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Sample records for bacterial drug resistance

  1. 75 FR 33317 - Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-06-11

    ... HUMAN SERVICES Food and Drug Administration Antibacterial Resistance and Diagnostic Device and Drug... resistance, rapid diagnostic device development for bacterial diseases, and antibacterial drug development. The workshop will address antibacterial drug resistance, mechanisms of resistance, epidemiology...

  2. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    DTIC Science & Technology

    2014-10-01

    Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections PRINCIPAL INVESTIGATOR: Andrew M. Gulick, PhD...Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-11-2-0218 5c... infections . Recently, community-acquired infections , infections in wounded U.S. service members, and infections in residents of long-term care facilities

  3. Drug resistance analysis of bacterial strains isolated from burn patients.

    PubMed

    Wang, L F; Li, J L; Ma, W H; Li, J Y

    2014-01-22

    This study aimed to analyze the spectrum and drug resistance of bacteria isolated from burn patients to provide a reference for rational clinical use of antibiotics. Up to 1914 bacterial strain specimens isolated from burn patients admitted to hospital between 2001 and 2010 were subjected to resistance monitoring by using the K-B paper disk method. Retrospective analysis was performed on drug resistance analysis of burn patients. The top eight bacterium strains according to detection rate. A total of 1355 strains of Gram-negative (G(-)) bacteria and 559 strains of Gram-positive (G(+)) bacteria were detected. The top eight bacterium strains, according to detection rate, were Acinetobacter baumannii, Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, Staphylococcus epidermidis, Klebsiella pneumoniae, Enterobacter cloacae, and Enterococcus. Drug resistance rates were higher than 90% in A. baumannii, P. aeruginosa, S. epidermidis, and S. aureus, which accounted for 52.2, 21.7, 27.8, and 33.3%, respectively, of the entire sample. Those with drug resistance rates lower than 30% accounted for 4.3, 30.4, 16.7, and 16.7%, respectively. Multidrug-resistant S. aureus (MRSA) and methicillin-resistant S. epidermidis (MRSE) accounted for 49.2 and 76.4% of the S. epidermis and S. aureus resistance, respectively. Antibacterial drugs that had drug resistance rates to MRSE and MRSA higher than 90% accounted for 38.9 and 72.2%, respectively, whereas those with lower than 30% drug resistance rates accounted for 11.1 and 16.7%, respectively. The burn patients enrolled in the study were mainly infected with G(-) bacteria. These results strongly suggest that clinicians should practice rational use of antibiotics based on drug susceptibility test results.

  4. Exploiting bacterial drug resistance: a single construct for the diagnosis and treatment of drug resistant infections

    NASA Astrophysics Data System (ADS)

    Sallum, Ulysses W.; Zheng, Xiang; Verma, Sarika; Hasan, Tayyaba

    2009-06-01

    β-lactamase enzyme-activated photosensitizer (β-LEAP). We aim to exploit drug resistance mechanisms to selectively release photosensitizers (PSs) for a specific photodynamic antimicrobial effect and reduced host tissue damage. Consequently, the fluorescence emission intensity of the PSs increases and allows for the detection of enzyme activity. In this work we sought to evaluate β-LEAP for use as a sensitive molecular probe. We have reported the enzyme specific antibacterial action of β-LEAP. Here we report the use of β-LEAP for the rapid functional definition of a β-lactamase.

  5. Adaptation or selection? Old issues and new stakes in the postwar debates over bacterial drug resistance.

    PubMed

    Creager, Angela N H

    2007-03-01

    The 1940s and 1950s were marked by intense debates over the origin of drug resistance in microbes. Bacteriologists had traditionally invoked the notions of 'training' and 'adaptation' to account for the ability of microbes to acquire new traits. As the field of bacterial genetics emerged, however, its participants rejected 'Lamarckian' views of microbial heredity, and offered statistical evidence that drug resistance resulted from the selection of random resistant mutants. Antibiotic resistance became a key issue among those disputing physiological (usually termed 'adaptationist') vs. genetic (mutation and selection) explanations of variation in bacteria. Postwar developments connected with the Lysenko affair gave this debate a new political valence. Proponents of the neo-Darwinian synthesis weighed in with support for the genetic theory. However, certain features of drug resistance seemed inexplicable by mutation and selection, particularly the phenomenon of 'multiple resistance'--the emergence of resistance in a single strain against several unrelated antibiotics. In the late 1950s, Tsutomu Watanabe and his collaborators solved this puzzle by determining that resistance could be conferred by cytoplasmic resistance factors rather than chromosomal mutation. These R factors could carry resistance to many antibiotics and seemed able to promote their own dissemination in bacterial populations. In the end, the vindication of the genetic view of drug resistance was accompanied by a recasting of the 'gene' to include extrachromosomal hereditary units carried on viruses and plasmids.

  6. The role played by drug efflux pumps in bacterial multidrug resistance.

    PubMed

    Chitsaz, Mohsen; Brown, Melissa H

    2017-02-28

    Antimicrobial resistance is a current major challenge in chemotherapy and infection control. The ability of bacterial and eukaryotic cells to recognize and pump toxic compounds from within the cell to the environment before they reach their targets is one of the important mechanisms contributing to this phenomenon. Drug efflux pumps are membrane transport proteins that require energy to export substrates and can be selective for a specific drug or poly-specific that can export multiple structurally diverse drug compounds. These proteins can be classified into seven groups based on protein sequence homology, energy source and overall structure. Extensive studies on efflux proteins have resulted in a wealth of knowledge that has made possible in-depth understanding of the structures and mechanisms of action, substrate profiles, regulation and possible inhibition of many clinically important efflux pumps. This review focuses on describing known families of drug efflux pumps using examples that are well characterized structurally and/or biochemically.

  7. Drug Resistance

    MedlinePlus

    HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  8. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens

    PubMed Central

    Thangamani, Shankar; Mohammad, Haroon; Abushahba, Mostafa F. N.; Sobreira, Tiago J. P.; Hedrick, Victoria E.; Paul, Lake N.; Seleem, Mohamed N.

    2016-01-01

    Traditional methods employed to discover new antibiotics are both a time-consuming and financially-taxing venture. This has led researchers to mine existing libraries of clinical molecules in order to repurpose old drugs for new applications (as antimicrobials). Such an effort led to the discovery of auranofin, a drug initially approved as an anti-rheumatic agent, which also possesses potent antibacterial activity in a clinically achievable range. The present study demonstrates auranofin’s antibacterial activity is a complex process that involves inhibition of multiple biosynthetic pathways including cell wall, DNA, and bacterial protein synthesis. We also confirmed that the lack of activity of auranofin observed against Gram-negative bacteria is due to the permeability barrier conferred by the outer membrane. Auranofin’s ability to suppress bacterial protein synthesis leads to significant reduction in the production of key methicillin-resistant Staphylococcus aureus (MRSA) toxins. Additionally, auranofin is capable of eradicating intracellular MRSA present inside infected macrophage cells. Furthermore, auranofin is efficacious in a mouse model of MRSA systemic infection and significantly reduces the bacterial load in murine organs including the spleen and liver. Collectively, this study provides valuable evidence that auranofin has significant promise to be repurposed as a novel antibacterial for treatment of invasive bacterial infections. PMID:26936660

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed

    Soares, Geisla Mary Silva; Figueiredo, Luciene Cristina; Faveri, Marcelo; Cortelli, Sheila Cavalca; Duarte, Poliana Mendes; Feres, Magda

    2012-01-01

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

  11. Origin and Proliferation of Multiple-Drug Resistance in Bacterial Pathogens

    PubMed Central

    Chang, Hsiao-Han; Cohen, Ted; Grad, Yonatan H.; Hanage, William P.; O'Brien, Thomas F.

    2015-01-01

    SUMMARY Many studies report the high prevalence of multiply drug-resistant (MDR) strains. Because MDR infections are often significantly harder and more expensive to treat, they represent a growing public health threat. However, for different pathogens, different underlying mechanisms are traditionally used to explain these observations, and it is unclear whether each bacterial taxon has its own mechanism(s) for multidrug resistance or whether there are common mechanisms between distantly related pathogens. In this review, we provide a systematic overview of the causes of the excess of MDR infections and define testable predictions made by each hypothetical mechanism, including experimental, epidemiological, population genomic, and other tests of these hypotheses. Better understanding the cause(s) of the excess of MDR is the first step to rational design of more effective interventions to prevent the origin and/or proliferation of MDR. PMID:25652543

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

    PubMed Central

    WILSON, BENJAMIN A.; GARUD, NANDITA R.; FEDER, ALISON F.; ASSAF, ZOE J.; PENNINGS, PLEUNI S.

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  14. Aminomethyl Spectinomycins as Novel Therapeutics for Drug Resistant Respiratory Tract and Sexually Transmitted Bacterial Infections

    PubMed Central

    Madhura, Dora B.; Shcherbakov, Dimitri; Zheng, Zhong; Liu, Jiuyu; Abdelrahman, Yasser M.; Singh, Aman P.; Duscha, Stefan; Rathi, Chetan; Lee, Robin B.; Belland, Robert J.; Meibohm, Bernd; Rosch, Jason W.; Böttger, Erik C.; Lee, Richard E.

    2015-01-01

    The antibiotic spectinomycin is a potent inhibitor of bacterial protein synthesis with a unique mechanism of action and an excellent safety index, but it lacks antibacterial activity against most clinically important pathogens. A novel series of N-benzyl substituted 3'-(R)- 3'-aminomethyl-3'-hydroxy spectinomycins was developed based on a computational analysis of the aminomethyl spectinomycin binding site and structure guided synthesis. These compounds had ribosomal inhibition values comparable to spectinomycin but showed increased potency against common respiratory tract pathogens Streptococcus pneumoniae, Haemophilus influenzae, Legionella pneumophila, and Moraxella catarrhalis as well as the sexually transmitted bacteria Neisseria gonorrhoeae and Chlamydia trachomatis. Non-ribosome binding 3'-(S) isomers of the leads demonstrated weak inhibitory activity in in vitro protein translation assays and poor antibacterial activity, indicating that the antibacterial activity of the series remains on target. In addition to improved antibacterial potency, compounds also demonstrated no mammalian cytotoxicity, improved microsomal stability, and favorable pharmacokinetic properties in rats. The lead compound from the series, compound 1, exhibited excellent chemical stability, which was superior to spectinomycin and had no significant interaction with a panel of human receptors and drug metabolism enzymes suggesting low potential for adverse reactions or drug-drug interactions in vivo. Compound 1 was active in vitro against a panel of penicillin, macrolide, and cephalosporin resistant S. pneumoniae clinical isolates and cured mice of fatal pneumococcal pneumonia and sepsis at a dose of 5 mg/kg. Together, these studies indicate N-benzyl aminomethyl spectinomycins possess suitable properties for further development as novel antibacterial agents to treat drug resistant respiratory tract and sexually transmitted bacterial infections. PMID:25995221

  15. Interactions of Antibiotics and Methanolic Crude Extracts of Afzelia Africana (Smith.) Against Drug Resistance Bacterial Isolates

    PubMed Central

    Aiyegoro, Olayinka; Adewusi, Adekanmi; Oyedemi, Sunday; Akinpelu, David; Okoh, Anthony

    2011-01-01

    Infection due to multidrug resistance pathogens is difficult to manage due to bacterial virulence factors and because of a relatively limited choice of antimicrobial agents. Thus, it is imperative to discover fresh antimicrobials or new practices that are effective for the treatment of infectious diseases caused by drug-resistant microorganisms. The objective of this experiment is to investigate for synergistic outcomes when crude methanolic extract of the stem bark of Afzelia africana and antibiotics were combined against a panel of antibiotic resistant bacterial strains that have been implicated in infections. Standard microbiological protocols were used to determine the minimum inhibitory concentrations (MICs) of the extract and antibiotics, as well as to investigate the effect of combinations of the methanolic extract of A. africana stem bark and selected antibiotics using the time-kill assay method. The extract of Afzelia africana exhibited antibacterial activities against both Gram-negative and Gram-positive bacteria made up of environmental and standard strains at a screening concentration of 5 mg/mL. The MICs of the crude extracts and the antibiotics varied between 1 μg/mL and 5.0 mg/mL. Overall, synergistic response constituted about 63.79% of all manner of combinations of extract and antibiotics against all test organisms; antagonism was not detected among the 176 tests carried out. The extract from A. africana stem bark showed potentials of synergy in combination with antibiotics against strains of pathogenic bacteria. The detection of synergy between the extract and antibiotics demonstrates the potential of this plant as a source of antibiotic resistance modulating compounds. PMID:21845091

  16. Inhibition of bacterial growth by iron oxide nanoparticles with and without attached drug: Have we conquered the antibiotic resistance problem?

    NASA Astrophysics Data System (ADS)

    Armijo, Leisha M.; Jain, Priyanka; Malagodi, Angelina; Fornelli, F. Zuly; Hayat, Allison; Rivera, Antonio C.; French, Michael; Smyth, Hugh D. C.; Osiński, Marek

    2015-03-01

    Pseudomonas aeruginosa is among the top three leading causative opportunistic human pathogens, possessing one of the largest bacterial genomes and an exceptionally large proportion of regulatory genes therein. It has been known for more than a decade that the size and complexity of the P. aeruginosa genome is responsible for the adaptability and resilience of the bacteria to include its ability to resist many disinfectants and antibiotics. We have investigated the susceptibility of P. aeruginosa bacterial biofilms to iron oxide (magnetite) nanoparticles (NPs) with and without attached drug (tobramycin). We also characterized the susceptibility of zero-valent iron NPs, which are known to inactivate microbes. The particles, having an average diameter of 16 nm were capped with natural alginate, thus doubling the hydrodynamic size. Nanoparticle-drug conjugates were produced via cross-linking drug and alginate functional groups. Drug conjugates were investigated in the interest of determining dosage, during these dosage-curve experiments, NPs unbound to drug were tested in cultures as a negative control. Surprisingly, we found that the iron oxide NPs inhibited bacterial growth, and thus, biofilm formation without the addition of antibiotic drug. The inhibitory dosages of iron oxide NPs were investigated and the minimum inhibitory concentrations are presented. These findings suggest that NP-drug conjugates may overcome the antibiotic drug resistance common in P. aeruginosa infections.

  17. Identification of New Drug Targets in Multi-Drug Resistant Bacterial Infections

    DTIC Science & Technology

    2015-06-15

    in either exponential or stationary phase of growth . Once again, the most highly over-expressed genes in the biofilm cultures were the genes that...identify the natural product through in vitro reconstitution and analysis of mutant strains, and assay the role of this pathway in bacterial growth and...group has developed a novel and efficient approach to identify GNB genes and their protein products that are essential for growth and/or survival

  18. Antimicrobial potential of Halophilic actinomycetes against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens.

    PubMed

    Aslam, Sana; Sajid, Imran

    2016-03-01

    A collection of forty halophilic actinomycetes isolated from water and mud samples of the saline lake at Kalar Kahar, salt range, Pakistan, was screened to investigate their antimicrobial potential against multi drug resistant (MDR) ventilator associated pneumonia causing bacterial pathogens. The isolates exhibited significant tolerance to alkaline conditions and grew well at pH 9-11. The taxonomic status of the isolated strains was determined by morphological, biochemical and physiological characterization and by 16s rRNA gene sequencing. The results revealed that majority of the isolates (90%) belong to the genus Streptomyces. Most of the isolates exhibited remarkable antimicrobial activity up to 20mm zone of inhibition against MDR ventilator associated pneumonia causing bacteria including Staphylococcus aureus, Pseudomonas aeruginosa, Proteus vulgaris, Klebsiella pneumoniae, Escherichia coli, Enterobacter and Acinetobacter spp. Additionally the isolates showed moderate to high cytotoxicity in the range of 40 to 80% larval mortality against Artemia salina in a micro well cytotoxicity assay. The chemical screening or the so called metabolic fingerprinting of the methanolic extracts of each isolate, by thin layer chromatography (TLC) using various staining reagents and by high performance liquid chromatography (HPLC-UV), indicated an impressive diversity of the compounds produced by these strains. The study reveals that these halophilic actinomycetes are a promising source of bioactive compounds. The preparative scale fermentation, isolation, purification and structure elucidation of the compounds produced by them may yield novel antimicrobial or chemotherapeutic agents.

