of the original circulating plasma volume. The intensification of shock caused by this transudation presumably intensified reticulo-endothelial injury, and thus further lowered the resistance of the rabbit to an intravenous injection of endotoxin 4 hours following retransfusion.

Greisman, Sheldon E.



Steroidal regulation of uterine resistance to bacterial infection in livestock  

PubMed Central

Postpartum uterine infections reduce reproductive efficiency and have significant animal welfare and economic consequences. Postpartum uterine infections are classified as nonspecific, but Arcanobacterium pyogenes and Escherichia coli are usually associated with them in cattle and sheep. Pyometra is the most common type of uterine infection in dairy cattle, and it is detected almost exclusively in cows with active corpora lutea. Luteal progesterone typically down-regulates uterine immune functions and prevents the uterus from resisting infections. Progesterone also can down-regulate uterine eicosanoid synthesis. This seems to be a critical event in the onset of uterine infections, because eicosanoids can up-regulate immune cell functions in vitro. In addition, exogenous prostaglandin F2 alpha stimulates uterine secretion of prostaglandin F2 alpha and enhances immune functions in vivo. Thus, one may hypothesize that eicosanoids can override the negative effects of progesterone and that the up-regulatory effects of exogenous prostaglandin F2 alpha allow the uterus to resolve an infection, regardless of progesterone concentrations. Based on the results of studies to test that hypothesis, cows, sheep, and pigs in various physiological statuses are resistant to intrauterine infusions of Arcanobacterium pyogenes and Escherichia coli, unless progesterone concentrations are increased. In sheep and pigs, exogenous prostaglandin F2 alpha stimulates uterine production of prostaglandin F2 alpha and allows the uterus to resolve Arcanobacterium pyogenes-Escherichia coli-induced infections, even when progesterone is maintained at luteal phase concentrations before and after treatment. Prostaglandin F2 alpha is a proinflammatory molecule that stimulates the production of various proinflammatory cytokines, and it may enhance uterine production of leukotriene B4. Proinflammatory cytokines and leukotriene B4 enhance phagocytosis and lymphocyte functions. Even though there are clear associations among prostaglandin F2 alpha, leukotriene B4, proinflammatory cytokines, phagocytosis, and lymphocyte functions, the mechanism of action of exogenous prostaglandin F2 alpha in overriding the down-regulatory effects of progesterone and resolving uterine infections has not been elucidated. Defining this mechanism should yield new prevention and treatment strategies for uterine infections that do not rely on antibiotic and antimicrobial compounds.

Lewis, Gregory S



Research Priorities, Profits, and Public Goods: The Case of Drug Resistant Disease  

Microsoft Academic Search

In this paper I argue that drug resistance is an important ethical issue in virtue of (1) the severe — and potentially catastrophic\\u000a — consequences of drug resistance, (2) the fact that drug resistance largely results from the way that medicines (and research\\u000a resources) are distributed, and (3) the fact that drug resistance is a clear example of a public

Michael J. Selgelid


MRP- and BCL2-mediated drug resistance in human SCLC: Effects of apoptotic sphingolipids in vitro  

Microsoft Academic Search

Multidrug-resistance-associated protein (MRP) and BCL-2 contribute to drug resistance expressed in SCLC. To establish whether MRP-mediated drug resistance affects sphingolipid (SL)-induced apoptosis in SCLC, we first examined the human SCLC cell line, UMCC-1, and its MRP over-expressing, drug-resistant subline, UMCC-1\\/VP. Despite significantly decreased sensitivity to doxorubicin (Dox) and to the etoposide, VP-16, the drug-selected line was essentially equally as sensitive

M. Khodadadian; M. E. Leroux; E. Auzenne; S. C. Ghosh; D. Farquhar; R. Evans; W. Spohn; Y. Zou; J. Klostergaard



Contribution of rural-to-urban migration in the prevalence of drug resistant tuberculosis in China  

Microsoft Academic Search

Increased drug resistance rates to the first-line anti-tuberculosis drugs and multidrug resistance (MDR) were observed in\\u000a China. The objectives of this study were to determine the prevalence and risk factors for drug-resistant tuberculosis (TB)\\u000a in urban China and, more specifically, to determine the contribution of migration to case burden and drug resistance rates\\u000a of urban cities. A facility-based epidemiological study

W. Wang; J. Wang; Q. Zhao; N. D. Darling; M. Yu; B. Zhou; B. Xu



Role of Calf-Adapted Escherichia coli in Maintenance of Antimicrobial Drug Resistance in Dairy Calves  

Microsoft Academic Search

The prevalence of antimicrobial drug-resistant bacteria is typically highest in younger animals, and prev- alence is not necessarily related to recent use of antimicrobial drugs. In dairy cattle, we hypothesize that antimicrobial drug-resistant, neonate-adapted bacteria are responsible for the observed high frequencies of resistant Escherichia coli in calves. To explore this issue, we examined the age distribution of antimicrobial drug-resistant

Artashes R. Khachatryan; Dale D. Hancock; Thomas E. Besser; Douglas R. Call



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

Microsoft Academic Search

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

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



Reversal of Multidrug Resistance by Guggulsterone in Drug-Resistant MCF7 Cell Lines  

Microsoft Academic Search

Background: Multidrug resistance (MDR) presents a serious problem in cancer chemotherapy. Our previous studies have shown that the MDR of K562\\/DOX cells could be reversed by guggulsterone through inhibiting the function and expression of P-glycoprotein. The purpose of this study was to investigate the reversal effect of guggulsterone on MDR in drug-resistant MCF-7 cells and the parental MCF-7 cells. Methods:

Hong-Bin Xu; Ling Li; Guo-Qing Liu



ABC transporters involved in drug resistance in human parasites.  