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

    PubMed

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

    2014-11-10

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

  20. Drug resistance of bacterial dental biofilm and the potential use of natural compounds as alternative for prevention and treatment.

    PubMed

    Kouidhi, Bochra; Al Qurashi, Yasir Mohammed A; Chaieb, Kamel

    2015-03-01

    Oral diseases, such as dental caries and periodontal disease are directly linked with the ability of bacteria to form biofilm. The development of dental caries involves acidogenic and aciduric Gram-positive bacteria colonizing the supragingival biofilm (Streptococcus, Lactobacillus and Actinomycetes). Periodontal diseases have been linked to anaerobic Gram-negative bacteria forming a subgingival plaque (Porphyromonas gingivalis, Actinobacillus, Prevotella and Fusobacterium). Cells embedded in biofilm are up to 1000-fold more resistant to antibiotics compared to their planctonic ones. Several mechanisms have been proposed to explain biofilms drug resistance. Given the increased bacterial resistance to antibiotics currently used in dentistry, a great importance is given to natural compounds for the prevention of oral bacterial growth, adhesion and colonization. Over the past decade, interest in drugs derived from medicinal plants has markedly increased. It has been well documented that medicinal plants and natural compounds confer considerable antibacterial activity against various microorganisms including cariogenic and periodontal pathogens. This paper provides a review of the literature focusing on the studies on (i) biofilm in the oral cavity, (ii) drug resistance of bacterial biofilm and (iii) the potential use of plant extracts, essential oils and natural compounds as biofilm preventive agents in dentistry, involving their origin and their mechanism of biofilm inhibition.

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

    PubMed

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

    2013-04-01

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

  2. Antimicrobial drug resistance.

    PubMed

    Martinez, Marilyn; Silley, Peter

    2010-01-01

    This chapter provides an overview of our current understanding of the mechanisms associated with the development of antimicrobial drug resistance, international differences in definitions of resistance, ongoing efforts to track shifts in drug susceptibility, and factors that can influence the selection of therapeutic intervention. The latter presents a matrix of complex variables that includes the mechanism of drug action, the pharmacokinetics (PK) of the antimicrobial agent in the targeted patient population, the pharmacodynamics (PD) of the bacterial response to the antimicrobial agent, the PK/PD relationship that will influence dose selection, and the integrity of the host immune system. Finally, the differences between bacterial tolerance and bacterial resistance are considered, and the potential for non-traditional anti-infective therapies is discussed.

  3. Biofilms and antibiotic therapy: is there a role for combating bacterial resistance by the use of novel drug delivery systems?

    PubMed

    Smith, Anthony W

    2005-07-29

    The conventional view of antibiotic resistance is one where bacteria exhibit significantly reduced susceptibility to antimicrobials in laboratory tests by mechanisms such as altered drug uptake, altered drug target and drug inactivation. Whilst these mechanisms undoubtedly make a major contribution to antibiotic failure in the clinic, the phenomenon of clinical failure in spite of sensitivity in laboratory tests is also well recognised. It is in this context that attention has focussed on bacteria growing as adherent biofilms, not only as the mode of growth of device-related infections associated for example with artificial joints and venous catheters, but also with other chronic infections such as those occurring in the respiratory tract. Growth as a biofilm almost always leads to a significant decrease in susceptibility to antimicrobial agents compared with cultures grown in suspension and, whilst there is no generally agreed mechanism for the resistance of biofilm bacteria, it is largely phenotypic. That is, when biofilm bacteria are grown in conventional laboratory suspension culture they become susceptible to antimicrobials. A number of elements in the process of biofilm formation have been studied as targets for novel drug delivery technologies. These include surface modification of devices to reduce bacterial attachment and biofilm development as well as incorporation of antimicrobials-again to prevent colonisation. Electrical approaches have been used either to release antimicrobials from device surfaces or to drive antimicrobials through the biofilm. Other technologies not specifically focussed on biofilms include aerosolized delivery of antibiotics to the lung and formulation into liposome and polymer-based vehicles. Liposomal systems have been widely studied, either to target antibiotics to the surface of bacterial biofilms, or by virtue of their property of being taken up cells of the reticuloendothelial system, to target antibiotics towards

  4. Antimicrobial (Drug) Resistance Prevention

    MedlinePlus

    ... Visitor Information Contact Us Research > NIAID's Role in Research > Antimicrobial (Drug) Resistance > Understanding share with facebook share with twitter ... Prevention, Antimicrobial (Drug) Resistance Antimicrobial (Drug) Resistance Antimicrobial ... To prevent antimicrobial resistance, you and your healthcare ...

  5. Identification of efflux-mediated multi-drug resistance in bacterial clinical isolates by two simple methods.

    PubMed

    Martins, Marta; Couto, Isabel; Viveiros, Miguel; Amaral, Leonard

    2010-01-01

    Two simple, instrument-free, user-friendly methods that can readily be implemented by a routine microbiology laboratory are described for the detection of multi-drug-resistant (MDR) isolates that overexpress efflux pump (EP) systems responsible for the MDR phenotype. The first method employs the universal EP substrate ethidium bromide (EB) at varying concentrations in agar-containing plates upon which the contents of an overnight culture are swabbed as spokes of a wheel. In this method, named the EB-agar cartwheel method, it is assumed that the smallest concentration of EB that produces fluorescence of the bacterial mass represents the highest concentration of EB that the bacteria can exclude. Consequently, as the efflux system(s) of a given MDR clinical bacterial isolate is overexpressed relative to that of a reference strain, the minimal concentration of EB producing fluorescence is significantly greater. A simple formula is provided which affords the ranking of MDR clinical isolates with respect to the degree of their efflux capacity. The second method, which can be used after the first one, determines whether the MDR phenotype is based upon an overexpressed efflux system. This method employs a 24-well microplate with separate wells containing or lacking an efflux pump inhibitor (EPI) and Kirby-Bauer discs that correspond to the antibiotics to which the MDR strain is resistant. After the wells are inoculated with the MDR clinical isolate, the plate is incubated overnight and each well is evaluated by eye for evidence of growth. Comparison of growth to the relevant control enables the observer to determine the following outcomes: no growth produced by the EPI-antibiotic combination (i.e., reversal of antibiotic resistance); reduced growth produced by the EPI-antibiotic combination; no difference in growth, i.e., EPI does not affect the resistance to the given antibiotic. If the first method showed that there was a significant difference between the minimum

  6. Mechanisms of drug resistance: quinolone resistance

    PubMed Central

    Hooper, David C.; Jacoby, George A.

    2015-01-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large. PMID:26190223

  7. Mechanisms of drug resistance: quinolone resistance.

    PubMed

    Hooper, David C; Jacoby, George A

    2015-09-01

    Quinolone antimicrobials are synthetic and widely used in clinical medicine. Resistance emerged with clinical use and became common in some bacterial pathogens. Mechanisms of resistance include two categories of mutation and acquisition of resistance-conferring genes. Resistance mutations in one or both of the two drug target enzymes, DNA gyrase and DNA topoisomerase IV, are commonly in a localized domain of the GyrA and ParE subunits of the respective enzymes and reduce drug binding to the enzyme-DNA complex. Other resistance mutations occur in regulatory genes that control the expression of native efflux pumps localized in the bacterial membrane(s). These pumps have broad substrate profiles that include quinolones as well as other antimicrobials, disinfectants, and dyes. Mutations of both types can accumulate with selection pressure and produce highly resistant strains. Resistance genes acquired on plasmids can confer low-level resistance that promotes the selection of mutational high-level resistance. Plasmid-encoded resistance is due to Qnr proteins that protect the target enzymes from quinolone action, one mutant aminoglycoside-modifying enzyme that also modifies certain quinolones, and mobile efflux pumps. Plasmids with these mechanisms often encode additional antimicrobial resistances and can transfer multidrug resistance that includes quinolones. Thus, the bacterial quinolone resistance armamentarium is large.

  8. Aloe vera extract functionalized zinc oxide nanoparticles as nanoantibiotics against multi-drug resistant clinical bacterial isolates.

    PubMed

    Ali, Khursheed; Dwivedi, Sourabh; Azam, Ameer; Saquib, Quaiser; Al-Said, Mansour S; Alkhedhairy, Abdulaziz A; Musarrat, Javed

    2016-06-15

    ZnO nanoparticles (ZnONPs) were synthesised through a simple and efficient biogenic synthesis approach, exploiting the reducing and capping potential of Aloe barbadensis Miller (A. vera) leaf extract (ALE). ALE-capped ZnO nanoparticles (ALE-ZnONPs) were characterized using UV-Vis spectroscopy, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and transmission electron microscopy (TEM) analyses. XRD analysis provided the average size of ZnONPs as 15 nm. FTIR spectral analysis suggested the role of phenolic compounds, terpenoids and proteins present in ALE, in nucleation and stability of ZnONPs. Flow cytometry and atomic absorption spectrophotometry (AAS) data analyses revealed the surface binding and internalization of ZnONPs in Gram +ve (Staphylococcus aureus) and Gram -ve (Escherichia coli) cells, respectively. Significant antibacterial activity of ALE-ZnONPs was observed against extended spectrum beta lactamases (ESBL) positive E. coli, Pseudomonas aeruginosa, and methicillin resistant S. aureus (MRSA) clinical isolates exhibiting the MIC and MBC values of 2200, 2400 μg/ml and 2300, 2700 μg/ml, respectively. Substantial inhibitory effects of ALE-ZnONPs on bacterial growth kinetics, exopolysaccharides and biofilm formation, unequivocally suggested the antibiotic and anti-biofilm potential. Overall, the results elucidated a rapid, environmentally benign, cost-effective, and convenient method for ALE-ZnONPs synthesis, for possible applications as nanoantibiotics or drug carriers.

  9. Bacterial strategies of resistance to antimicrobial peptides.

    PubMed

    Joo, Hwang-Soo; Fu, Chih-Iung; Otto, Michael

    2016-05-26

    Antimicrobial peptides (AMPs) are a key component of the host's innate immune system, targeting invasive and colonizing bacteria. For successful survival and colonization of the host, bacteria have a series of mechanisms to interfere with AMP activity, and AMP resistance is intimately connected with the virulence potential of bacterial pathogens. In particular, because AMPs are considered as potential novel antimicrobial drugs, it is vital to understand bacterial AMP resistance mechanisms. This review gives a comparative overview of Gram-positive and Gram-negative bacterial strategies of resistance to various AMPs, such as repulsion or sequestration by bacterial surface structures, alteration of membrane charge or fluidity, degradation and removal by efflux pumps.This article is part of the themed issue 'Evolutionary ecology of arthropod antimicrobial peptides'.

  10. Synthetic interaction between the TipN polarity factor and an AcrAB-family efflux pump implicates cell polarity in bacterial drug resistance.

    PubMed

    Kirkpatrick, Clare L; Viollier, Patrick H

    2014-05-22

    Quinolone antibiotics are clinically important drugs that target bacterial DNA replication and chromosome segregation. Although the AcrAB-family efflux pumps generally protect bacteria from such drugs, the physiological role of these efflux systems and their interplay with other cellular events are poorly explored. Here, we report an intricate relationship between antibiotic resistance and cell polarity in the model bacterium Caulobacter crescentus. We show that a polarity landmark protein, TipN, identified by virtue of its ability to direct flagellum placement to the new cell pole, protects cells from toxic misregulation of an AcrAB efflux pump through a cis-encoded nalidixic acid-responsive transcriptional repressor. Alongside the importance of polarity in promoting the inheritance and activity of virulence functions including motility, we can now ascribe to it an additional role in drug resistance that is distinct from classical efflux mechanisms.

  11. Boosting bacterial metabolism to combat antibiotic resistance.

    PubMed

    Bhargava, Prerna; Collins, James J

    2015-02-03

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

  12. Polysaccharide-capped silver Nanoparticles inhibit biofilm formation and eliminate multi-drug-resistant bacteria by disrupting bacterial cytoskeleton with reduced cytotoxicity towards mammalian cells

    PubMed Central

    Sanyasi, Sridhar; Majhi, Rakesh Kumar; Kumar, Satish; Mishra, Mitali; Ghosh, Arnab; Suar, Mrutyunjay; Satyam, Parlapalli Venkata; Mohapatra, Harapriya; Goswami, Chandan; Goswami, Luna

    2016-01-01

    Development of effective anti-microbial therapeutics has been hindered by the emergence of bacterial strains with multi-drug resistance and biofilm formation capabilities. In this article, we report an efficient green synthesis of silver nanoparticle (AgNP) by in situ reduction and capping with a semi-synthetic polysaccharide-based biopolymer (carboxymethyl tamarind polysaccharide). The CMT-capped AgNPs were characterized by UV, DLS, FE-SEM, EDX and HR-TEM. These AgNPs have average particle size of ~20–40 nm, and show long time stability, indicated by their unchanged SPR and Zeta-potential values. These AgNPs inhibit growth and biofilm formation of both Gram positive (B. subtilis) and Gram negative (E. coli and Salmonella typhimurium) bacterial strains even at concentrations much lower than the minimum inhibitory concentration (MIC) breakpoints of antibiotics, but show reduced or no cytotoxicity against mammalian cells. These AgNPs alter expression and positioning of bacterial cytoskeletal proteins FtsZ and FtsA. CMT-capped AgNPs can effectively block growth of several clinical isolates and MDR strains representing different genera and resistant towards multiple antibiotics belonging to different classes. We propose that the CMT-capped AgNPs can have potential bio-medical application against multi-drug-resistant microbes with minimal cytotoxicity towards mammalian cells. PMID:27125749

  13. Polysaccharide-capped silver Nanoparticles inhibit biofilm formation and eliminate multi-drug-resistant bacteria by disrupting bacterial cytoskeleton with reduced cytotoxicity towards mammalian cells

    NASA Astrophysics Data System (ADS)

    Sanyasi, Sridhar; Majhi, Rakesh Kumar; Kumar, Satish; Mishra, Mitali; Ghosh, Arnab; Suar, Mrutyunjay; Satyam, Parlapalli Venkata; Mohapatra, Harapriya; Goswami, Chandan; Goswami, Luna

    2016-04-01

    Development of effective anti-microbial therapeutics has been hindered by the emergence of bacterial strains with multi-drug resistance and biofilm formation capabilities. In this article, we report an efficient green synthesis of silver nanoparticle (AgNP) by in situ reduction and capping with a semi-synthetic polysaccharide-based biopolymer (carboxymethyl tamarind polysaccharide). The CMT-capped AgNPs were characterized by UV, DLS, FE-SEM, EDX and HR-TEM. These AgNPs have average particle size of ~20–40 nm, and show long time stability, indicated by their unchanged SPR and Zeta-potential values. These AgNPs inhibit growth and biofilm formation of both Gram positive (B. subtilis) and Gram negative (E. coli and Salmonella typhimurium) bacterial strains even at concentrations much lower than the minimum inhibitory concentration (MIC) breakpoints of antibiotics, but show reduced or no cytotoxicity against mammalian cells. These AgNPs alter expression and positioning of bacterial cytoskeletal proteins FtsZ and FtsA. CMT-capped AgNPs can effectively block growth of several clinical isolates and MDR strains representing different genera and resistant towards multiple antibiotics belonging to different classes. We propose that the CMT-capped AgNPs can have potential bio-medical application against multi-drug-resistant microbes with minimal cytotoxicity towards mammalian cells.

  14. Transfer between an Algerian and a French hospital of four multi-drug resistant bacterial strains together via a single patient

    PubMed Central

    Moissenet, Didier; Richard, Patrick; Granados, Maria; Mérens, Audrey; Fournier, Damien; Fines-Guyon, Marguerite; Arlet, Guillaume; Vu-Thien, Hoang

    2015-01-01

    A 5 years-old girl, seriously burnt with fire, was first hospitalized during four days in an hospital at Alger, and then transferred to our hospital at Paris. Admitted in our intensive care burns unit, she was third degree burnt on 78% of total body surface area, already treated with imipenem and vancomycin at her arrival. Clinical aggravation was rapidly observed and death occurred within 24 hours. Cultures of blood and multiple wound swabs yielded 3 multi-drug resistant bacterial strains: Acinetobacter baumannii with carbapenemase OXA-23, Pseudomonas aeruginosa serotype O11 with metallo-ß-lactamase VIM-4 and Klebsiella pneumoniae with CTX-M-15 extended-spectrum ß-lactamase. Culture of a rectal swab showed colonization by Enterococcus faecium with vanA glycopeptides resistance. Patients colonized with one or two multi-drug-resistant strains were not rare in our burns unit, especially those transferred from Algeria, but this case of a single patient harboring four multi-drug-resistant strains is exceptional. PMID:26550534

  15. Bacterial cheating limits antibiotic resistance

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

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

  16. Quorum sensing and microbial drug resistance.

    PubMed

    Yufan, Chen; Shiyin, Liu; Zhibin, Liang; Mingfa, Lv; Jianuan, Zhou; Lianhui, Zhang

    2016-10-20

    Microbial drug resistance has become a serious problem of global concern, and the evolution and regulatory mechanisms of microbial drug resistance has become a hotspot of research in recent years. Recent studies showed that certain microbial resistance mechanisms are regulated by quorum sensing system. Quorum sensing is a ubiquitous cell-cell communication system in the microbial world, which associates with cell density. High-density microbial cells produce sufficient amount of small signal molecules, activating a range of downstream cellular processes including virulence and drug resistance mechanisms, which increases bacterial drug tolerance and causes infections on host organisms. In this review, the general mechanisms of microbial drug resistance and quorum-sensing systems are summarized with a focus on the association of quorum sensing and chemical signaling systems with microbial drug resistance mechanisms, including biofilm formation and drug efflux pump. The potential use of quorum quenching as a new strategy to control microbial resistance is also discussed.

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

    PubMed Central

    Olajuyigbe, Olufunmiso O.; Coopoosamy, Roger M.

    2014-01-01

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

  18. Ethics and drug resistance.

    PubMed

    Selgelid, Michael J

    2007-05-01

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

  19. Regulation of Bacterial Drug Export Systems

    PubMed Central

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

    2002-01-01

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

  20. Antimicrobial (Drug) Resistance

    MedlinePlus

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

  1. Bacterial Enzymes and Antibiotic Resistance- Oral Presentation

    SciTech Connect

    Maltz, Lauren

    2015-08-25

    By using protein crystallography and X-ray diffraction, structures of bacterial enzymes were solved to gain a better understanding of how enzymatic modification acts as an antibacterial resistance mechanism. Aminoglycoside phosphotransferases (APHs) are one of three aminoglycoside modifying enzymes that confer resistance to the aminoglycoside antibiotics via enzymatic modification, rendering many drugs obsolete. Specifically, the APH(2”) family vary in their substrate specificities and also in their preference for the phosphate donor (ADP versus GDP). By solving the structures of members of the APH(2”) family of enzymes, we can see how domain movements are important to their substrate specificity. Our structure of the ternary complex of APH(2”)-IIIa with GDP and kanamycin, when compared to the known structures of APH(2”)-IVa, reveals that there are real physical differences between these two enzymes, a structural finding that explains why the two enzymes differ in their preferences for certain aminoglycosides. Another important group of bacterial resistance enzymes are the Class D β-lactamases. Oxacillinase carbapenemases (OXAs) are part of this enzyme class and have begun to confer resistance to ‘last resort’ drugs, most notably carbapenems. Our structure of OXA-143 shows that the conformational flexibility of a conserved hydrophobic residue in the active site (Val130) serves to control the entry of a transient water molecule responsible for a key step in the enzyme’s mechanism. Our results provide insight into the structural mechanisms of these two different enzymes.

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

    SciTech Connect

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

    2000-10-01

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

  3. Bacterial proteases, untapped antimicrobial drug targets.

    PubMed

    Culp, Elizabeth; Wright, Gerard D

    2017-04-01

    Bacterial proteases are an extensive collection of enzymes that have vital roles in cell viability, stress response and pathogenicity. Although their perturbation clearly offers the potential for antimicrobial drug development, both as traditional antibiotics and anti-virulence drugs, they are not yet the target of any clinically used therapeutics. Here we describe the potential for and recent progress in the development of compounds targeting bacterial proteases with a focus on AAA+ family proteolytic complexes and signal peptidases (SPs). Caseinolytic protease (ClpP) belongs to the AAA+ family of proteases, a group of multimeric barrel-shaped complexes whose activity is tightly regulated by associated AAA+ ATPases. The opportunity for chemical perturbation of these complexes is demonstrated by compounds targeting ClpP for inhibition, activation or perturbation of its associated ATPase. Meanwhile, SPs are also a proven antibiotic target. Responsible for the cleavage of targeting peptides during protein secretion, both type I and type II SPs have been successfully targeted by chemical inhibitors. As the threat of pan-antibiotic resistance continues to grow, these and other bacterial proteases offer an arsenal of novel antibiotic targets ripe for development.

  4. Targeting bacterial topoisomerases: how to counter mechanisms of resistance.

    PubMed

    Tse-Dinh, Yuk-Ching

    2016-06-01

    DNA gyrase and topoisomerase IV are type IIA bacterial topoisomerases that are targeted by highly effective antibiotics. However, resistance via multiple mechanisms arises to limit the efficacies of these drugs. Continued research on type IIA bacterial topoisomerases has provided novel approaches to counter the most common resistance mechanism for utilization of these proven targets in antibacterial therapy. Bacterial topoisomerase I is being explored as an alternative target that is not expected to show cross-resistance. Dual targeting or combination therapy could be strategies for circumventing the development of resistance to topoisomerase-targeting antibiotics. Bacterial topoisomerases are high-value bactericidal targets that could continue to be exploited for antibacterial therapy, if new tactics to counter resistance can be adopted.

  5. Antibacterial drug discovery in the resistance era.

    PubMed

    Brown, Eric D; Wright, Gerard D

    2016-01-21

    The looming antibiotic-resistance crisis has penetrated the consciousness of clinicians, researchers, policymakers, politicians and the public at large. The evolution and widespread distribution of antibiotic-resistance elements in bacterial pathogens has made diseases that were once easily treatable deadly again. Unfortunately, accompanying the rise in global resistance is a failure in antibacterial drug discovery. Lessons from the history of antibiotic discovery and fresh understanding of antibiotic action and the cell biology of microorganisms have the potential to deliver twenty-first century medicines that are able to control infection in the resistance era.

  6. Drug-resistant tuberculous meningitis.

    PubMed

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

    2013-06-01

    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.

  7. Drugs and drug resistance in African trypanosomiasis.

    PubMed

    Delespaux, Vincent; de Koning, Harry P

    2007-01-01

    Despite the many decades of use of most of the current trypanocides, we know little of their mode of action. This may in part be because most of these will act on multiple targets once inside the cell, and they derive their selective action on the parasite from selective accumulation by the pathogen. Loss of this capacity for drug uptake by the trypanosome would thus be a major cause for drug resistance. We here discuss the use of current drugs against human and veterinary African trypanosomiasis, the prevalence, causes and mechanisms of drug resistance and new developments in trypanosomiasis therapy such as the introduction of nifurtimox and DB289.

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

    PubMed Central

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

    2013-01-01

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

  9. [Genetics and genomics for the study of bacterial resistance].

    PubMed

    Garza-Ramos, Ulises; Silva-Sánchez, Jesús; Martínez-Romero, Esperanza

    2009-01-01

    Bacterial resistance is a public health problem causing high rates of morbidity and mortality in hospital settings. To the extent that different antibiotics are used, bacteria resistant to multiple drugs are selected. The development of new molecular genomic and proteomic tools such as real-time PCR, DNA pyrosequencing, mass spectrometry, DNA microarrays, and bioinformatics allow for more in-depth knowledge about the physiology and structure of bacteria and mechanisms involved in antibiotic resistance. These studies identify new targets for drugs and design specific antibiotics to provide more accurate treatments to combat infections caused by bacteria. Using these techniques, it will also be possible to rapidly identify genes that confer resistance to antibiotics, and to identify complex genetic structures, such as integrons that are involved in the spread of genes that confer multidrug-resistance.

  10. Bedaquiline: a novel antitubercular drug for multidrug-resistant tuberculosis.

    PubMed

    Nagabushan, H; Roopadevi, H S

    2014-01-01

    Multidrug-resistant and extensively drug-resistant tuberculosis (TB) are emerging global health threats. Bedaquiline is a new antituberculous drug belonging to the diarylquinoline class that efficiently inhibits the adenosine triphosphate synthase enzyme of Mycobacterium tuberculosis. It is a bactericidal and long-acting drug. It inhibits both dormant as well as replicating bacterial sub-populations and thus shortens the duration of TB treatment. This drug has been approved by the Food and Drug Administration in December 2012 for the management of multidrug resistant-TB. The drug marks the introduction of a new addition to the TB armamentarium after four decades.

  11. Antibiotics and Bacterial Resistance in the 21st Century

    PubMed Central

    Fair, Richard J; Tor, Yitzhak

    2014-01-01

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

  12. Potential of novel antimicrobial peptide P3 from bovine erythrocytes and its analogs to disrupt bacterial membranes in vitro and display activity against drug-resistant bacteria in a mouse model.

    PubMed

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

    2015-05-01

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

  13. Antimicrobial Drugs in Fighting against Antimicrobial Resistance

    PubMed Central

    Cheng, Guyue; Dai, Menghong; Ahmed, Saeed; Hao, Haihong; Wang, Xu; Yuan, Zonghui

    2016-01-01

    The outbreak of antimicrobial resistance, together with the lack of newly developed antimicrobial drugs, represents an alarming signal for both human and animal healthcare worldwide. Selection of rational dosage regimens for traditional antimicrobial drugs based on pharmacokinetic/pharmacodynamic principles as well as development of novel antimicrobials targeting new bacterial targets or resistance mechanisms are key approaches in tackling AMR. In addition to the cellular level resistance (i.e., mutation and horizontal gene transfer of resistance determinants), the community level resistance (i.e., bilofilms and persisters) is also an issue causing antimicrobial therapy difficulties. Therefore, anti-resistance and antibiofilm strategies have currently become research hotspot to combat antimicrobial resistance. Although metallic nanoparticles can both kill bacteria and inhibit biofilm formation, the toxicity is still a big challenge for their clinical applications. In conclusion, rational use of the existing antimicrobials and combinational use of new strategies fighting against antimicrobial resistance are powerful warranties to preserve potent antimicrobial drugs for both humans and animals. PMID:27092125

  14. Communicating trends in resistance using a drug resistance index

    PubMed Central

    Klugman, Keith P

    2011-01-01

    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

  15. Communicating trends in resistance using a drug resistance index.

    PubMed

    Laxminarayan, Ramanan; Klugman, Keith P

    2011-01-01

    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

  16. New Technologies for Rapid Bacterial Identification and Antibiotic Resistance Profiling.

    PubMed

    Kelley, Shana O

    2017-04-01

    Conventional approaches to bacterial identification and drug susceptibility testing typically rely on culture-based approaches that take 2 to 7 days to return results. The long turnaround times contribute to the spread of infectious disease, negative patient outcomes, and the misuse of antibiotics that can contribute to antibiotic resistance. To provide new solutions enabling faster bacterial analysis, a variety of approaches are under development that leverage single-cell analysis, microfluidic concentration and detection strategies, and ultrasensitive readout mechanisms. This review discusses recent advances in this area and the potential of new technologies to enable more effective management of infectious disease.

  17. Mechanisms and consequences of bacterial resistance to antimicrobial peptides.

    PubMed

    Andersson, D I; Hughes, D; Kubicek-Sutherland, J Z

    2016-05-01

    Cationic antimicrobial peptides (AMPs) are an intrinsic part of the human innate immune system. Over 100 different human AMPs are known to exhibit broad-spectrum antibacterial activity. Because of the increased frequency of resistance to conventional antibiotics there is an interest in developing AMPs as an alternative antibacterial therapy. Several cationic peptides that are derivatives of AMPs from the human innate immune system are currently in clinical development. There are also ongoing clinical studies aimed at modulating the expression of AMPs to boost the human innate immune response. In this review we discuss the potential problems associated with these therapeutic approaches. There is considerable experimental data describing mechanisms by which bacteria can develop resistance to AMPs. As for any type of drug resistance, the rate by which AMP resistance would emerge and spread in a population of bacteria in a natural setting will be determined by a complex interplay of several different factors, including the mutation supply rate, the fitness of the resistant mutant at different AMP concentrations, and the strength of the selective pressure. Several studies have already shown that AMP-resistant bacterial mutants display broad cross-resistance to a variety of AMPs with different structures and modes of action. Therefore, routine clinical administration of AMPs to treat bacterial infections may select for resistant bacterial pathogens capable of better evading the innate immune system. The ramifications of therapeutic levels of exposure on the development of AMP resistance and bacterial pathogenesis are not yet understood. This is something that needs to be carefully studied and monitored if AMPs are used in clinical settings.

  18. [Travellers and multi-drug resistance bacteria].

    PubMed

    Takeshita, Nozomi

    2012-02-01

    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.

  19. Antifungal agents: mode of action, mechanisms of resistance, and correlation of these mechanisms with bacterial resistance.

    PubMed

    Ghannoum, M A; Rice, L B

    1999-10-01

    The increased use of antibacterial and antifungal agents in recent years has resulted in the development of resistance to these drugs. The significant clinical implication of resistance has led to heightened interest in the study of antimicrobial resistance from different angles. Areas addressed include mechanisms underlying this resistance, improved methods to detect resistance when it occurs, alternate options for the treatment of infections caused by resistant organisms, and strategies to prevent and control the emergence and spread of resistance. In this review, the mode of action of antifungals and their mechanisms of resistance are discussed. Additionally, an attempt is made to discuss the correlation between fungal and bacterial resistance. Antifungals can be grouped into three classes based on their site of action: azoles, which inhibit the synthesis of ergosterol (the main fungal sterol); polyenes, which interact with fungal membrane sterols physicochemically; and 5-fluorocytosine, which inhibits macromolecular synthesis. Many different types of mechanisms contribute to the development of resistance to antifungals. These mechanisms include alteration in drug target, alteration in sterol biosynthesis, reduction in the intercellular concentration of target enzyme, and overexpression of the antifungal drug target. Although the comparison between the mechanisms of resistance to antifungals and antibacterials is necessarily limited by several factors defined in the review, a correlation between the two exists. For example, modification of enzymes which serve as targets for antimicrobial action and the involvement of membrane pumps in the extrusion of drugs are well characterized in both the eukaryotic and prokaryotic cells.

  20. Antibiotic resistance in prevalent bacterial and protozoan sexually transmitted infections

    PubMed Central

    Krupp, Karl; Madhivanan, Purnima

    2015-01-01

    The emergence of multi-drug resistant sexually transmitted infections (STIs) is causing a treatment crisis across the globe. While cephalosporin-resistant gonorrhea is one of the most pressing issues, extensively antibiotic resistant Chlamydia trachomatis and Mycoplasma hominis are also becoming commonplace. Experts have suggested that the failure of current treatment regimens are “largely inevitable” and have called for entirely new classes of antimicrobial agents. With the exception of several new classes of drugs primarily targeting nosocomial infections, progress has been slow. While pharmaceutical companies continue to introduce new drugs, they are based on decade-old discoveries. While there is disagreement about what constitutes new classes of antibiotics, many experts suggest that the last truly new family of antimicrobials was discovered in 1987. This review summarizes the existing literature on antibiotic resistance in common bacterial and protozoal STIs. It also briefly discusses several of the most promising alternatives to current therapies, and further examines how advances in drug delivery, formulation, concentration, and timing are improving the efficacy of existing treatments. Finally, the paper discusses the current state of pharmaceutical development for multidrug-resistant STI. PMID:26392647

  1. Drug resistance in eukaryotic microorganisms.

    PubMed

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

    2016-06-24

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

  2. Drug resistance in eukaryotic microorganisms

    PubMed Central

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

    2016-01-01

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

  3. Colourful parrot feathers resist bacterial degradation.

    PubMed

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

    2011-04-23

    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.