The ABC (ATP-binding cassette) protein superfamily is a ubiquitous and functionally versatile family of proteins that is conserved from archaea to humans. In eukaryotes, most of these proteins are implicated in the transport of a variety of molecules across cellular membranes, whereas the remaining ones are involved in biological processes unrelated to transport. The biological functions of several ABC proteins have been described in clinically important parasites and nematode worms and include vesicular trafficking, phospholipid movement, translation and drug resistance. This chapter reviews our current understanding of the role of ABC proteins in drug resistance and treatment failure in apicomplexan, trypanosomatid and amitochondriate parasites of medical relevance as well as in helminths. PMID:21967055

Leprohon, Philippe; Légaré, Danielle; Ouellette, Marc



Facultative bacterial symbionts in aphids confer resistance to parasitic wasps  

PubMed Central

Symbiotic relationships between animals and microorganisms are common in nature, yet the factors controlling the abundance and distributions of symbionts are mostly unknown. Aphids have an obligate association with the bacterium Buchnera aphidicola (the primary symbiont) that has been shown to contribute directly to aphid fitness. In addition, aphids sometimes harbor other vertically transmitted bacteria (secondary symbionts), for which few benefits of infection have been previously documented. We carried out experiments to determine the consequences of these facultative symbioses in Acyrthosiphon pisum (the pea aphid) for vulnerability of the aphid host to a hymenopteran parasitoid, Aphidius ervi, a major natural enemy in field populations. Our results show that, in a controlled genetic background, infection confers resistance to parasitoid attack by causing high mortality of developing parasitoid larvae. Compared with uninfected controls, experimentally infected aphids were as likely to be attacked by ovipositing parasitoids but less likely to support parasitoid development. This strong interaction between a symbiotic bacterium and a host natural enemy provides a mechanism for the persistence and spread of symbiotic bacteria.

Oliver, Kerry M.; Russell, Jacob A.; Moran, Nancy A.; Hunter, Martha S.



Simple colorimetric bacterial detection and high-throughput drug screening based on a graphene-enzyme complex  

NASA Astrophysics Data System (ADS)

A simple, colorimetric, sensitive, cost-effective and high-throughput system based on a positively charged graphene oxide-enzyme complex was developed for bacterial detection and drug screening.A simple, colorimetric, sensitive, cost-effective and high-throughput system based on a positively charged graphene oxide-enzyme complex was developed for bacterial detection and drug screening. Electronic supplementary information (ESI) available: Experimental details and supporting figures and procedures. See DOI: 10.1039/c2nr32704j

Li, Juan; Wu, Ling-Jie; Guo, Shan-Shan; Fu, Hua-E.; Chen, Guo-Nan; Yang, Huang-Hao



Acute bacterial meningitis caused by Streptococcus pneumoniae resistant to the antimicrobian agents and their serotypes.  


The main objectives of this study are to evaluate the resistance rates of Streptococcus pneumonia to penicillin G, ceftriaxone and vancomycin in patients with meningitis; to analyze possible risk factors to the antimicrobian resistance; to describe the serotypes detected and to suggest an initial empirical treatment for meningitis. The sensitiveness and serotypes of all isolated S. pneumoniae of patients with acute bacterial meningitis received by the Paraná State Central Laboratory from April 2001 to august 2002 have been evaluated. One hundred S. pneumoniae have been isolated, of which 15% were resistant to penicillin, 1% to cephalosporin and 0% to vancomycin. The serotypes most found were 14 (19%), 3 and 23F (10% each). When only the resistant serotypes were analyzed, the most prevalent was the 14 with 44%. The risk factors found in relation to the S. pneumoniae resistance were: age under one year old (p=0.01) and previous use of antibiotic (p=0.046). The resistance rates found, which were moderate to penicillin, low to cephalosporin and neutral to vancomycin, suggest the isolated use of a 3rd generation cephalosporin as an initial empirical therapy for the treatment of acute bacterial meningitis with a communitarian background. PMID:18813710

Rossoni, Andrea Maciel de Oliveira; Dalla Costa, Libera Maria; Berto, Denize Bonato; Farah, Sônia Santos; Gelain, Marilene; Brandileone, Maria Cristina de Cunto; Ramos, Vitor Hugo Mariano; Almeida, Sergio Monteiro de



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

PubMed Central

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.

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



Antimalarial Drug Resistance in Africa: Strategies for Monitoring and Deterrence  

Microsoft Academic Search

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

C. V. Plowe


Cellular Resistance to Oxaliplatin and Drug Accumulation Defects  

Microsoft Academic Search

\\u000a Platinum drugs are employed in a wide range of solid tumors, and represent the mainstay of the first-line therapy of ovarian\\u000a carcinoma. Although cisplatin has shown efficacy in the treatment of different types of tumors including ovarian carcinoma,\\u000a resistance to treatment is a major limitation. At present, one of the most clinically relevant cisplatin analogues is the\\u000a mononuclear compound oxaliplatin,

Laura Gatti; Paola Perego


Toward Repurposing Ciclopirox as an Antibiotic against Drug-Resistant Acinetobacter baumannii, Escherichia coli, and Klebsiella pneumoniae  

PubMed Central

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.

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



Transferrin overcomes drug resistance to artemisinin in human small-cell lung carcinoma cells  

Microsoft Academic Search

Multiple drug resistance is a significant problem in small-cell lung cancer (SCLC). Artemisinin (ART) is a natural product used to treat drug-resistant malaria. The drug is effective because the Fe2+ present in infected erythrocytes acts non-enzymatically to convert ART to toxic products. We tested the effects of ART on drug-sensitive (H69) and multi-drug-resistant (H69VP) SCLC cells, pretreated with transferrin (TF)

David Sadava; Tiphanie Phillips; Cindy Lin; Susan E Kane



Threshold survey evaluating transmitted HIV drug resistance among public antenatal clinic clients in Addis Ababa, Ethiopia  

Microsoft Academic Search

Background: Expanded access to HIV therapy in the developing world raises serious concerns regarding the potential emergence and transmission of drug-resistant HIV strains. Although HIV drug resistance surveillance is recommended to track transmitted HIV drug resistance among newly infected individuals, the financial constraints in resource-limited countries prohibit such surveillance on a regular basis. The World Health Organization (WHO) recently introduced

Woldaregay Erku Abegaz; Zehava Grossman; Dawit Wolday; Daniela Ram; Jonathan Kaplan; Kassim Sibide; Tadesse Wuhib; Shabbir Ismael; John Nkengasong; Teferi Mekonen; Hiwot Berhanu; Tsehaynesh Messele; Sileshi Lulseged; Shlomo Maayan; Yohannes Mengistu



Enhanced complement resistance in drug-selected P-glycoprotein expressing multi-drug-resistant ovarian carcinoma cells  

PubMed Central

Multi-drug resistance (MDR) is a major obstacle in cancer chemotherapy. There are contrasting data on a possible correlation between the level of expression of the drug transporter P-glycoprotein (P-gp) and susceptibility to complement-dependent cytotoxicity (CDC). We therefore investigated the sensitivity of human ovarian carcinoma cells and their P-gp expressing MDR variants to complement. Chemoselected P-gp expressing MDR cells showed increased resistance to CDC associated with overexpression of membrane-bound complement regulatory proteins (mCRP) and increased release of the soluble inhibitors C1 inhibitor and factor I. MDR1 gene transfection alone did not alter the susceptibility of P-gp expressing A2780-MDR and SKOV3-MDR cells to CDC. However, subsequent vincristine treatment conferred an even higher resistance to complement to these cells, again associated with increased expression of mCRP. Blocking the function of P-gp with verapamil, cyclosporine A or the anti-P-gp-antibody MRK16 had no impact on their complement resistance, whereas blocking of mCRP enhanced their susceptibility to complement. These results suggest that enhanced resistance of chemoselected MDR ovarian carcinoma cells to CDC is not conferred by P-gp, but is due at least partly to overexpression of mCRP, probably induced by treatment with the chemotherapeutic agents.

Odening, K E; Li, W; Rutz, R; Laufs, S; Fruehauf, S; Fishelson, Z; Kirschfink, M



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.

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



Multidrug and Extensively Drug-resistant Tuberculosis in Canada 1997-2008: Demographic and Disease Characteristics  

PubMed Central

Setting Nationwide Canadian public health surveillance. Objective Description of demographic features and disease characteristics of drug-resistant tuberculosis (TB) in Canada over a 12 year period. Design Continuous surveillance of all cases of culture-confirmed TB in Canada. Demographic and microbiologic features were analyzed and comparisons between drug-susceptible, multidrug-resistant (MDR), and drug-resistant not-MDR were made. Cases of extensively drug resistant TB are described. Results 15,993 cases of culture-confirmed TB were reported during the study period. There were 5 cases of XDR-TB, 177 cases of MDR-TB, and 1,234 cases of first-line drug resistance not-MDR. The majority of drug-resistant cases were reported in foreign-born individuals, with drug-resistant cases diagnosed earlier post-arrival in Canada compared to drug-susceptible cases. In MDR-TB isolates, there was a high rate of drug-resistance to other first- and second-line drugs, making reliable empiric therapeutic recommendations for MDR-TB difficult. There was a statistically significant association between both MDR and drug-resistance not-MDR, and the risk of a negative treatment outcome (defined as treatment failure, absconded, or treatment ongoing >3 yrs). Conclusion Drug-resistance complicates TB management even in developed nations with well-established TB control programs. The predominantly international origin of drug-resistant cases highlights the need for global strategies to combat TB.

Minion, Jessica; Gallant, Victor; Wolfe, Joyce; Jamieson, Frances; Long, Richard



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

NASA Astrophysics Data System (ADS)

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

Singh, Rita; Singh, Durgeshwer



Primary trastuzumab resistance: new tricks for an old drug  

PubMed Central

Trastuzumab (Herceptin®) is the first FDA-approved therapeutic targeting a HER-family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2-positive breast cancer, a substantial proportion of patients will not respond to trastuzumab-based regimens (primary resistance), and those who do respond will often lose clinical benefit (i.e., secondary resistance). While multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which, together, demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of “resistance” as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.

Wilken, Jason A.; Maihle, Nita J.



Ethanol-resistant polymeric film coatings for controlled drug delivery.  


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

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



HIV-1 genetic variation and drug resistance development.  


Up until 10 years ago, basic and clinical HIV-1 research was mainly performed on HIV-1 subtype B that predominated in resource-rich settings. Over the past decade, HIV-1 care and therapy has been scaled up substantially in Latin America, Africa and Asia. These regions are largely dominated by non-B subtype infections, and especially the African continent is affected by the HIV pandemic. Insight on the potency of antiviral drugs and regimens as well as on the emergence of drug resistance in non-B subtypes was lacking triggering research in this field, also partly driven by the introduction and spreading of HIV-1 non-B subtypes in Europe. The scope of this article was to review and discuss the state-of-the-art on the impact of HIV-1 genetic variation on the in vitro activity of antiviral drugs and in vivo response to antiviral therapy; as well as on the in vitro and in vivo emergence of drug resistance. PMID:24151833

Megens, Sarah; Laethem, Kristel Van



Identification of QTL associated with resistance to bacterial spot race T4 in tomato.  