  4. Colourful parrot feathers resist bacterial degradation

    PubMed Central

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

    2011-01-01

    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

  5. Proteome studies of bacterial antibiotic resistance mechanisms.

    PubMed

    Vranakis, Iosif; Goniotakis, Ioannis; Psaroulaki, Anna; Sandalakis, Vassilios; Tselentis, Yannis; Gevaert, Kris; Tsiotis, Georgios

    2014-01-31

    Ever since antibiotics were used to help humanity battle infectious diseases, microorganisms straight away fought back. Antibiotic resistance mechanisms indeed provide microbes with possibilities to by-pass and survive the action of antibiotic drugs. Several methods have been employed to identify these microbial resistance mechanisms in an ongoing effort to reduce the steadily increasing number of treatment failures due to multi-drug-resistant microbes. Proteomics has evolved to an important tool for this area of research. Following rapid advances in whole genome sequencing, proteomic technologies have been widely used to investigate microbial gene expression. This review highlights the contribution of proteomics in identifying microbial drug resistance mechanisms. It summarizes different proteomic studies on bacteria resistant to different antibiotic drugs. The review further includes an overview of the methodologies used, as well as lists key proteins identified, thus providing the reader not only a summary of research already done, but also directions for future research. This article is part of a Special Issue entitled: Trends in Microbial Proteomics.

  6. Persistence of antibiotic resistance in bacterial populations.

    PubMed

    Andersson, Dan I; Hughes, Diarmaid

    2011-09-01

    Unfortunately for mankind, it is very likely that the antibiotic resistance problem we have generated during the last 60 years due to the extensive use and misuse of antibiotics is here to stay for the foreseeable future. This view is based on theoretical arguments, mathematical modeling, experiments and clinical interventions, suggesting that even if we could reduce antibiotic use, resistant clones would remain persistent and only slowly (if at all) be outcompeted by their susceptible relatives. In this review, we discuss the multitude of mechanisms and processes that are involved in causing the persistence of chromosomal and plasmid-borne resistance determinants and how we might use them to our advantage to increase the likelihood of reversing the problem. Of particular interest is the recent demonstration that a very low antibiotic concentration can be enriching for resistant bacteria and the implication that antibiotic release into the environment could contribute to the selection for resistance. Several mechanisms are contributing to the stability of antibiotic resistance in bacterial populations and even if antibiotic use is reduced it is likely that most resistance mechanisms will persist for considerable times.

  7. Antibacterial Cleaning Products and Drug Resistance

    PubMed Central

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

    2005-01-01

    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. PMID:16318697

  8. Mechanisms of Drug Resistance: Daptomycin Resistance

    PubMed Central

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

    2016-01-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction in clinical practice in 2003, DAP has become an important key front-line antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP-resistance (R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp, and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP resistance are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have offered novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria. PMID:26495887

  9. A Hybrid Drug Limits Resistance by Evading the Action of the Multiple Antibiotic Resistance Pathway

    PubMed Central

    Wang, Kathy K.; Stone, Laura K.; Lieberman, Tami D.; Shavit, Michal; Baasov, Timor; Kishony, Roy

    2016-01-01

    Hybrid drugs are a promising strategy to address the growing problem of drug resistance, but the mechanism by which they modulate the evolution of resistance is poorly understood. Integrating high-throughput resistance measurements and genomic sequencing, we compared Escherichia coli populations evolved in a hybrid antibiotic that links ciprofloxacin and neomycin B with populations evolved in combinations of the component drugs. We find that populations evolved in the hybrid gain less resistance than those evolved in an equimolar mixture of the hybrid’s components, in part because the hybrid evades resistance mediated by the multiple antibiotic resistance (mar) operon. Furthermore, we find that the ciprofloxacin moiety of the hybrid inhibits bacterial growth whereas the neomycin B moiety diminishes the effectiveness of mar activation. More generally, comparing the phenotypic and genotypic paths to resistance across different drug treatments can pinpoint unique properties of new compounds that limit the emergence of resistance. PMID:26538141

  10. A Hybrid Drug Limits Resistance by Evading the Action of the Multiple Antibiotic Resistance Pathway.

    PubMed

    Wang, Kathy K; Stone, Laura K; Lieberman, Tami D; Shavit, Michal; Baasov, Timor; Kishony, Roy

    2016-02-01

    Hybrid drugs are a promising strategy to address the growing problem of drug resistance, but the mechanism by which they modulate the evolution of resistance is poorly understood. Integrating high-throughput resistance measurements and genomic sequencing, we compared Escherichia coli populations evolved in a hybrid antibiotic that links ciprofloxacin and neomycin B with populations evolved in combinations of the component drugs. We find that populations evolved in the hybrid gain less resistance than those evolved in an equimolar mixture of the hybrid's components, in part because the hybrid evades resistance mediated by the multiple antibiotic resistance (mar) operon. Furthermore, we find that the ciprofloxacin moiety of the hybrid inhibits bacterial growth whereas the neomycin B moiety diminishes the effectiveness of mar activation. More generally, comparing the phenotypic and genotypic paths to resistance across different drug treatments can pinpoint unique properties of new compounds that limit the emergence of resistance.

  11. PCP prevention--more cases of resistance to sulfa drugs.

    PubMed

    1998-09-01

    Three studies that are highlighted suggest that PCP-causing microbes are developing resistance to Bactrim/Septra (B/S), the drug of choice for preventing the life-threatening complications caused by PCP, toxoplasmosis, and bacterial pneumonia. While resistance does not appear to be happening on a large scale, it is a concern because no other drug has the same beneficial effects of B/S. Research is needed for simple, low-toxicity treatments and prophylactic drugs for PCP, before resistance becomes a common problem.

  12. Mechanisms of drug resistance: daptomycin resistance.

    PubMed

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

    2015-09-01

    Daptomycin (DAP) is a cyclic lipopeptide with in vitro activity against a variety of Gram-positive pathogens, including multidrug-resistant organisms. Since its introduction into clinical practice in 2003, DAP has become an important key frontline antibiotic for severe or deep-seated infections caused by Gram-positive organisms. Unfortunately, DAP resistance (DAP-R) has been extensively documented in clinically important organisms such as Staphylococcus aureus, Enterococcus spp., and Streptococcus spp. Studies on the mechanisms of DAP-R in Bacillus subtilis and other Gram-positive bacteria indicate that the genetic pathways of DAP-R are diverse and complex. However, a common phenomenon emerging from these mechanistic studies is that DAP-R is associated with important adaptive changes in cell wall and cell membrane homeostasis with critical changes in cell physiology. Findings related to these adaptive changes have provided novel insights into the genetics and molecular mechanisms of bacterial cell envelope stress response and the manner in which Gram-positive bacteria cope with the antimicrobial peptide attack and protect vital structures of the cell envelope, such as the cell membrane. In this review, we will examine the most recent findings related to the molecular mechanisms of resistance to DAP in relevant Gram-positive pathogens and discuss the clinical implications for therapy against these important bacteria.

  13. Fitness cost of chromosomal drug resistance-conferring mutations.

    PubMed

    Sander, Peter; Springer, Burkhard; Prammananan, Therdsak; Sturmfels, Antje; Kappler, Martin; Pletschette, Michel; Böttger, Erik C

    2002-05-01

    To study the cost of chromosomal drug resistance mutations to bacteria, we investigated the fitness cost of mutations that confer resistance to different classes of antibiotics affecting bacterial protein synthesis (aminocyclitols, 2-deoxystreptamines, macrolides). We used a model system based on an in vitro competition assay with defined Mycobacterium smegmatis laboratory mutants; selected mutations were introduced by genetic techniques to address the possibility that compensatory mutations ameliorate the resistance cost. We found that the chromosomal drug resistance mutations studied often had only a small fitness cost; compensatory mutations were not involved in low-cost or no-cost resistance mutations. When drug resistance mutations found in clinical isolates were considered, selection of those mutations that have little or no fitness cost in the in vitro competition assay seems to occur. These results argue against expectations that link decreased levels of antibiotic consumption with the decline in the level of resistance.

  14. Drug resistance in Giardia duodenalis.

    PubMed

    Ansell, Brendan R E; McConville, Malcolm J; Ma'ayeh, Showgy Y; Dagley, Michael J; Gasser, Robin B; Svärd, Staffan G; Jex, Aaron R

    2015-11-01

    Giardia duodenalis is a microaerophilic parasite of the human gastrointestinal tract and a major contributor to diarrheal and post-infectious chronic gastrointestinal disease world-wide. Treatment of G. duodenalis infection currently relies on a small number of drug classes. Nitroheterocyclics, in particular metronidazole, have represented the front line treatment for the last 40 years. Nitroheterocyclic-resistant G. duodenalis have been isolated from patients and created in vitro, prompting considerable research into the biomolecular mechanisms of resistance. These compounds are redox-active and are believed to damage proteins and DNA after being activated by oxidoreductase enzymes in metabolically active cells. In this review, we explore the molecular phenotypes of nitroheterocyclic-resistant G. duodenalis described to date in the context of the protist's unusual glycolytic and antioxidant systems. We propose that resistance mechanisms are likely to extend well beyond currently described resistance-associated enzymes (i.e., pyruvate ferredoxin oxidoreductases and nitroreductases), to include NAD(P)H- and flavin-generating pathways, and possibly redox-sensitive epigenetic regulation. Mechanisms that allow G. duodenalis to tolerate oxidative stress may lead to resistance against both oxygen and nitroheterocyclics, with implications for clinical control. The present review highlights the potential for systems biology tools and advanced bioinformatics to further investigate the multifaceted mechanisms of nitroheterocyclic resistance in this important pathogen.

  15. Pattern of Pediatric Bacterial Infection and Antibiotic Resistance in New Delhi.

    PubMed

    Roy, Manas Pratim; Gaind, Rajni; Aggarwal, Kailash Chander; Chellani, Harish Kumar; Biswal, Indu

    2017-02-15

    The retrospective study analyzed 1025 bacterial isolates from blood cultures collected from pediatric patients admitted in a tertiary-care hospital in New Delhi to find out drug sensitivity patterns. Staphylococcus was isolated from approximate 70% of the cultures, with 63.7% of them being methicillin-resistant. Meropenem resistance among acinetobacter was 38.6%.

  16. The Assembly Motif of a Bacterial Small Multidrug Resistance Protein*

    PubMed Central

    Poulsen, Bradley E.; Rath, Arianna; Deber, Charles M.

    2009-01-01

    Multidrug transporters such as the small multidrug resistance (SMR) family of bacterial integral membrane proteins are capable of conferring clinically significant resistance to a variety of common therapeutics. As antiporter proteins of ∼100 amino acids, SMRs must self-assemble into homo-oligomeric structures for efflux of drug molecules. Oligomerization centered at transmembrane helix four (TM4) has been implicated in SMR assembly, but the full complement of residues required to mediate its self-interaction remains to be characterized. Here, we use Hsmr, the 110-residue SMR family member of the archaebacterium Halobacterium salinarum, to determine the TM4 residue motif required to mediate drug resistance and SMR self-association. Twelve single point mutants that scan the central portion of the TM4 helix (residues 85–104) were constructed and were tested for their ability to confer resistance to the cytotoxic compound ethidium bromide. Six residues were found to be individually essential for drug resistance activity (Gly90, Leu91, Leu93, Ile94, Gly97, and Val98), defining a minimum activity motif of 90GLXLIXXGV98 within TM4. When the propensity of these mutants to dimerize on SDS-PAGE was examined, replacements of all but Ile resulted in ∼2-fold reduction of dimerization versus the wild-type antiporter. Our work defines a minimum activity motif of 90GLXLIXXGV98 within TM4 and suggests that this sequence mediates TM4-based SMR dimerization along a single helix surface, stabilized by a small residue heptad repeat sequence. These TM4-TM4 interactions likely constitute the highest affinity locus for disruption of SMR function by directly targeting its self-assembly mechanism. PMID:19224913

  17. Mechanisms of bacterial resistance to macrolide antibiotics.

    PubMed

    Nakajima, Yoshinori

    1999-06-01

    Macrolides have been used in the treatment of infectious diseases since the late 1950s. Since that time, a finding of antagonistic action between erythromycin and spiramycin in clinical isolates1 led to evidence of the biochemical mechanism and to the current understanding of inducible or constitutive resistance to macrolides mediated by erm genes containing, respectively, the functional regulation mechanism or constitutively mutated regulatory region. These resistant mechanisms to macrolides are recognized in clinically isolated bacteria. (1) A methylase encoded by the erm gene can transform an adenine residue at 2058 (Escherichia coli equivalent) position of 23S rRNA into an 6N, 6N-dimethyladenine. Position 2058 is known to reside either in peptidyltransferase or in the vicinity of the enzyme region of domain V. Dimethylation renders the ribosome resistant to macrolides (MLS). Moreover, another finding adduced as evidence is that a mutation in the domain plays an important role in MLS resistance: one of several mutations (transition and transversion) such as A2058G, A2058C or U, and A2059G, is usually associated with MLS resistance in a few genera of bacteria. (2) M (macrolide antibiotics)- and MS (macrolide and streptogramin type B antibiotics)- or PMS (partial macrolide and streptogramin type B antibiotics)-phenotype resistant bacteria cause decreased accumulation of macrolides, occasionally including streptogramin type B antibiotics. The decreased accumulation, probably via enhanced efflux, is usually inferred from two findings: (i) the extent of the accumulated drug in a resistant cell increases as much as that in a susceptible cell in the presence of an uncoupling agent such as carbonylcyanide-m-chlorophenylhydrazone (CCCP), 2,4-dinitrophenol (DNP), and arsenate; (ii) transporter proteins, in M-type resistants, have mutual similarity to the 12-transmembrane domain present in efflux protein driven by proton-motive force, and in MS- or PMS-type resistants

  18. Drug resistance mechanisms and novel drug targets for tuberculosis therapy.

    PubMed

    Islam, Md Mahmudul; Hameed, H M Adnan; Mugweru, Julius; Chhotaray, Chiranjibi; Wang, Changwei; Tan, Yaoju; Liu, Jianxiong; Li, Xinjie; Tan, Shouyong; Ojima, Iwao; Yew, Wing Wai; Nuermberger, Eric; Lamichhane, Gyanu; Zhang, Tianyu

    2017-01-20

    Drug-resistant tuberculosis (TB) poses a significant challenge to the successful treatment and control of TB worldwide. Resistance to anti-TB drugs has existed since the beginning of the chemotherapy era. New insights into the resistant mechanisms of anti-TB drugs have been provided. Better understanding of drug resistance mechanisms helps in the development of new tools for the rapid diagnosis of drug-resistant TB. There is also a pressing need in the development of new drugs with novel targets to improve the current treatment of TB and to prevent the emergence of drug resistance in Mycobacterium tuberculosis. This review summarizes the anti-TB drug resistance mechanisms, furnishes some possible novel drug targets in the development of new agents for TB therapy and discusses the usefulness using known targets to develop new anti-TB drugs. Whole genome sequencing is currently an advanced technology to uncover drug resistance mechanisms in M. tuberculosis. However, further research is required to unravel the significance of some newly discovered gene mutations in their contribution to drug resistance.

  19. Developing live bacterial vaccines by selecting resistance to antibacterials

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Four chemicals were used in this study to modify bacterial isolates through chemical-resistance strategy. All bacteria were able to develop high resistance to gossypol. However, none of the gossypol-resistant isolate was attenuated. Although majority of the proflavine hemisulfate-resistant isolates ...

  20. Bacterial and archaeal resistance to ionizing radiation

    NASA Astrophysics Data System (ADS)

    Confalonieri, F.; Sommer, S.

    2011-01-01

    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

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

    PubMed Central

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

    1999-01-01

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

  2. Management of multidrug resistant bacterial endemic.

    PubMed

    Zahar, J-R; Lesprit, P

    2014-09-01

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

  3. A computational model to monitor and predict trends in bacterial resistance.

    PubMed

    Alawieh, Ali; Sabra, Zahraa; Bizri, Abdul Rahman; Davies, Christopher; White, Roger; Zaraket, Fadi A

    2015-09-01

    Current concern over the emergence of multidrug-resistant superbugs has renewed interest in approaches that can monitor existing trends in bacterial resistance and make predictions of future trends. Recent advances in bacterial surveillance and the development of online repositories of susceptibility tests across wide geographical areas provide an important new resource, yet there are only limited computational tools for its exploitation. Here we propose a hybrid computational model called BARDmaps for automated analysis of antibacterial susceptibility tests from surveillance records and for performing future predictions. BARDmaps was designed to include a structural computational model that can detect patterns among bacterial resistance changes as well as a behavioural computational model that can use the detected patterns to predict future changes in bacterial resistance. Data from the European Antimicrobial Resistance Surveillance Network (EARS-Net) were used to validate and apply the model. BARDmaps was compared with standard curve-fitting approaches used in epidemiological research. Here we show that BARDmaps can reliably predict future trends in bacterial resistance across Europe. BARDmaps performed better than other curve-fitting approaches for predicting future resistance levels. In addition, BARDmaps was also able to detect abrupt changes in bacterial resistance in response to outbreaks and interventions as well as to compare bacterial behaviour across countries and drugs. In conclusion, BARDmaps is a reliable tool to automatically predict and analyse changes in bacterial resistance across Europe. We anticipate that BARDmaps will become an invaluable tool both for clinical providers and governmental agencies to help combat the threat posed by antibiotic-resistant bacteria.