Bacterial spot of tomato (Solanum lycopersicum L.), caused by several Xanthomonas sp., is a serious but difficult disease to control by chemical means. Development of resistance has been hindered by emergence of races virulent to tomato, by the quantitative inheritance of resistance, and by a low correlation between seedling assays and resistance in the field. Resistance to multiple races, including race T4, has been described in the S. lycopersicum var. cerasiformae accession PI 114490. We used molecular markers to identify associations with quantitative trait loci (QTL) in an elite inbred backcross (IBC) population derived from OH 9242, PI 114490 and Fla. 7600, a breeding line with tomato accession Hawaii 7998 (H7998) in its pedigree. Race T4 resistance has also been described in the advanced breeding lines Fla. 8233, Fla. 8517, and Fla. 8326, and a selective genotyping approach was used to identify introgressions associated with resistance in segregating progeny derived from crosses with these lines. In the IBC population, loci on chromosomes 11 and 3, respectively, explained as much as 29.4 and 4.8% of resistance variation. Both these loci were also confirmed by selective genotyping: PI 114490 and H7998 alleles on chromosome 11 each provided resistance. The PI 114490 allele on chromosome 3 was confirmed in the Fla. 8517 population, and an allele of undetermined descent was confirmed at this locus in the Fla. 8326 population. A chromosome 12 allele was associated with susceptibility in the Fla. 8517 population. Additional loci contributing minor effects were also implicated in the IBC population or by selective genotyping. Selection for the major QTL in a marker-directed phenotyping approach should significantly improve the efficiency of breeding for resistance to bacterial spot race T4, although as yet undetected QTL would be necessary to carry out strict marker assisted selection. PMID:20563547

Hutton, Samuel F; Scott, Jay W; Yang, Wencai; Sim, Sung-Chur; Francis, David M; Jones, Jeffrey B



Catalysis and sulfa drug resistance in dihydropteroate synthase.  


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

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



Catalysis and Sulfa Drug Resistance in Dihydropteroate Synthase  

PubMed Central

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. Here, 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 SN1 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.



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


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

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



Advances in understanding the genetic basis of antimalarial drug resistance  

PubMed Central

Summary The acquisition of drug resistance by Plasmodium falciparum has severely curtailed global efforts to control malaria. Our ability to define resistance has been greatly enhanced by recent advances in Plasmodium genetics and genomics. Sequencing and microarray studies have identified thousands of polymorphisms in the P. falciparum genome, and linkage disequilibrium analyses have exploited these to rapidly identify known and novel loci that influence parasite susceptibility to antimalarials such as chloroquine, quinine, and sulfadoxine-pyrimethamine. Genetic approaches have also been designed to predict determinants of in vivo resistance to new antimalarials such as the artemisinins. Transfection methodologies have defined the role of determinants including pfcrt, pfmdr1 and dhfr. This knowledge can be leveraged to develop more efficient methods of surveillance and treatment.

Ekland, Eric H.; Fidock, David A.



Regulatory Circuitry Governing Fungal Development, Drug Resistance, and Disease  

PubMed Central

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

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



Tuberculosis Drug Resistance in an Area of Low Endemicity in 2004 to 2006: Semiquantitative Drug Susceptibility Testing and Genotyping?  

PubMed Central

We determined the quantitative levels and the genetic mechanisms of resistance in drug-resistant clinical isolates of Mycobacterium tuberculosis sampled over a period of 3 years (n = 45; 17 of the isolate were multidrug resistant). Our results led us to hypothesize that some strains categorized as resistant to isoniazid, ethambutol, or streptomycin by standard laboratory procedures of in vitro drug susceptibility testing may still respond to a treatment regimen that includes these agents.

Springer, Burkhard; Calligaris-Maibach, Romana C.; Ritter, Claudia; Bottger, Erik C.



Multiple Mechanisms Confer Drug Resistance to Mitoxantrone in the Human 8226 Myeloma Cell Line1  

Microsoft Academic Search

Selection for in vitro drug resistance can result in a complex phenotype with more than one mechanism of resistance emerging concurrently or sequentially. We examined emerging mechanisms of drug resistance dur- ing selection with mitoxantrone in the human myeloma cell line 8226. A novel transport mechanism appeared early in the selection process that was associated with a 10-fold resistance to

Lori A. Hazlehurst; Nils E. Foley; Mary C. Gleason-Guzman; Miles P. Hacker; Anne E. Cress; Lee W. Greenberger; Mariska C. De Jong; William S. Dalton


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


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

Yang, C H; Ho, G D



Mechanisms, molecular and sero-epidemiology of antimicrobial resistance in bacterial respiratory pathogens isolated from Japanese children  

Microsoft Academic Search

BACKGROUND: The clinical management of community-acquired respiratory tract infections (RTIs) is complicated by the increasing worldwide prevalence of antibacterial resistance, in particular, ?-lactam and macrolide resistance, among the most common causative bacterial pathogens. This study aimed to determine the mechanisms and molecular- and sero-epidemiology of antibacterial resistance among the key paediatric respiratory pathogens in Japan. METHODS: Isolates were collected at

Keisuke Sunakawa; David J Farrell



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

Microsoft Academic Search

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

M. Dröge; A. Pühler; W. Selbitschka



IL1 receptor regulates S100A8\\/A9-dependent keratinocyte resistance to bacterial invasion  

Microsoft Academic Search

Previously, we reported that epithelial cells respond to exogenous interleukin (IL)-1? by increasing expression of several genes involved in the host response to microbes, including the antimicrobial protein complex calprotectin (S100A8\\/A9). Given that S100A8\\/A9 protects epithelial cells against invading bacteria, we studied whether IL-1? augments S100A8\\/A9-dependent resistance to bacterial invasion of oral keratinocytes. When inoculated with Listeria monocytogenes, human buccal

B S Sorenson; A Khammanivong; B D Guenther; K F Ross; M C Herzberg



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



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

Microsoft Academic Search

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

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



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.

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



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

PubMed Central

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

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



[Molecular mapping of a bacterial blight resistance gene Xa-25 in rice].  


Xa-25 was a bacterial blight resistance gene identified in a somaclonal mutant HX-3. A doubled-haploid (DH) population including 129 stable lines was derived from anther culture of a typical japanica 02428 and a typical indica HX-3 cross. The bacterial blight strain Zhe173, a typical bacterial blight strain in Yangtze River valley, was used to test the resistance or susceptible of the DH population lines, and the results showed that the resistance lines and susceptible lines were 62 and 67, respectively. A total of 300 SSR primer pairs covering 12 rice chromosomes were used for polymorphism survey of 02428 and HX-3. Among these primers, 74 showed polymorphism between the parents. Using these polymorphic SSR markers, bulked segregant analysis was conducted on the DH population. As the result, Xa-25 was located at the terminal region of the long arm of chromosome 4 between the two SSR markers RM6748 and RM1153, the map distance between Xa-25 and the two SSR markers was 9.3 cM and 3.0 cM, respectively. PMID:15759866

Gao, Dong-Ying; Liu, Ai-Min; Zhou, Yi-Hong; Cheng, Yan-Jun; Xiang, Yang-Hai; Sun, Li-Hua; Zhai, Wen-Xue



Overcoming Platinum Drug Resistance with Copper-lowering Agents.  


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

Chen, Helen H W; Kuo, Macus Tien



Inhibition of drug-resistant HIV-1 by RNA interference.  


RNA interference is a powerful tool used to inhibit human immunodeficiency virus type 1 (HIV-1) replication in vitro. Almost all HIV-1 genes have been targets for small interfering RNA (siRNA) molecules, and HIV-1 replication can be specifically and successfully inhibited by this technique. RNA interference has been proposed as an alternative strategy to inhibit replication of drug-resistant viruses that emerge during suboptimal antiretroviral therapy for HIV-1. To investigate specific inhibition of drug-resistant HIV-1 by RNA interference, we designed siRNA molecules that recognize codons 181-188 of the reverse transcriptase (RT) gene of wild-type HIV-1 and HIV-1 carrying the M184V mutation, which confers high-level resistance to the RT inhibitor lamivudine. Using viral variants with single point mutations at codon 184, we measured the impact of these mutations on virus replication. We have demonstrated that siRNA targeting either wild-type HIV-1 or M184V variants inhibits replication of the corresponding virus, but does not influence replication of virus with a mismatch in the targeted region. Combining two effective siRNAs did not show synergistic inhibitory effect on HIV-1 replication. However, a combination of lamivudine and siRNA-M184V was very effective in inhibiting replication of both wild-type and variant M184V viruses in mixed infection experiments. Taken together, these results demonstrate that RNA interference might be useful in the treatment of drug-resistant HIV-1 infection. PMID:16290277

Huelsmann, Peter M; Rauch, Pia; Allers, Kristina; John, Matthias J; Metzner, Karin J



Development of a drug resistance model for hepatoblastoma.  


Multidrug resistance (MDR) is a major reason for poor treatment results in hepatoblastoma (HB). The objective of this study was to establish a drug resistance model for HB to analyse alternative treatment options in vitro. Both HB cell lines HUH6 and HepT1 were xenotransplanted in NMRI mice (nu/nu) and 2 cycles of cisplatin (CDDP) treatment were administered. Thereafter, xenotransplants were excised and viable tumour cells were re-cultured. 3D cultures of HUH6 and HepT1 cells were generated on a low binding culture surface. Cell viability in response to CDDP/DOXO (doxorubicin) and apoptosis was assessed by MTT-assay and caspase 3 activity, respectively. Efflux of doxorubicin was measured by flow cytometry. Cellular levels of ABC-transporters (MDR1, MRP1, cMOAT and BRCP) were determined by real time rt-PCR. Only HepT1 cells isolated from HB xenografts showed resistance to CDDP, but did not survive repeated passages. Culturing HUH6 and HepT1 cells as spheroids was successful and 3D cultures showed an IC50-drift to higher drug concentrations for CDDP and DOXO compared to 2D cultures. Treatment with CDDP and DOXO led to homogeneous apoptosis in spheroids. Increased doxorubicin efflux in HUH6 spheroids was not influenced by the P-glycoprotein inhibitor tariquidar. Expression levels of MDR1, MRP1, cMOAT and BRCP in 3D cultures were similar to those in 2D cultures and were higher in HepT1 than in HUH6 cells. In conclusion, a 3D cell culture model for multidrug resistance was established for hepatoblastoma. The underlying mechanism involves altered accessibility of the cells for drugs rather than up-regulation of ABC-transporters. PMID:21132272

Eicher, Carmen; Dewerth, Alexander; Kirchner, Bettina; Warmann, Steven W; Fuchs, Jörg; Armeanu-Ebinger, Sorin



Inhibitors of bacterial efflux pumps as adjuvants in antibiotic treatments and diagnostic tools for detection of resistance by efflux.  


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 efflux determinants in clinical isolates. Structurally dissimilar classes of inhibitors have been patented in the last decade, some are analogs of antibiotic substrates [tetracyclines, quinolones or aminoglycosides] and others, new chemical entities [including substituted indoles, ureas, aromatic amides, piperidinecarboxylic acids, alkylamino- or alkoxyquinolines, peptidomimetics, and pyridopyrimidines]. Their spectrum of activity, in terms of antibiotics and bacteria, differ significantly. Narrow spectrum inhibitors are of prime interest as diagnostic tools, while broad spectrum inhibitors are expected for adjuvant therapies. Apart from (i) a peptidomimetic inhibitor of Mex pumps in Pseudomonas aeruginosa (MC-04,124), for which efficacy was evaluated in animal models, and (ii) a piperidinecarboxylic acid inhibitor of fluoroquinolone efflux in Gram-positive (VX-710), which was safely administered to humans, most of these products have only demonstrated their activity in vitro, so further investigations are needed to evaluate their clinical potential. PMID:18221142

Van Bambeke, Françoise; Pagès, Jean-Marie; Lee, Ving J



Bacterial self-resistance to the natural proteasome inhibitor salinosporamide A  

PubMed Central

Proteasome inhibitors have recently emerged as a therapeutic strategy in cancer chemotherapy but susceptibility to drug resistance limits their efficacy. The marine actinobacterium Salinispora tropica produces salinosporamide A (NPI-0052, marizomib), a potent proteasome inhibitor and promising clinical agent in the treatment of multiple myeloma. Actinobacteria also possess 20S proteasome machinery, raising the question of self-resistance. We identified a redundant proteasome ?-subunit, SalI, encoded within the salinosporamide biosynthetic gene cluster and biochemically characterized the SalI proteasome complex. The SalI ?-subunit has an altered substrate specificity profile, 30-fold resistance to salinosporamide A, and cross-resistance to the FDA-approved proteasome inhibitor bortezomib. An A49V mutation in SalI correlates to clinical bortezomib resistance from a human proteasome ? 5-subunit A49T mutation, suggesting that intrinsic resistance to natural proteasome inhibitors may predict clinical outcomes.