  4. Overcoming drug resistance through in silico prediction.

    PubMed

    Carbonell, Pablo; Trosset, Jean-Yves

    2014-03-01

    Prediction tools are commonly used in pre-clinical research to assist target selection, to optimize drug potency or to predict the pharmacological profile of drug candidates. In silico prediction and overcoming drug resistance is a new opportunity that creates a high interest in pharmaceutical research. This review presents two main in silico strategies to meet this challenge: a structure-based approach to study the influence of mutations on the drug-target interaction and a system-biology approach to identify resistance pathways for a given drug. In silico screening of synergies between therapeutic and resistant pathways through biological network analysis is an example of technique to escape drug resistance. Structure-based drug design and in silico system biology are complementary approaches to reach few objectives at once: increase efficiency, reduce toxicity and overcoming drug resistance.

  5. Bacterial mercury resistance from atoms to ecosystems.

    PubMed

    Barkay, Tamar; Miller, Susan M; Summers, Anne O

    2003-06-01

    Bacterial resistance to inorganic and organic mercury compounds (HgR) is one of the most widely observed phenotypes in eubacteria. Loci conferring HgR in Gram-positive or Gram-negative bacteria typically have at minimum a mercuric reductase enzyme (MerA) that reduces reactive ionic Hg(II) to volatile, relatively inert, monoatomic Hg(0) vapor and a membrane-bound protein (MerT) for uptake of Hg(II) arranged in an operon under control of MerR, a novel metal-responsive regulator. Many HgR loci encode an additional enzyme, MerB, that degrades organomercurials by protonolysis, and one or more additional proteins apparently involved in transport. Genes conferring HgR occur on chromosomes, plasmids, and transposons and their operon arrangements can be quite diverse, frequently involving duplications of the above noted structural genes, several of which are modular themselves. How this very mobile and plastic suite of proteins protects host cells from this pervasive toxic metal, what roles it has in the biogeochemical cycling of Hg, and how it has been employed in ameliorating environmental contamination are the subjects of this review.

  6. Understanding drug resistance in human intestinal protozoa.

    PubMed

    El-Taweel, Hend Aly

    2015-05-01

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

  7. Targeting bacterial adherence inhibits multidrug-resistant Pseudomonas aeruginosa infection following burn injury

    PubMed Central

    Huebinger, Ryan M.; Stones, Daniel H.; de Souza Santos, Marcela; Carlson, Deborah L.; Song, Juquan; Vaz, Diana Pereira; Keen, Emma; Wolf, Steven E.; Orth, Kim; Krachler, Anne Marie

    2016-01-01

    Classical antimicrobial drugs target proliferation and therefore place microbes under extreme selective pressure to evolve resistance. Alternative drugs that target bacterial virulence without impacting survival directly offer an attractive solution to this problem, but to date few such molecules have been discovered. We previously discovered a widespread group of bacterial adhesins, termed Multivalent Adhesion Molecules (MAMs) that are essential for initial binding of bacteria to host tissues and virulence. Thus, targeting MAM-based adherence is a promising strategy for displacing pathogens from host tissues and inhibiting infection. Here, we show that topical application of polymeric microbeads functionalized with the adhesin MAM7 to a burn infected with multidrug-resistant Pseudomonas aeruginosa substantially decreased bacterial loads in the wound and prevented the spread of the infection into adjacent tissues. As a consequence, the application of this adhesion inhibitor allowed for vascularization and wound healing, and maintained local and systemic inflammatory responses to the burn. We propose that MAM7-functionalized microbeads can be used as a topical treatment, to reduce bacterial attachment and hence prevent bacterial colonization and infection of wounds. As adhesion is not required for microbial survival, this anti-infective strategy has the potential to treat multidrug-resistant infections and limit the emergence of drug-resistant pathogens. PMID:27996032

  8. Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms

    PubMed Central

    Hu, Jianye; Ke, Fei

    2016-01-01

    Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa. Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I. PMID:27480861

  9. Experimental Induction of Bacterial Resistance to the Antimicrobial Peptide Tachyplesin I and Investigation of the Resistance Mechanisms.

    PubMed

    Hong, Jun; Hu, Jianye; Ke, Fei

    2016-10-01

    Tachyplesin I is a 17-amino-acid cationic antimicrobial peptide (AMP) with a typical cyclic antiparallel β-sheet structure that is a promising therapeutic for infections, tumors, and viruses. To date, no bacterial resistance to tachyplesin I has been reported. To explore the safety of tachyplesin I as an antibacterial drug for wide clinical application, we experimentally induced bacterial resistance to tachyplesin I by using two selection procedures and studied the preliminary resistance mechanisms. Aeromonas hydrophila XS91-4-1, Pseudomonas aeruginosa CGMCC1.2620, and Escherichia coli ATCC 25922 and F41 showed resistance to tachyplesin I under long-term selection pressure with continuously increasing concentrations of tachyplesin I. In addition, P. aeruginosa and E. coli exhibited resistance to tachyplesin I under UV mutagenesis selection conditions. Cell growth and colony morphology were slightly different between control strains and strains with induced resistance. Cross-resistance to tachyplesin I and antimicrobial agents (cefoperazone and amikacin) or other AMPs (pexiganan, tachyplesin III, and polyphemusin I) was observed in some resistant mutants. Previous studies showed that extracellular protease-mediated degradation of AMPs induced bacterial resistance to AMPs. Our results indicated that the resistance mechanism of P. aeruginosa was not entirely dependent on extracellular proteolytic degradation of tachyplesin I; however, tachyplesin I could induce increased proteolytic activity in P. aeruginosa Most importantly, our findings raise serious concerns about the long-term risks associated with the development and clinical use of tachyplesin I.

  10. [Bacterial proteases and bacterial resistance against human innate immunity factors].

    PubMed

    Tiurin, Iu A; Mustafin, I G; Fassakhov, R S

    2011-01-01

    The molecular and cell-mediated mechanisms that are developed by certain opportunistic and pathogenic bacteria and were obtained over the course of evolution to preserve resistance against principal components of human body innate immunity are summarized.

  11. Medical Management of Drug-Resistant Tuberculosis.

    PubMed

    Jeon, Doosoo

    2015-07-01

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

  12. New Drugs and Drug Resistance in Malaria: Molecular Genetic Analysis.

    DTIC Science & Technology

    1996-06-26

    heterologous expressions system in yeast for potential drug target enzymes. The yeast expression system should allow rapid screening of new drugs , greatly...medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new ... drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective

  13. New Drugs and Drug Resistance in Malaria: Molecular Genetic Analysis.

    DTIC Science & Technology

    1995-06-20

    heterologous expressions system in yeast for potential drug target enzymes. The yeast expression system should allow rapid screening of new drugs , greatly...medication yet the world faces a crisis-drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new ... drugs has all but stopped. This represents a particular threat to the US Military. In a short time there may be parts of the world where no effective

  14. Preventing drug resistance in severe influenza

    NASA Astrophysics Data System (ADS)

    Dobrovolny, Hana; Deecke, Lucas

    2015-03-01

    Severe, long-lasting influenza infections are often caused by new strains of influenza. The long duration of these infections leads to an increased opportunity for the emergence of drug resistant mutants. This is particularly problematic for new strains of influenza since there is often no vaccine, so drug treatment is the first line of defense. One strategy for trying to minimize drug resistance is to apply periodic treatment. During treatment the wild-type virus decreases, but resistant virus might increase; when there is no treatment, wild-type virus will hopefully out-compete the resistant virus, driving down the number of resistant virus. We combine a mathematical model of severe influenza with a model of drug resistance to study emergence of drug resistance during a long-lasting infection. We apply periodic treatment with two types of antivirals: neuraminidase inhibitors, which block release of virions; and adamantanes, which block replication of virions. We compare the efficacy of the two drugs in reducing emergence of drug resistant mutants and examine the effect of treatment frequency on the emergence of drug resistant mutants.

  15. SCREENING OF TRANSGENIC ANTHURIUMS FOR BACTERIAL BLIGHT AND NEMATODE RESISTANCE

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

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

    PubMed Central

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

    2012-01-01

    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. PMID:22206257

  17. Architecture and conservation of the bacterial DNA replication machinery, an underexploited drug target.

    PubMed

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

    2012-03-01

    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.

  18. Recovery and identification of bacterial DNA from illicit drugs.

    PubMed

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

    2014-02-01

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

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

    PubMed Central

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

    2015-01-01

    Bacterial infection remains one of the leading causes of death worldwide, and the options for treating such infections are decreasing, due the rise of antibiotic-resistant bacteria. The pharmaceutical industry has produced few new types of antibiotics in more than a decade. Researchers are taking several approaches toward developing new classes of antibiotics, including (1) focusing on new targets and processes, such as bacterial cell–cell communication that upregulates virulence; (2) designing inhibitors of bacterial resistance, such as blockers of multidrug efflux pumps; and (3) using alternative antimicrobials such as bacteriophages. In addition, the strategy of finding new uses for existing drugs is beginning to produce results: antibacterial properties have been discovered for existing anticancer, antifungal, anthelmintic, and anti-inflammatory drugs. In this review, we discuss the antimicrobial properties of gallium compounds, 5-fluorouracil, ciclopirox, diflunisal, and some other FDA-approved drugs and argue that their repurposing for the treatment of bacterial infections, including those that are multidrug resistant, is a feasible strategy. PMID:25914685

  20. Acquisition of second-line drug resistance and extensive drug resistance during recent transmission of Mycobacterium tuberculosis in rural China.

    PubMed

    Hu, Y; Mathema, B; Zhao, Q; Chen, L; Lu, W; Wang, W; Kreiswirth, B; Xu, B

    2015-12-01

    Multidrug-resistant tuberculosis (MDR-TB) is prevalent in countries with a high TB burden, like China. As little is known about the emergence and spread of second-line drug (SLD) -resistant TB, we investigate the emergence and transmission of SLD-resistant Mycobacterium tuberculosis in rural China. In a multi-centre population-based study, we described the bacterial population structure and the transmission characteristics of SLD-resistant TB using Spoligotyping in combination with genotyping based on 24-locus MIRU-VNTR (mycobacterial interspersed repetitive unit-variable-number tandem repeat) plus four highly variable loci for the Beijing family, in four rural Chinese regions with diverse geographic and socio-demographic characteristics. Transmission networks among genotypically clustered patients were constructed using social network analysis. Of 1332 M. tuberculosis patient isolates recovered, the Beijing family represented 74.8% of all isolates and an association with MDR and simultaneous resistance between first-line drugs and SLDs. The genotyping analysis revealed that 189 isolates shared MIRU-VNTR patterns in 78 clusters with clustering rate and recent transmission rate of 14.2% and 8.3%, respectively. Fifty-three SLD-resistant isolates were observed in 31 clusters, 30 of which contained the strains with different drug susceptibility profiles and genetic mutations. In conjunction with molecular data, socio-network analysis indicated a key role of Central Township in the transmission across a highly interconnected network where SLD resistance accumulation occurred during transmission. SLD-resistant M. tuberculosis has been spreading in rural China with Beijing family being the dominant strains. Primary transmission of SLD-resistant strains in the population highlights the importance of routine drug susceptibility testing and effective anti-tuberculosis regimens for drug-resistant TB.

  1. Bacterial Cheating Limits the Evolution of Antibiotic Resistance

    NASA Astrophysics Data System (ADS)

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

    2012-02-01

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

  2. Selection of bacterial wilt-resistant tomato through tissue culture.

    PubMed

    Toyoda, H; Shimizu, K; Chatani, K; Kita, N; Matsuda, Y; Ouchi, S

    1989-06-01

    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 delay the growth of the inoculated bacteria. On the other hand, complete resistance was obtained in self-pollinated progeny of regenerants derived from non-selected callus tissues. These plants showed a high resistance when inoculated with this strain, and were also resistant when planted in a field infested with a different strain of the pathogen.

  3. Assessment of Bacterial Antibiotic Resistance Transfer in the Gut

    PubMed Central

    Schjørring, Susanne; Krogfelt, Karen A.

    2011-01-01

    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

  4. Plasmodium falciparum drug resistance in Angola.

    PubMed

    Fançony, Cláudia; Brito, Miguel; Gil, Jose Pedro

    2016-02-09

    Facing chloroquine drug resistance, Angola promptly adopted artemisinin-based combination therapy as the first-line to treat malaria. Currently, the country aims to consolidate malaria control, while preparing for the elimination of the disease, along with others African countries in the region. However, the remarkable capacity of Plasmodium to develop drug resistance represents an alarming threat for those achievements. Herein, the available, but relatively scarce and dispersed, information on malaria drug resistance in Angola, is reviewed and discussed. The review aims to inform but also to encourage future research studies that monitor and update the information on anti-malarial drug efficacy and prevalence of molecular markers of drug resistance, key fields in the context and objectives of elimination.

  5. Enhanced Efflux Activity Facilitates Drug Tolerance in Dormant Bacterial Cells

    PubMed Central

    Pu, Yingying; Zhao, Zhilun; Li, Yingxing; Zou, Jin; Ma, Qi; Zhao, Yanna; Ke, Yuehua; Zhu, Yun; Chen, Huiyi; Baker, Matthew A.B.; Ge, Hao; Sun, Yujie; Xie, Xiaoliang Sunney; Bai, Fan

    2016-01-01

    Summary Natural variations in gene expression provide a mechanism for multiple phenotypes to arise in an isogenic bacterial population. In particular, a sub-group termed persisters show high tolerance to antibiotics. Previously, their formation has been attributed to cell dormancy. Here we demonstrate that bacterial persisters, under β-lactam antibiotic treatment, show less cytoplasmic drug accumulation as a result of enhanced efflux activity. Consistently, a number of multi-drug efflux genes, particularly the central component TolC, show higher expression in persisters. Time-lapse imaging and mutagenesis studies further establish a positive correlation between tolC expression and bacterial persistence. The key role of efflux systems, among multiple biological pathways involved in persister formation, indicates that persisters implement a positive defense against antibiotics prior to a passive defense via dormancy. Finally, efflux inhibitors and antibiotics together effectively attenuate persister formation, suggesting a combination strategy to target drug tolerance. PMID:27105118

  6. The Association between Mycobacterium Tuberculosis Genotype and Drug Resistance in Peru

    PubMed Central

    Grandjean, Louis; Iwamoto, Tomotada; Lithgow, Anna; Gilman, Robert H; Arikawa, Kentaro; Nakanishi, Noriko; Martin, Laura; Castillo, Edith; Alarcon, Valentina; Coronel, Jorge; Solano, Walter; Aminian, Minoo; Guezala, Claudia; Rastogi, Nalin; Couvin, David; Sheen, Patricia; Zimic, Mirko; Moore, David AJ

    2015-01-01

    Background The comparison of Mycobacterium tuberculosis bacterial genotypes with phenotypic, demographic, geospatial and clinical data improves our understanding of how strain lineage influences the development of drug-resistance and the spread of tuberculosis. Methods To investigate the association of Mycobacterium tuberculosis bacterial genotype with drug-resistance. Drug susceptibility testing together with genotyping using both 15-loci MIRU-typing and spoligotyping, was performed on 2,139 culture positive isolates, each from a different patient in Lima, Peru. Demographic, geospatial and socio-economic data were collected using questionnaires, global positioning equipment and the latest national census. Results The Latin American Mediterranean (LAM) clade (OR 2.4, p<0.001) was significantly associated with drug-resistance and alone accounted for more than half of all drug resistance in the region. Previously treated patients, prisoners and genetically clustered cases were also significantly associated with drug-resistance (OR's 2.5, 2.4 and 1.8, p<0.001, p<0.05, p<0.001 respectively). Conclusions Tuberculosis disease caused by the LAM clade was more likely to be drug resistant independent of important clinical, genetic and socio-economic confounding factors. Explanations for this include; the preferential co-evolution of LAM strains in a Latin American population, a LAM strain bacterial genetic background that favors drug-resistance or the "founder effect" from pre-existing LAM strains disproportionately exposed to drugs. PMID:25984723

  7. 77 FR 61417 - Guidance for Industry on Acute Bacterial Sinusitis: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-09

    ...: Developing Drugs for Treatment; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice... entitled ``Acute Bacterial Sinusitis: Developing Drugs for Treatment.'' This guidance addresses FDA's... an indication for the treatment of acute bacterial sinusitis (ABS). This guidance finalizes...

  8. Preventing and managing antiretroviral drug resistance.

    PubMed

    Kuritzkes, Daniel R

    2004-05-01

    Development of resistance to antiretroviral drugs (ARVs) is a major impediment to optimum treatment of HIV-1 infection. Although resistance testing can help to select subsequent regimens when virologic failure occurs, cross-resistance, which affects all classes of ARVs, may make it more difficult to achieve optimum control of HIV. We have known for some time that our first choice of antiretroviral therapy offers the best chance to control HIV replication and that initial therapy should be selected with an eye on future options. Potency is the first line of defense against the development of resistance. Other factors that affect resistance development include: tolerability, potential for optimum adherence, and genetic and pharmacologic barriers to development of resistance. If resistance emerges, only a single drug may be affected initially, and a rapid change in ARVs may preserve the efficacy of other components. One cautionary note is that we can no longer assume that a patient's HIV is fully susceptible to all ARVs even in the initial regimen. Transmission of drug-resistant HIV means that the genetic composition may be that of an "experienced" virus with reduced susceptibility to ARVs. Resistance testing at the time of transmission is most likely to reveal this resistance, but over time the dominant genetic pattern may revert to wild-type, and be missed by resistance testing. Because "archived" resistant HIV may emerge quickly once treatment is initiated, we need to keep this in mind when selecting initial therapy.

  9. Emerging pathogens: Dynamics, mutation and drug resistance

    SciTech Connect

    Perelson, A.S.; Goldstein, B.; Korber, B.T.

    1997-10-01

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

  10. Giardiasis, drug resistance, and new target discovery.

    PubMed

    Tian, Hai-Feng; Chen, Bing; Wen, Jian-Fan

    2010-08-01

    Giardiasis is a worldwide parasitic disease caused by the protozoan Giardia lamblia in humans and other animals, especially live stocks. Here, we briefly review the current state of therapeutic availability for giardiasis, including chemical drugs and vaccines, and the dilemma in the prevention and treatment of this disease, including the emergence of drug resistance and the shortage of vaccine (especially for humans). Future efforts and progress in controlling giardiasis are expected in three aspects: clarification of the drug resistance mechanisms, development of efficient vaccines, and identification of more targets for new drugs and vaccines.

  11. Identifying representative drug resistant mutants of HIV

    PubMed Central

    2015-01-01

    Background Drug resistance is one of the most important causes for failure of anti-AIDS treatment. During therapy, multiple mutations accumulate in the HIV genome, eventually rendering the drugs ineffective in blocking replication of the mutant virus. The huge number of possible mutants precludes experimental analysis to explore the molecular mechanisms of resistance and develop improved antiviral drugs. Results In order to solve this problem, we have developed a new algorithm to reveal the most representative mutants from the whole drug resistant mutant database based on our newly proposed unified protein sequence and 3D structure encoding method. Mean shift clustering and multiple regression analysis were applied on genotype-resistance data for mutants of HIV protease and reverse transcriptase. This approach successfully chooses less than 100 mutants with the highest resistance to each drug out of about 10K in the whole database. When considering high level resistance to multiple drugs, the numbers reduce to one or two representative mutants. Conclusion This approach for predicting the most representative mutants for each drug has major importance for experimental verification since the results provide a small number of representative sequences, which will be amenable for in vitro testing and characterization of the expressed mutant proteins. PMID:26678327

  12. Trojan Horse Antibiotics—A Novel Way to Circumvent Gram-Negative Bacterial Resistance?

    PubMed Central

    Tillotson, Glenn S.

    2016-01-01

    Antibiotic resistance has been emerged as a major global health problem. In particular, gram-negative species pose a significant clinical challenge as bacteria develop or acquire more resistance mechanisms. Often, these bacteria possess multiple resistance mechanisms, thus nullifying most of the major classes of drugs. Novel approaches to this issue are urgently required. However, the challenges of developing new agents are immense. Introducing novel agents is fraught with hurdles, thus adapting known antibiotic classes by altering their chemical structure could be a way forward. A chemical addition to existing antibiotics known as a siderophore could be a solution to the gram-negative resistance issue. Siderophore molecules rely on the bacterial innate need for iron ions and thus can utilize a Trojan Horse approach to gain access to the bacterial cell. The current approaches to using this potential method are reviewed. PMID:27773991

  13. Antibiotic resistant bacterial profiles of anaerobic swine lagoon effluent.

    PubMed

    Brooks, J P; McLaughlin, M R

    2009-01-01

    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.

  14. Mechanisms of echinocandin antifungal drug resistance

    PubMed Central

    Perlin, David S.

    2015-01-01

    Fungal infections due to Candida and Aspergillus species cause extensive morbidity and mortality, especially among immunosuppressed patients, and antifungal therapy is critical to patient management. Yet only a few drug classes are available to treat invasive fungal diseases, and this problem is compounded by the emergence of antifungal resistance. Echinocandin drugs are the preferred choice to treat candidiasis. They are the first cell wall–active agents and target the fungal-specific enzyme glucan synthase, which catalyzes the biosynthesis of β-1,3-glucan, a key cell wall polymer. Therapeutic failures occur rarely among common Candida species, with the exception of Candida glabrata, which are frequently multidrug resistant. Echinocandin resistance in susceptible species is always acquired during therapy. The mechanism of resistance involves amino acid changes in hot-spot regions of Fks subunits of glucan synthase, which decrease the sensitivity of the enzyme to drug. Cellular stress response pathways lead to drug adaptation, which promote the formation of resistant fks strains. Clinical factors promoting echinocandin resistance include empiric therapy, prophylaxis, gastrointestinal reservoirs, and intra-abdominal infections. A better understanding of the echinocandin resistance mechanism, along with cellular and clinical factors promoting resistance, will promote more effective strategies to overcome and prevent echinocandin resistance. PMID:26190298

  15. Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants

    PubMed Central

    Blanco, Paula; Hernando-Amado, Sara; Reales-Calderon, Jose Antonio; Corona, Fernando; Lira, Felipe; Alcalde-Rico, Manuel; Bernardini, Alejandra; Sanchez, Maria Blanca; Martinez, Jose Luis

    2016-01-01

    Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics. PMID:27681908

  16. Bacterial Multidrug Efflux Pumps: Much More Than Antibiotic Resistance Determinants.

    PubMed

    Blanco, Paula; Hernando-Amado, Sara; Reales-Calderon, Jose Antonio; Corona, Fernando; Lira, Felipe; Alcalde-Rico, Manuel; Bernardini, Alejandra; Sanchez, Maria Blanca; Martinez, Jose Luis

    2016-02-16

    Bacterial multidrug efflux pumps are antibiotic resistance determinants present in all microorganisms. With few exceptions, they are chromosomally encoded and present a conserved organization both at the genetic and at the protein levels. In addition, most, if not all, strains of a given bacterial species present the same chromosomally-encoded efflux pumps. Altogether this indicates that multidrug efflux pumps are ancient elements encoded in bacterial genomes long before the recent use of antibiotics for human and animal therapy. In this regard, it is worth mentioning that efflux pumps can extrude a wide range of substrates that include, besides antibiotics, heavy metals, organic pollutants, plant-produced compounds, quorum sensing signals or bacterial metabolites, among others. In the current review, we present information on the different functions that multidrug efflux pumps may have for the bacterial behaviour in different habitats as well as on their regulation by specific signals. Since, in addition to their function in non-clinical ecosystems, multidrug efflux pumps contribute to intrinsic, acquired, and phenotypic resistance of bacterial pathogens, the review also presents information on the search for inhibitors of multidrug efflux pumps, which are currently under development, in the aim of increasing the susceptibility of bacterial pathogens to antibiotics.

  17. MICROBIAL DRUG RESISTANCE (EPIDEMIOLOGY, GENETICS).

    DTIC Science & Technology

    resistance. Antibacterial and inducer activities of LM and its derivatives were examined. Mechanisms of Mac-resistance after induction was investigated...combination of ribosomes from S.aureus and supernatant of E.coli. The ribosomes decrease their binding to spiramycin (SP) in parallel with the increase

  18. Antibiotic Restriction Might Facilitate the Emergence of Multi-drug Resistance.

    PubMed

    Obolski, Uri; Stein, Gideon Y; Hadany, Lilach

    2015-06-01

    High antibiotic resistance frequencies have become a major public health issue. The decrease in new antibiotics' production, combined with increasing frequencies of multi-drug resistant (MDR) bacteria, cause substantial limitations in treatment options for some bacterial infections. To diminish overall resistance, and especially the occurrence of bacteria that are resistant to all antibiotics, certain drugs are deliberately scarcely used--mainly when other options are exhausted. We use a mathematical model to explore the efficiency of such antibiotic restrictions. We assume two commonly used drugs and one restricted drug. The model is examined for the mixing strategy of antibiotic prescription, in which one of the drugs is randomly assigned to each incoming patient. Data obtained from Rabin medical center, Israel, is used to estimate realistic single and double antibiotic resistance frequencies in incoming patients. We find that broad usage of the hitherto restricted drug can reduce the number of incorrectly treated patients, and reduce the spread of bacteria resistant to both common antibiotics. Such double resistant infections are often eventually treated with the restricted drug, and therefore are prone to become resistant to all three antibiotics. Thus, counterintuitively, a broader usage of a formerly restricted drug can sometimes lead to a decrease in the emergence of bacteria resistant to all drugs. We recommend re-examining restriction of specific drugs, when multiple resistance to the relevant alternative drugs already exists.

  19. Alleviating Cancer Drug Toxicity by Inhibiting a Bacterial Enzyme

    SciTech Connect

    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.

    2011-08-12

    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.

  20. Bacterial resistance to antibodies: a model evolutionary study.

    PubMed

    Schulman, Lawrence S

    2017-03-21

    The tangled nature model of evolution (reviewed in the main text) is adapted for use in the study of antibody resistance acquired by horizontal gene transfer. Exchanges of DNA and the acquisition of resistant gene sequences are considered. For the parameters used, resistant strains rapidly proliferate and dominate, although initial intense antibiotic treatment can occasionally prevent this. Variation in genome distribution appears to be long tailed. If this is reflected in nature, the occurrence of resistant bacterial strains can be expected, as well as considerable variation in patient outcomes.

  1. Malaria epidemic and drug resistance, Djibouti.

    PubMed

    Rogier, Christophe; Pradines, Bruno; Bogreau, H; Koeck, Jean-Louis; Kamil, Mohamed-Ali; Mercereau-Puijalon, Odile

    2005-02-01

    Analysis of Plasmodium falciparum isolates collected before, during, and after a 1999 malaria epidemic in Djibouti shows that, despite a high prevalence of resistance to chloroquine, the epidemic cannot be attributed to a sudden increase in drug resistance of local parasite populations.

  2. Evolution of antibiotic resistance by human and bacterial niche construction.

    PubMed

    Boni, Maciej F; Feldman, Marcus W

    2005-03-01

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

  3. Antibiotic Adjuvants: Diverse Strategies for Controlling Drug-Resistant Pathogens

    PubMed Central

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

    2015-01-01

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

  4. Alternatives to overcoming bacterial resistances: State-of-the-art.

    PubMed

    Rios, Alessandra C; Moutinho, Carla G; Pinto, Flávio C; Del Fiol, Fernando S; Jozala, Angela; Chaud, Marco V; Vila, Marta M D C; Teixeira, José A; Balcão, Victor M

    2016-10-01

    Worldwide, bacterial resistance to chemical antibiotics has reached such a high level that endangers public health. Presently, the adoption of alternative strategies that promote the elimination of resistant microbial strains from the environment is of utmost importance. This review discusses and analyses several (potential) alternative strategies to current chemical antibiotics. Bacteriophage (or phage) therapy, although not new, makes use of strictly lytic phage particles as an alternative, or a complement, in the antimicrobial treatment of bacterial infections. It is being rediscovered as a safe method, because these biological entities devoid of any metabolic machinery do not possess any affinity whatsoever to eukaryotic cells. Lysin therapy is also recognized as an innovative antimicrobial therapeutic option, since the topical administration of preparations containing purified recombinant lysins with amounts in the order of nanograms, in infections caused by Gram-positive bacteria, demonstrated a high therapeutic potential by causing immediate lysis of the target bacterial cells. Additionally, this therapy exhibits the potential to act synergistically when combined with certain chemical antibiotics already available on the market. Another potential alternative antimicrobial therapy is based on the use of antimicrobial peptides (AMPs), amphiphilic polypeptides that cause disruption of the bacterial membrane and can be used in the treatment of bacterial, fungal and viral infections, in the prevention of biofilm formation, and as antitumoral agents. Interestingly, bacteriocins are a common strategy of bacterial defense against other bacterial agents, eliminating the potential opponents of the former and increasing the number of available nutrients in the environment for their own growth. They can be applied in the food industry as biopreservatives and as probiotics, and also in fighting multi-resistant bacterial strains. The use of antibacterial antibodies

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

    PubMed

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

    2015-08-16

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

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

    PubMed Central

    Labby, Kristin J; Garneau-Tsodikova, Sylvie

    2013-01-01

    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

  7. Antiplaque biocides and bacterial resistance: a review.

    PubMed

    Sreenivasan, Prem; Gaffar, Abdul

    2002-11-01

    Modern dentistry emphasizes the importance of dental plaque control to improve oral health. The use of oral care formulations with antiplaque biocides plays a crucial role in patient-directed approaches for plaque control. The antiplaque efficacies of these formulations have been extensively studied in many long-term clinical studies designed in accordance with well-accepted guidelines. The results from these studies conclusively demonstrate that long-term use of oral care formulations with well-known antiplaque biocides such as chlorhexidine and triclosan reduce supragingival plaque and gingivitis. This review summarizes microbiological results from clinical studies conducted with oral care formulations containing antiplaque biocides. Results from a number of long-term clinical studies conducted under real-life use conditions indicate no adverse alterations in the bacteria found in dental plaque or emergent microbial resistance. Additionally, microbial sampling of dental plaque subsequent to extended use of antiplaque biocides reveals no increase in resistant microflora. Large numbers of common oral bacteria isolated from patients using chlorhexidine indicate no increase in microbial resistance to chlorhexidine or to commonly used antibiotics. The effects of antiplaque biocides containing oral care formulations on dental plaque that exists naturally as a biofilm are examined. These formulations contain biocide, surfactants, polymers and other components that are effective against the biofilm. In summary, the results of studies on the real-life use of oral care formulations with antiplaque biocides show no emergence of resistant microflora or alterations of the oral microbiota, while such formulations have been found to provide the benefits of reducing plaque and gingivitis.