Kale, Andrew J.; McGlinchey, Ryan P.; Lechner, Anna; Moore, Bradley S.



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.  


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



Bacterial efflux pumps involved in multidrug resistance and their inhibitors: rejuvinating the antimicrobial chemotherapy.  


Active efflux of antibiotics is one of the major mechanisms of drug resistance in bacteria. The efflux process is mediated by membrane transporters with a large variety of unrelated compounds as their substrates. Though these pumps are responsible for the low intrinsic resistance of a bacterium to a drug, their overexpression, accumulation of mutations in these proteins and their synergy with other drug resistance mechanisms hampers effective antimicrobial treatment. As efflux pumps have been reported to play vital roles in mediating multidrug resistance in clinical isolates from varied geographic locations and varied populations, the inhibition of efflux pumps appears to be an attractive approach to combat the problem of drug resistance. Efflux pump inhibitors can be utilized for increasing the antibiotic concentration inside a pathogenic cell making these drugs more effective, reduce the accumulation of other resistance mechanisms in a cell and for diagnostic purposes to evaluate the presence and contribution of the efflux mechanism in a pathogen. A large number of inhibitors have been discovered and patented in last two decades but the process of discovery, testing and commercialization is rather slow. Some of the important inhibitors include the energy decouplers, phenothiazines, analogs of popular antibiotics, inhibitors of serotonin re-uptake, to name a few, that have been used as adjuvants in the antimicrobial chemotherapy to potentiate the activity of some important antimicrobials in deadly pathogens that have worried the mankind since long. This review describes the role of efflux pumps in governing the resistance phenotype of a pathogen, efflux pumps found in bacteria and the efflux pump inhibitors that have been studied and patented so far. PMID:22353004

Bhardwaj, Ashima K; Mohanty, Priyabrata



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


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

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



Screening for drug-resistant Candida yeasts with chromogenic agar.  


We examined the utility of agar dilution to screen yeasts for reduced susceptibility to several newer antifungal drugs including echinocandins and azoles. We compared agar dilution susceptibility screening with the Clinical and Laboratory Standards Institute (CLSI) method for Candida isolates. We added echinocandins and azoles to CHROMagar Candida medium prior to its solidification. Assessment of resistance was based on growth characteristics, wherein decreased colony size in the presence of antifungal drugs was used as an indicator of susceptibility. Clinical Candida isolates of C. albicans, C. glabrata, C. parapsilosis, C. tropicalis, C. guilliermondii, C. lusitaniae, C. rugosa and C. dubliniensis were screened for drug susceptibility. Overall, antifungal susceptibility of the yeasts to anidulafungin, caspofungin, micafungin, posaconazole and voriconazole, determined using CHROMagar agar dilution, were shown to be 96, 80, 94, 90 and 97% as accurate, respectively, as those determined by the CLSI method, i.e., within one tube dilution of CLSI MICs. Categorical errors by percentage had a broader range. Major errors noted with anidulafungin, caspofungin and micafungin were 3, 6 and 0%, respectively, while very major errors were 15, 55 and 38%, respectively. Major errors with posaconazole and voriconazole were 12 and 0%, respectively, while very major errors were 0 and 22%, respectively, compared to CLSI standards. Most of the assessment errors were found with C. glabrata and C. parapsilosis. Agar dilution screening for drug susceptibility with the current panel of antifungal drugs is rapid, accurate and effective. However, the determination of resistance or non-susceptibility in yeasts may be more problematic, and may be species dependent. PMID:20109095

Kirkpatrick, William R; Zimmerman, Joseph D; Haikal, Fadi P; Broker, Michael J; Brockway, Erin; Fothergill, Annette W; McCarthy, Dora I; Patterson, Thomas F; Redding, Spencer W



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


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

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



Bacterial profile and drug susceptibility pattern of urinary tract infection in pregnant women at University of Gondar Teaching Hospital, Northwest Ethiopia  

PubMed Central

Background Urinary tract infection (UTI) is a common health problem among pregnant women. Proper investigation and prompt treatment are needed to prevent serious life threatening condition and morbidity due to urinary tract infection that can occur in pregnant women. Recent report in Addis Ababa, Ethiopia indicated the prevalence of UTI in pregnant women was 11.6?% and Gram negative bacteria was the predominant isolates and showed multi drug resistance. This study aimed to assess bacterial profile that causes urinary tract infection and their antimicrobial susceptibility pattern among pregnant women visiting antenatal clinic at University of Gondar Teaching Hospital, Northwest Ethiopia. Methods A cross-sectional study was conducted at University of Gondar Teaching Hospital from March 22 to April 30, 2011. Mid stream urine samples were collected and inoculated into Cystine Lactose Electrolyte Deficient medium (CLED). Colony counts yielding bacterial growth of 105/ml of urine or more of pure isolates were regarded as significant bacteriuria for infection. Colony from CLED was sub cultured onto MacConkey agar and blood agar plates. Identification was done using cultural characteristics and a series of biochemical tests. A standard method of agar disc diffusion susceptibility testing method was used to determine susceptibility patterns of the isolates. Results The overall prevalence of UTI in pregnant women was 10.4?%. The predominant bacterial pathogens were Escherichia coli 47.5?% followed by coagulase-negative staphylococci 22.5?%, Staphylococcus aureus 10?%, and Klebsiella pneumoniae 10?%. Gram negative isolates were resulted low susceptibility to co-trimoxazole (51.9?%) and tetracycline (40.7?%) whereas Gram positive showed susceptibility to ceftriaxon (84.6?%) and amoxicillin–clavulanic acid (92.3?%). Multiple drug resistance (resistance to two or more drugs) was observed in 95?% of the isolates. Conclusion Significant bacteriuria was observed in asymptomatic pregnant women. Periodic studies are recommended to check the outcome of asymptomatic bacteriuria and also monitor any changes in the susceptibility patterns of urinary tract pathogens in pregnant women.