  8. Bacterial ghosts as drug carrier and targeting vehicles.

    PubMed

    Huter, V; Szostak, M P; Gampfer, J; Prethaler, S; Wanner, G; Gabor, F; Lubitz, W

    1999-08-27

    A novel system for the packaging of drugs as well as vaccines is presented. Bacterial ghosts are intact, non-denatured bacterial envelopes that are created by lysis of bacteria through the expression of cloned phage PhiX174 gene E. Inhibition of induced E-mediated lysis by MgSO(4), harvesting of cells by centrifugation, and resuspension in low-ionic-strength buffers leads to rapid, violent lysis and results in empty bacterial envelopes with large (approximately 1 microm in diameter) openings. The construction of plasmid pAV1, which encodes a streptavidin fusion protein with an N-terminal membrane anchor sequence, allows the loading of the inner side of the cytoplasmic membrane with streptavidin. The functionality and efficacy of binding of even large biotinylated compounds in such streptavidin ghosts (SA-ghosts) was assessed using the enzyme alkaline phosphatase. The successful binding of biotinylated fluorescent dextran, as well as fluorescent DNA complexed with biotinylated polylysine, was demonstrated microscopically. The display by bacterial ghosts of morphological and antigenic surface structures of their living counterparts permits their attachment to target tissues such as the mucosal surfaces of the gastrointestinal and respiratory tract, and their uptake by phagocytes and M cells. In consequence, SA-ghosts are proposed as drug carriers for site-specific drug delivery.

  9. Repurposing non-antimicrobial drugs and clinical molecules to treat bacterial infections

    PubMed Central

    Younis, Waleed; Thangamani, Shankar; Seleem, Mohamed N.

    2015-01-01

    There is a pressing need to develop novel antimicrobials to circumvent the scourge of antimicrobial resistance. The objective of this study is to identify non-antibiotic drugs with potent antimicrobial activity, within an applicable clinical range. A library, containing 727 FDA approved drugs and small molecules, was screened against ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae). Drugs that showed antimicrobial activity in an applicable clinical range were further tested in vitro and in vivo in an infected mouse model. The initial screening identified 24 non-antibiotic drugs and clinical molecules active against Gram-positive pathogens including methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococcus (VRE) isolates. Two non-antibiotic drugs showed activity against Gram-negative pathogens. Among the active non-antibiotic drugs, only ebselen (EB) and 5-fluoro-2′-deoxyuridine (FdUrd), showed bactericidal activity, in an applicable clinical range, against multi-drug-resistant Staphylococcus isolates including MRSA, vancomycin-resistant S. aureus (VRSA), and vancomycin-intermediate S. aureus (VISA). The minimum inhibitory concentration at which 90% of clinical isolates of S. aureus were inhibited (MIC90) was found to be 0.25 and 0.0039 mg/L for EB and FdUrd, respectively. Treatment with EB orally significantly increased mice survival in a lethal model of septicemic MRSA-infection by (60%) compared to that of control. FdUrd oral and intraperitoneal treatment significantly enhanced mouse survival by 60% and 100%, respectively. These data encourage screening and repurposing of non-antibiotic drugs and clinical molecules to treat multidrug-resistant bacterial infections. PMID:25961308

  10. Detection of bacterial blight resistance genes in basmati rice landraces.

    PubMed

    Ullah, I; Jamil, S; Iqbal, M Z; Shaheen, H L; Hasni, S M; Jabeen, S; Mehmood, A; Akhter, M

    2012-07-20

    Aromatic basmati rice is vulnerable to bacterial blight disease. Genes conferring resistance to bacterial blight have been identified in coarse rice; however, their incorporation into basmati varieties compromises the prized basmati aroma. We identified bacterial blight resistance genes Xa4, xa5, Xa7, and xa13 in 52 basmati landraces and five basmati cultivars using PCR markers. The Xa7 gene was found to be the most prevalent among the cultivars and landraces. The cultivars Basmati-385 and Basmati-2000 also contained the Xa4 gene; however, xa5 and xa13 were confined to landraces only. Ten landraces were found to have multiple resistance genes. Landraces Basmati-106, Basmati-189 and Basmati-208 contained Xa4 and Xa7 genes. Whereas, landraces Basmati-122, Basmati-427, Basmati-433 were observed to have xa5 and Xa7 genes. Landraces Basmati-48, Basmati-51A, Basmati-334, and Basmati-370A possessed Xa7 and xa13 genes. The use of landraces containing recessive genes xa5 and xa13 as donor parents in hybridization with cultivars Basmati-385 and Basmati-2000, which contain the genes Xa4 and Xa7, will expedite efforts to develop bacterial blight-resistant basmati rice cultivars through marker assisted selection, based on a pyramiding approach, without compromising aroma and grain quality.

  11. Genetics and breeding of bacterial leaf spot resistance

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial leaf spot (BLS) caused by the pathogen Xanthomonas campestris pv. vitians (Xcv) is a globally important disease of whole head and baby leaf lettuce that reduces crop yield and quality. Host resistance is the most feasible method to reduce disease losses. Screening Lactuca accessions has id...

  12. Drug-resistant Neisseria gonorrhoeae: latest developments.

    PubMed

    Suay-García, B; Pérez-Gracia, M T

    2017-02-16

    Gonorrhea is the second most frequently reported notifiable disease in the United States and is becoming increasingly common in Europe. The purpose of this review was to assess the current state of drug-resistant Neisseria gonorrhoeae in order to evaluate future prospects for its treatment. An exhaustive literature search was conducted to include the latest research regarding drug resistance and treatment guidelines for gonorrhea. Gonococci have acquired all known resistance mechanisms to all antimicrobials used for treatment. Currently, the European Union, the United States, and the United Kingdom have established surveillance programs to assess, on a yearly basis, the development of gonococcal resistance. Current treatment guidelines are being threatened by the increasing number of ceftriaxone-, cefixime-, and azithromycin-resistant N. gonorrhoeae strains being detected worldwide. This has led the scientific community to develop new treatment options with new molecules in order to persevere in the battle against this "superbug".

  13. Test for bacterial resistance build-up against plasma treatment

    NASA Astrophysics Data System (ADS)

    Zimmermann, J. L.; Shimizu, T.; Schmidt, H.-U.; Li, Y.-F.; Morfill, G. E.; Isbary, G.

    2012-07-01

    It is well known that the evolution of resistance of microorganisms to a range of different antibiotics presents a major problem in the control of infectious diseases. Accordingly, new bactericidal ‘agents’ are in great demand. Using a cold atmospheric pressure (CAP) plasma dispenser operated with ambient air, a more than five orders of magnitude inactivation or reduction of Methicillin-resistant Staphylococcus aureus (MRSA; resistant against a large number of the tested antibiotics) was obtained in less than 10 s. This makes CAP the most promising candidate for combating nosocomial (hospital-induced) infections. To test for the occurrence and development of bacterial resistance against such plasmas, experiments with Gram-negative bacteria (Escherichia coli) and Gram-positive bacteria (Enterococcus mundtii) were performed. The aim was to determine quantitative limits for primary (naturally) or secondary (acquired) resistance against the plasma treatment. Our results show that E. coli and E. mundtii possess no primary resistance against the plasma treatment. By generating four generations of bacteria for every strain, where the survivors of the plasma treatment were used for the production of the next generation, a lower limit to secondary resistance was obtained. Our results indicate that CAP technology could contribute to the control of infections in hospitals, in outpatient care and in disaster situations, providing a new, fast and efficient broad-band disinfection technology that is not constrained by bacterial resistance mechanisms.

  14. Persistence and resistance as complementary bacterial adaptations to antibiotics.

    PubMed

    Vogwill, T; Comfort, A C; Furió, V; MacLean, R C

    2016-06-01

    Bacterial persistence represents a simple of phenotypic heterogeneity, whereby a proportion of cells in an isogenic bacterial population can survive exposure to lethal stresses such as antibiotics. In contrast, genetically based antibiotic resistance allows for continued growth in the presence of antibiotics. It is unclear, however, whether resistance and persistence are complementary or alternative evolutionary adaptations to antibiotics. Here, we investigate the co-evolution of resistance and persistence across the genus Pseudomonas using comparative methods that correct for phylogenetic nonindependence. We find that strains of Pseudomonas vary extensively in both their intrinsic resistance to antibiotics (ciprofloxacin and rifampicin) and persistence following exposure to these antibiotics. Crucially, we find that persistence correlates positively to antibiotic resistance across strains. However, we find that different genes control resistance and persistence implying that they are independent traits. Specifically, we find that the number of type II toxin-antitoxin systems (TAs) in the genome of a strain is correlated to persistence, but not resistance. Our study shows that persistence and antibiotic resistance are complementary, but independent, evolutionary adaptations to stress and it highlights the key role played by TAs in the evolution of persistence.

  15. CancerDR: cancer drug resistance database.

    PubMed

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

    2013-01-01

    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 http://crdd.osdd.net/raghava/cancerdr/

  16. Drug targeting of leptin resistance.

    PubMed

    Santoro, Anna; Mattace Raso, Giuseppina; Meli, Rosaria

    2015-11-01

    Leptin regulates glucose, lipid and energy homeostasis as well as feeding behavior, serving as a bridge between peripheral metabolically active tissues and the central nervous system (CNS). Indeed, this adipocyte-derived hormone, whose circulating levels mirror fat mass, not only exerts its anti-obesity effects mainly modulating the activity of specific hypothalamic neurons expressing the long form of the leptin receptor (Ob-Rb), but it also shows pleiotropic functions due to the activation of Ob-Rb in peripheral tissues. Nevertheless, several mechanisms have been suggested to mediate leptin resistance, including obesity-associated hyperleptinemia, impairment of leptin access to CNS and the reduction in Ob-Rb signal transduction effectiveness, among others. During the onset and progression of obesity, the dampening of leptin sensitivity often occurs, preventing the efficacy of leptin replacement therapy from overcoming obesity and/or its comorbidities. This review focuses on obesity-associated leptin resistance and the mechanisms underpinning this condition, to highlight the relevance of leptin sensitivity restoration as a useful therapeutic strategy to treat common obesity and its complications. Interestingly, although promising strategies to counteract leptin resistance have been proposed, these pharmacological approaches have shown limited efficacy or even relevant adverse effects in preclinical and clinical studies. Therefore, the numerous findings from this review clearly indicate a lack of a single and efficacious treatment for leptin resistance, highlighting the necessity to find new therapeutic tools to improve leptin sensitivity, especially in patients with most severe disease profiles.

  17. Drug-resistant tuberculosis: an insurmountable epidemic?

    PubMed

    Chakroborty, Amitabha

    2011-06-01

    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.

  18. Chemotherapy of drug-resistant malaria

    PubMed Central

    Kain, Kevin C

    1996-01-01

    OBJECTIVE: To review the impact of drug-resistant malaria on current management of plasmodial infections. DATA SOURCES: A MEDLINE search of the English-language medical literature from 1985 to 1995; bibliographies of selected papers; international malaria advisory experts. DATA SYNTHESIS: Combinations of artemisinin derivatives and mefloquine or atovaquone plus proguanil appear to be the most active drug regimens against multidrug-resistant falciparum malaria from Southeast Asia. The optimal therapy for chloroquine-resistant Plasmodium vivax is unknown, but recent data indicate that halofantrine or chloroquine plus high doses of primaquine are efficacious. CONCLUSIONS: The incidence of drug-resistant malaria continues to increase at a rate that exceeds new drug development. Ultimately the control of malaria will require more creative approaches than just the development of additional inhibitory drugs. These might include the identification of biochemical pathways unique to the parasite (such as drug efflux and heme polymerization), making it possible to design new classes of antimalarial agents that are selectively toxic to the parasite; methods to block parasite development in the mosquito vector; and multistage vaccines against asexual and sexual stages to block both the pathophysiology and the transmission of disease. PMID:22514413

  19. Cooperative Bacterial Growth Dynamics Predict the Evolution of Antibiotic Resistance

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  20. Resistance to antibiotics targeted to the bacterial cell wall.

    PubMed

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

    2014-03-01

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

  1. Erythromycin resistance by L4/L22 mutations and resistance masking by drug efflux pump deficiency

    PubMed Central

    Lovmar, Martin; Nilsson, Karin; Lukk, Eliisa; Vimberg, Vladimir; Tenson, Tanel; Ehrenberg, Måns

    2009-01-01

    We characterized the effects of classical erythromycin resistance mutations in ribosomal proteins L4 and L22 of the large ribosomal subunit on the kinetics of erythromycin binding. Our data are consistent with a mechanism in which the macrolide erythromycin enters and exits the ribosome through the nascent peptide exit tunnel, and suggest that these mutations both impair passive transport through the tunnel and distort the erythromycin-binding site. The growth-inhibitory action of erythromycin was characterized for bacterial populations with wild-type and L22-mutated ribosomes in drug efflux pump deficient and proficient backgrounds. The L22 mutation conferred reduced erythromycin susceptibility in the drug efflux pump proficient, but not deficient, background. This ‘masking' of drug resistance by pump deficiency was reproduced by modelling with input data from our biochemical experiments. We discuss the general principles behind the phenomenon of drug resistance ‘masking', and highlight its potential importance for slowing down the evolution of drug resistance among pathogens. PMID:19197244

  2. Phylogenetic Sequence Variations in Bacterial rRNA Affect Species-Specific Susceptibility to Drugs Targeting Protein Synthesis▿‡

    PubMed Central

    Akshay, Subramanian; Bertea, Mihai; Hobbie, Sven N.; Oettinghaus, Björn; Shcherbakov, Dimitri; Böttger, Erik C.; Akbergenov, Rashid

    2011-01-01

    Antibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences in Mycobacterium smegmatis ribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket. PMID:21730122

  3. Antifungal drug resistance to azoles and polyenes.

    PubMed

    Masiá Canuto, Mar; Gutiérrez Rodero, Félix

    2002-09-01

    There is an increased awareness of the morbidity and mortality associated with fungal infections caused by resistant fungi in various groups of patients. Epidemiological studies have identified risk factors associated with antifungal drug resistance. Selection pressure due to the continuous exposure to azoles seems to have an essential role in developing resistance to fluconazole in Candida species. Haematological malignancies, especially acute leukaemia with severe and prolonged neutropenia, seem to be the main risk factors for acquiring deep-seated mycosis caused by resistant filamentous fungi, such us Fusarium species, Scedosporium prolificans, and Aspergillus terreus. The still unacceptably high mortality rate associated with some resistant mycosis indicates that alternatives to existing therapeutic options are needed. Potential measures to overcome antifungal resistance ranges from the development of new drugs with better antifungal activity to improving current therapeutic strategies with the present antifungal agents. Among the new antifungal drugs, inhibitors of beta glucan synthesis and second-generation azole and triazole derivatives have characteristics that render them potentially suitable agents against some resistant fungi. Other strategies including the use of high doses of lipid formulations of amphotericin B, combination therapy, and adjunctive immune therapy with cytokines are under investigation. In addition, antifungal control programmes to prevent extensive and inappropriate use of antifungals may be needed.

  4. [Effect of Three Typical Disinfection Byproducts on Bacterial Antibiotic Resistance].

    PubMed

    Lü, Lu; Zhang, Meng-lu; Wang, Chun-ming; Lin, Hui-rong; Yu, Xin

    2015-07-01

    The effect of typical disinfection byproducts (DBPs) on bacterial antibiotic resistance was investigated in this study. chlorodibromomethane (CDBM), iodoacetic acid (IAA) and chloral hydrate (CH) were selected, which belong to trihalomethanes (THMs), haloacetic acids (HAAs) and aldehydes, respectively. After exposure to the selected DBPs, the resistance change of the tested strains to antibiotics was determined. As a result, all of the three DBPs induced Pseudomonas aeruginosa PAO1 to gain increased resistance to the five antibiotics tested, and the DBPs ranked as IAA > CH > CDBM according to their enhancement effects. Multidrug resistance could also be enhanced by treatment with IAA. The same result was observed in Escherichia coli K12, suggesting that the effect of DBPs on antibiotic resistance was a common phenomenon. The mechanism was probably that DBPs stimulated oxidative stress, which induced mutagenesis. And the antibiotic resistance mutation frequency could be increased along with mutagenesis. This study revealed that the acquisition of bacterial antibiotic resistance might be related to DBPs in drinking water systems. Besides the genotoxicological risks, the epidemiological risks of DBPs should not be overlooked.