Mycobacteria: laboratory methods for testing drug sensitivity and resistance  

PubMed Central

In its seventh report, published in 1960, the WHO Expert Committee on Tuberculosis “noted the need for international standards for the definition and determination of drug resistance which will permit comparisons to be made from one area to another, and recommended that the World Health Organization take appropriate steps to establish such standards”.10 Acting on this recommendation, WHO took the first step towards standardization by convening in Geneva, in December 1961, an informal international meeting of specialists in the bacteriology of tuberculosis. At this meeting an attempt was made to formulate prerequisites for reliable sensitivity tests and to specify the technical procedures for them. The first part of the present paper is a joint contribution by the participants in the meeting, summarizing the general conclusions reached and recommendations made with regard to tests of sensitivity to the three main antituberculosis drugs—isoniazid, streptomycin and p-aminosalicylic acid. The other three parts describe, in turn, three different tests for determining drug sensitivity—the absolute-concentration method, the resistance-ratio method and the proportion method—that are generally considered to give reasonably accurate results.

Canetti, G.; Froman, S.; Grosset, J.; Hauduroy, P.; Langerova, Miloslava; Mahler, H. T.; Meissner, Gertrud; Mitchison, D. A.; Sula, L.



Epidemiological impact of prolonged systematic use of topical SDD on bacterial colonization of the tracheobronchial tree and antibiotic resistance  

Microsoft Academic Search

Objective: to evaluate the effect of the pro- longed systematic use of topical SDD (tobramycin 80 rag, polymyxin E 100 mg, amphotericin B 500 rag) on ICU ecology as expressed by changes in tracheal colonization and bacterial resistances. Design: Prospective microbiological survey. Setting: Polyvalent ICU of a 2000 beds general hospital. Patients: Data concerning bacterial strains isolated from the tracheo-bronchial

G. Nardi; U. Valentinis; A. Proietti; A. De Monte; A. Di Silvestre; R. Muzzi; R. Peressutti; M. G. Troncon; F. Giordano



Rainbow trout resistance to bacterial cold-water disease is moderately heritable and is not adversely correlated with growth  

Technology Transfer Automated Retrieval System (TEKTRAN)

The objective of this study was to estimate the heritabilities for and genetic correlations among resistance to bacterial cold-water disease and growth traits in a population of rainbow trout. Bacterial cold-water disease, a chronic disease of rainbow trout, is caused by Flavobacterium psychrophilu...


Clinical and operational value of the extensively drug-resistant tuberculosis definition  

Microsoft Academic Search

Currently, no information is available on the effect of resistance\\/susceptibility to first-line drugs different from isoniazid and rifampicin in determining the outcome of extensively drug-resistant tuberculosis (XDR-TB) patients, and whether being XDR-TB is a more accurate indicator of poor clinical outcome than being resistant to all first-line anti-tuberculosis (TB) drugs. To investigate this issue, a large series of multidrug-resistant TB

G. B. Migliori; G. Besozzi; E. Girardi; K. Kliiman; C. Lange; O. S. Toungoussova; G. Ferrara; D. M. Cirillo; A. Gori; A. Matteelli; A. Spanevello; L. R. Codecasa; M. C. Raviglione



Testing for bacterial resistance to arsenic in monitoring well water by the direct viable counting method  

SciTech Connect

Direct viable counting of metal-resistant bacteria (DVCMR) has been found to be useful in both enumerating and differentiating metal-resistant and metal-sensitive strains of bacteria. The DVCMR bioassay was used to detect effects of low and high concentrations of arsenic and arsenicals on bacterial populations in ground water. The level of resistance of the bacterial populations to arsenate was determined by the DVCMR bioassay, and the results showed a linear correlation with the total arsenic concentrations in the monitoring well water samples; no correlation was observed by culture methods with the methods employed. Bacteria resistant to 2000 of arsenate per ml were isolated from all monitoring well water samples studied. Strains showed similar antibiotic and heavy-metal profiles, suggesting that the arsenic was not a highly selective pressure for arsenic alone. The monitoring well water samples were amended with arsenate and nutrients to determine the biotransformation mechanisms involved. Preliminary results suggest that bacteria indigenous to the monitoring well water samples did not directly transform, i.e., precipitate or volatilize, dissolved arsenic. It was concluded that arsenic contamination of the ground water can be monitored by the DVCMR bioassay.

Zelibor, J.L. Jr.; Doughten, M.W.; Grimes, D.J.; Colwell, R.R.



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.

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



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

PubMed Central

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

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



Comparison of rhizosphere bacterial communities in Arabidopsis thaliana mutants for systemic acquired resistance.  


Systemic acquired resistance (SAR) is an inducible systemic plant defense against a broad spectrum of plant pathogens, with the potential to secrete antimicrobial compounds into the soil. However, its impact on rhizosphere bacteria is not known. In this study, we examined fingerprints of bacterial communities in the rhizosphere of the model plant Arabidopsis thaliana to determine the effect of SAR on bacterial community structure and diversity. We compared Arabidopsis mutants that are constitutive and non-inducible for SAR and verified SAR activation by measuring pathogenesis-related protein activity via a beta-glucoronidase (GUS) reporter construct driven by the beta-1-3 glucanase promoter. We used terminal restriction fragment length polymorphism (T-RFLP) analysis of MspI- and HaeIII-digested 16S rDNA to estimate bacterial rhizosphere community diversity, with Lactobacillus sp. added as internal controls. T-RFLP analysis showed a clear rhizosphere effect on community structure, and diversity analysis of both rhizosphere and bulk soil operational taxonomic units (as defined by terminal restriction fragments) using richness, Shannon-Weiner, and Simpson's diversity indices and evenness confirmed that the presence of Arabidopsis roots significantly altered bacterial communities. This effect of altered soil microbial community structure by plants was also seen upon multivariate cluster analysis of the terminal restriction fragments. We also found visible differences in the rhizosphere community fingerprints of different Arabidopsis SAR mutants; however, there was no clear decrease of rhizosphere diversity because of constitutive SAR expression. Our study suggests that SAR can alter rhizosphere bacterial communities, opening the door to further understanding and application of inducible plant defense as a driving force in structuring soil bacterial assemblages. PMID:17619212

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



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



Drug Efflux by a Small Multidrug Resistance Protein Is Inhibited by a Transmembrane Peptide  

PubMed Central

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.

Poulsen, Bradley E.



High prevalence of multidrug resistance in bacterial uropathogens from Kathmandu, Nepal  

PubMed Central

Background Urinary Tract Infection (UTI) is one of the most common infectious diseases and people of all age-groups and geographical locations are affected. The impact of disease is even worst in low-resource developing countries due to unaware of the UTIs caused by multidrug-resistant (MDR) pathogens and the possibility of transfer of MDR traits between them. The present study aimed to determine the prevalence of MDR bacterial isolates from UTI patients, the antibiotic resistance pattern and the conjugational transfer of multidrug resistance phenotypes in Escherichia coli (E. coli). Results Two hundred and nineteen bacterial isolates were recovered from 710 urine samples at Kathmandu Model hospital during the study period. All samples and isolates were investigated by standard laboratory procedures. Among the significant bacterial growth (30.8%, 219 isolates), 41.1% isolates were MDR. The most prevailing organism, E. coli (81.3%, 178 isolates) was 38.2% MDR, whereas second most common organism, Citrobacter spp. (5%, 11 isolates) was found 72.7% MDR. Extended-spectrum ?-lactamase (ESBL) production was detected in 55.2% of a subset of MDR E. coli isolates. Among the 29 MDR E. coli isolates, plasmids of size ranging 2-51 kb were obtained with different 15 profiles. The most common plasmid of size 32 kb was detected in all of the plasmid-harbored E. coli strains. The majority of E. coli isolates investigated for the multidrug resistance transfer were able to transfer plasmid-mediated MDR phenotypes along with ESBL pattern with a frequency ranging from 0.3 × 10-7 to 1.5 × 10-7 to an E. coli HB101 recipient strain by conjugation. Most of the donor and recipient strain showed high levels of minimum inhibitory concentration (MIC) values for commonly-used antibiotics. Conclusions The high prevalence of multidrug resistance in bacterial uropathogens was observed. Particularly, resistance patterns were alarmingly higher for amoxycillin, co-trimoxazole, flouroquinolones and third-generation cephalosporins, which necessitate the re-evaluation of first and second line therapies for UTI. In addition, conjugational co-transfer of MDR phenotypes with ESBL-positive phenotypes was observed in MDR E. coli.



Positive autoregulation of the yeast transcription factor Pdr3p, which is involved in control of drug resistance.  

PubMed Central

Simultaneous resistance to an array of drugs with different cytotoxic activities is a property of Saccharomyces cerevisiae, in which the protein Pdr3p has recently been shown to play a role as a transcriptional regulator. We provide evidence that the yeast PDR3 gene, which encodes a zinc finger transcription factor implicated in certain drug resistance phenomena, is under positive autoregulation by Pdr3p. DNase I footprinting analyses using bacterially expressed Pdr3p showed specific recognition by this protein of at least two upstream activating sequences in the PDR3 promoter. The use of lacZ reporter constructs, a mutational analysis of the upstream activating sequences, as well as band shift experiments enabled the identification of two 5'TC CGCGGA3' sequence motifs in the PDR3 gene as consensus elements for the binding of Pdr3p. Several similar sequence motifs can be found in the promoter of PDR5, a gene encoding an ATP-dependent drug pump whose Pdr3p-induced overexpression is responsible for drug resistance phenomena. Recently one of these sequence elements was shown to be the target of Pdr3p to elevate the level of PDR5 transcription. Finally, we provide evidence in the absence of PDR1 for a PDR3-controlled transcriptional induction of the drug pump by cycloheximide and propose a model for the mechanism governing the transcriptional autoregulation of Pdr3p.

Delahodde, A; Delaveau, T; Jacq, C



Non-genetic mechanisms communicating antibiotic resistance: rethinking strategies for antimicrobial drug design.  


Introduction: Infections by multidrug-resistant bacteria are of great concern worldwide. In many cases, resistance is not due to the presence of specific antibiotic-modifying enzymes, but rather associated with a general impermeability of the bacterial cell envelope. The molecular bases of this intrinsic resistance are not completely understood. Moreover, horizontal gene transfers cannot solely explain the spread of intrinsic resistance among bacterial strains. Areas covered: This review focuses on the increased intrinsic antibiotic resistance mediated by small molecules. These small molecules can either be secreted from bacterial cells of the same or different species (e.g., indole, polyamines, ammonia, and the Pseudomonas quinolone signal) or be present in the bacterial cell milieu, whether in the environment, such as indole acetic acid and other plant hormones, or in human tissues and body fluids, such as polyamines. These molecules are metabolic byproducts that act as infochemicals and modulate bacterial responses toward antibiotics leading to increasing or decreasing resistance levels. Expert opinion: The non-genetic mechanisms of antibiotic response modulation and communication discussed in this review should reorient our thinking of the mechanisms of intrinsic resistance to antibiotics and its spread across bacterial cell populations. The identification of chemical signals mediating increased intrinsic antibiotic resistance will expose novel critical targets for the development of new antimicrobial strategies. PMID:22860901

El-Halfawy, Omar M; Valvano, Miguel A