  5. Drug-resistant tuberculosis: emerging treatment options

    PubMed Central

    Adhvaryu, Meghna; Vakharia, Bhasker

    2011-01-01

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

  6. The drinking water treatment process as a potential source of affecting the bacterial antibiotic resistance.

    PubMed

    Bai, Xiaohui; Ma, Xiaolin; Xu, Fengming; Li, Jing; Zhang, Hang; Xiao, Xiang

    2015-11-15

    Two waterworks, with source water derived from the Huangpu or Yangtze River in Shanghai, were investigated, and the effluents were plate-screened for antibiotic-resistant bacteria (ARB) using five antibiotics: ampicillin (AMP), kanamycin (KAN), rifampicin (RFP), chloramphenicol (CM) and streptomycin (STR). The influence of water treatment procedures on the bacterial antibiotic resistance rate and the changes that bacteria underwent when exposed to the five antibiotics at concentration levels ranging from 1 to 100 μg/mL were studied. Multi-drug resistance was also analyzed using drug sensitivity tests. The results indicated that bacteria derived from water treatment plant effluent that used the Huangpu River rather than the Yangtze River as source water exhibited higher antibiotic resistance rates against AMP, STR, RFP and CM but lower antibiotic resistance rates against KAN. When the antibiotic concentration levels ranged from 1 to 10 μg/mL, the antibiotic resistance rates of the bacteria in the water increased as water treatment progressed. Biological activated carbon (BAC) filtration played a key role in increasing the antibiotic resistance rate of bacteria. Chloramine disinfection can enhance antibiotic resistance. Among the isolated ARB, 75% were resistant to multiple antibiotics. Ozone oxidation, BAC filtration and chloramine disinfection can greatly affect the relative abundance of bacteria in the community.

  7. Mechanisms of Drug Resistance in Plasmodium Falciparum

    DTIC Science & Technology

    1994-06-14

    major threat to world health. Efforts to control the disease have focused on chemotherapy, mosquito control and most recently vaccine development. These...resistant mosquitoes and upheavals in spraying programs and the complicated problems of vaccine development and testing. The world is facing an...development of vaccines for several important bacterial pathogens. The malaria parasite presents a unique challenge for transfection in that it is

  8. Bacterial resistance to Quaternary Ammonium Compounds (QAC) disinfectants.

    PubMed

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

    2014-01-01

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

  9. Bacterial resistance to arsenic protects against protist killing.

    PubMed

    Hao, Xiuli; Li, Xuanji; Pal, Chandan; Hobman, Jon; Larsson, D G Joakim; Saquib, Quaiser; Alwathnani, Hend A; Rosen, Barry P; Zhu, Yong-Guan; Rensing, Christopher

    2017-04-01

    Protists kill their bacterial prey using toxic metals such as copper. Here we hypothesize that the metalloid arsenic has a similar role. To test this hypothesis, we examined intracellular survival of Escherichia coli (E. coli) in the amoeba Dictyostelium discoideum (D. discoideum). Deletion of the E. coli ars operon led to significantly lower intracellular survival compared to wild type E. coli. This suggests that protists use arsenic to poison bacterial cells in the phagosome, similar to their use of copper. In response to copper and arsenic poisoning by protists, there is selection for acquisition of arsenic and copper resistance genes in the bacterial prey to avoid killing. In agreement with this hypothesis, both copper and arsenic resistance determinants are widespread in many bacterial taxa and environments, and they are often found together on plasmids. A role for heavy metals and arsenic in the ancient predator-prey relationship between protists and bacteria could explain the widespread presence of metal resistance determinants in pristine environments.

  10. Synthesis and evaluation of inhibitors of bacterial drug efflux pumps of the major facilitator superfamily.

    PubMed

    Okandeji, Babajide O; Greenwald, Daniel M; Wroten, Jessica; Sello, Jason K

    2011-12-15

    Inhibitors of drug efflux pumps have great potential as pharmacological agents that restore the drug susceptibility of multidrug resistant bacterial pathogens. Most attention has been focused on the discovery of small molecules that inhibit the resistance nodulation division (RND) family drug efflux pumps in Gram-negative bacteria. The prototypical inhibitor of RND-family efflux pumps in Gram-negative bacteria is MC-207,110 (Phe-Arg-β-naphthylamide), a C-capped dipeptide. Here, we report that C-capped dipeptides inhibit two chloramphenicol-specific efflux pumps in Streptomyces coelicolor, a Gram-positive bacterium that is a relative of the human pathogen Mycobacterium tuberculosis. Diversity-oriented synthesis of a library of structurally related C-capped dipeptides via an Ugi four component reaction and screening of the resulting compounds resulted in the discovery of a compound that is threefold more potent as a suppressor of chloramphenicol resistance in S. coelicolor than MC-207,110. Since chloramphenicol resistance in S. coelicolor is mediated by major facilitator superfamily drug efflux pumps, our findings provide the first evidence that C-capped dipeptides can inhibit drug efflux pumps outside of the RND superfamily.

  11. Essential Oils, A New Horizon in Combating Bacterial Antibiotic Resistance

    PubMed Central

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

    2014-01-01

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

  12. Drug resistance confounding prion therapeutics

    PubMed Central

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

    2013-01-01

    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

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

    EPA Science Inventory

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

  14. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    DTIC Science & Technology

    2013-08-01

    vesicular stomatitis virus (VSV) can exert a dual antitumor effect by triggering direct tumor lysis and eliciting tumor specific immunity. VSV can also...tumors, and the levels of infiltrating leukocytes were similar across the VSV-treated tumors. Altogether the data indicate that VSV-based therapy is...effective against a cisplatin-resistant lung tumor model. 15. SUBJECT TERMS Drug resistance, oncolytic virotherapy, vesicular stomatitis virus, lung

  15. Environment-Mediated Drug Resistance in Neuroblastoma

    DTIC Science & Technology

    2013-10-01

    Neuroblastoma PRINCIPAL INVESTIGATOR: Yves A. DeClerck, MD CONTRACTING ORGANIZATION: Children’s Hospital Los Angeles Los Angeles, CA...3. DATES COVERED 30September2012 – 29September2013 4. TITLE AND SUBTITLE Environment-Mediated Drug Resistance in Neuroblastoma 5a. CONTRACT...demonstrating that interleukin-6 protects neuroblastoma cells from drug-induced apoptosis via activation of signal transduction and activator of

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

    PubMed

    Bodoev, I N; Il'ina, E N

    2015-01-01

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

  17. Virologic Tools for HCV Drug Resistance Testing

    PubMed Central

    Fourati, Slim; Pawlotsky, Jean-Michel

    2015-01-01

    Recent advances in molecular biology have led to the development of new antiviral drugs that target specific steps of the Hepatitis C Virus (HCV) lifecycle. These drugs, collectively termed direct-acting antivirals (DAAs), include non-structural (NS) HCV protein inhibitors, NS3/4A protease inhibitors, NS5B RNA-dependent RNA polymerase inhibitors (nucleotide analogues and non-nucleoside inhibitors), and NS5A inhibitors. Due to the high genetic variability of HCV, the outcome of DAA-based therapies may be altered by the selection of amino-acid substitutions located within the targeted proteins, which affect viral susceptibility to the administered compounds. At the drug developmental stage, preclinical and clinical characterization of HCV resistance to new drugs in development is mandatory. In the clinical setting, accurate diagnostic tools have become available to monitor drug resistance in patients who receive treatment with DAAs. In this review, we describe tools available to investigate drug resistance in preclinical studies, clinical trials and clinical practice. PMID:26690198

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

    SciTech Connect

    Hoelzel, Christina S.; Mueller, Christa; Harms, Katrin S.; Mikolajewski, Sabine; Schaefer, Stefanie; Schwaiger, Karin; Bauer, Johann

    2012-02-15

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

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

    PubMed

    Hölzel, Christina S; Müller, Christa; Harms, Katrin S; Mikolajewski, Sabine; Schäfer, Stefanie; Schwaiger, Karin; Bauer, Johann

    2012-02-01

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

  20. Drug resistance in human African trypanosomiasis.

    PubMed

    Barrett, Michael P; Vincent, Isabel M; Burchmore, Richard J S; Kazibwe, Anne J N; Matovu, Enock

    2011-09-01

    Human African trypanosomiasis or 'sleeping sickness' is a neglected tropical disease caused by the parasite Trypanosoma brucei. A decade of intense international cooperation has brought the incidence to fewer than 10,000 reported cases per annum with anti-trypanosomal drugs, particularly against stage 2 disease where the CNS is involved, being central to control. Treatment failures with melarsoprol started to appear in the 1990s and their incidence has risen sharply in many foci. Loss of plasma membrane transporters involved in drug uptake, particularly the P2 aminopurine transporter and also a transporter termed the high affinity pentamidine transporter, relate to melarsoprol resistance selected in the laboratory. The same two transporters are also responsible for the uptake of the stage 1 drug pentamidine and, to varying extents, other diamidines. However, reports of treatment failures with pentamidine have been rare from the field. Eflornithine (difluoromethylornithine) has replaced melarsoprol as first-line treatment in many regions. However, a need for protracted and complicated drug dosing regimens slowed widespread implementation of eflornithine monotherapy. A combination of eflornithine with nifurtimox substantially decreases the required dose and duration of eflornithine administration and this nifurtimox-eflornithine combination therapy has enjoyed rapid implementation. Unfortunately, selection of resistance to eflornithine in the laboratory is relatively easy (through loss of an amino acid transporter believed to be involved in its uptake), as is selection of resistance to nifurtimox. The first anecdotal reports of treatment failures with eflornithine monotherapy are emerging from some foci. The possibility that parasites resistant to melarsoprol on the one hand, and eflornithine on the other, are present in the field indicates that genes capable of conferring drug resistance to both drugs are in circulation. If new drugs, that act in ways that will not

  1. Differential resistance of drinking water bacterial populations to monochloramine disinfection.

    PubMed

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

    2014-04-01

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

  2. Environment-Mediated Drug Resistance in Neuroblastoma

    DTIC Science & Technology

    2014-10-01

    Neuroblastoma PRINCIPAL INVESTIGATOR: Yves A. DeClerck CONTRACTING ORGANIZATION... Neuroblastoma 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-12-1-0571 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) DE CLERCK, YVES 5d. PROJECT...experiments have demonstrated that monocytes collaborate with MSC in inducing STAT3-dependent drug resistance in neuroblastoma . Further

  3. Population Dynamics of Patients with Bacterial Resistance in Hospital Environment

    PubMed Central

    Qu, Leilei; Pan, Qiuhui; Gao, Xubin; He, Mingfeng

    2016-01-01

    During the past decades, the increase of antibiotic resistance has become a major concern worldwide. The researchers found that superbugs with new type of resistance genes (NDM-1) have two aspects of transmission characteristics; the first is that the antibiotic resistance genes can horizontally transfer among bacteria, and the other is that the superbugs can spread between humans through direct contact. Based on these two transmission mechanisms, we study the dynamics of population in hospital environment where superbugs exist. In this paper, we build three mathematic models to illustrate the dynamics of patients with bacterial resistance in hospital environment. The models are analyzed using stability theory of differential equations. Positive equilibrium points of the system are investigated and their stability analysis is carried out. Moreover, the numerical simulation of the proposed model is also performed which supports the theoretical findings. PMID:26904150

  4. Population Dynamics of Patients with Bacterial Resistance in Hospital Environment.

    PubMed

    Qu, Leilei; Pan, Qiuhui; Gao, Xubin; He, Mingfeng

    2016-01-01

    During the past decades, the increase of antibiotic resistance has become a major concern worldwide. The researchers found that superbugs with new type of resistance genes (NDM-1) have two aspects of transmission characteristics; the first is that the antibiotic resistance genes can horizontally transfer among bacteria, and the other is that the superbugs can spread between humans through direct contact. Based on these two transmission mechanisms, we study the dynamics of population in hospital environment where superbugs exist. In this paper, we build three mathematic models to illustrate the dynamics of patients with bacterial resistance in hospital environment. The models are analyzed using stability theory of differential equations. Positive equilibrium points of the system are investigated and their stability analysis is carried out. Moreover, the numerical simulation of the proposed model is also performed which supports the theoretical findings.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2012-04-01

    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.

  7. Screening Rice Cultivars for Resistance to Bacterial Leaf Blight.

    PubMed

    Fred, Agaba Kayihura; Kiswara, Gilang; Yi, Gihwan; Kim, Kyung-Min

    2016-05-28

    Bacterial leaf blight (BLB) caused by Xanthomonas oryzae pv. oryzae (Xoo) is one of the most serious threats to rice production. In this study, screening of rice for resistance to BLB was carried out at two different times and locations; that is, in a greenhouse during winter and in an open field during summer. The pathogenicity of Xoo race K1 was tested on 32 Korean rice cultivars. Inoculation was conducted at the maximum tillering stage, and the lesion length was measured after 14 days of inoculation. Five cultivars, Hanareum, Namcheon, Samgdeok, Samgang, and Yangjo, were found to be resistant in both the greenhouse and open-field screenings. Expression of the plant defense-related genes JAmyb, OsNPR1, OsPR1a, OsWRKY45, and OsPR10b was observed in resistant and susceptible cultivars by qRT-PCR. Among the five genes tested, only OsPR10b showed coherent expression with the phenotypes. Screening of resistance to Xoo in rice was more accurate when conducted in open fields in the summer cultivation period than in greenhouses in winter. The expression of plant defenserelated genes after bacterial inoculation could give another perspective in elucidating defense mechanisms by using both resistant and susceptible individuals.

  8. Absence of bacterial resistance following repeat exposure to photodynamic therapy

    NASA Astrophysics Data System (ADS)

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

    2009-06-01

    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.

  9. Different drugs for bad bugs: antivirulence strategies in the age of antibiotic resistance.

    PubMed

    Dickey, Seth W; Cheung, Gordon Y C; Otto, Michael

    2017-03-24

    The rapid evolution and dissemination of antibiotic resistance among bacterial pathogens are outpacing the development of new antibiotics, but antivirulence agents provide an alternative. These agents can circumvent antibiotic resistance by disarming pathogens of virulence factors that facilitate human disease while leaving bacterial growth pathways - the target of traditional antibiotics - intact. Either as stand-alone medications or together with antibiotics, these drugs are intended to treat bacterial infections in a largely pathogen-specific manner. Notably, development of antivirulence drugs requires an in-depth understanding of the roles that diverse virulence factors have in disease processes. In this Review, we outline the theory behind antivirulence strategies and provide examples of bacterial features that can be targeted by antivirulence approaches. Furthermore, we discuss the recent successes and failures of this paradigm, and new developments that are in the pipeline.

  10. Bacterial Transcription as a Target for Antibacterial Drug Development.

    PubMed

    Ma, Cong; Yang, Xiao; Lewis, Peter J

    2016-03-01

    Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design.

  11. Bacterial Transcription as a Target for Antibacterial Drug Development

    PubMed Central

    Ma, Cong; Yang, Xiao

    2016-01-01

    SUMMARY Transcription, the first step of gene expression, is carried out by the enzyme RNA polymerase (RNAP) and is regulated through interaction with a series of protein transcription factors. RNAP and its associated transcription factors are highly conserved across the bacterial domain and represent excellent targets for broad-spectrum antibacterial agent discovery. Despite the numerous antibiotics on the market, there are only two series currently approved that target transcription. The determination of the three-dimensional structures of RNAP and transcription complexes at high resolution over the last 15 years has led to renewed interest in targeting this essential process for antibiotic development by utilizing rational structure-based approaches. In this review, we describe the inhibition of the bacterial transcription process with respect to structural studies of RNAP, highlight recent progress toward the discovery of novel transcription inhibitors, and suggest additional potential antibacterial targets for rational drug design. PMID:26764017

  12. Membrane permeabilization of colistin toward pan-drug resistant Gram-negative isolates.

    PubMed

    Mohamed, Yasmine Fathy; Abou-Shleib, Hamida Moustafa; Khalil, Amal Mohamed; El-Guink, Nadia Mohamed; El-Nakeeb, Moustafa Ahmed

    2016-01-01

    Pan-drug resistant Gram-negative bacteria, being resistant to most available antibiotics, represent a huge threat to the medical community. Colistin is considered the last therapeutic option for patients in hospital settings. Thus, we were concerned in this study to demonstrate the membrane permeabilizing activity of colistin focusing on investigating its efficiency toward those pan-drug resistant isolates which represent a critical situation. We determined the killing dynamics of colistin against pan-drug resistant isolates. The permeability alteration was confirmed by different techniques as: leakage, electron microscopy and construction of an artificial membrane model; liposomes. Moreover, selectivity of colistin against microbial cells was also elucidated. Colistin was proved to be rapid bactericidal against pan-drug resistant isolates. It interacts with the outer bacterial membrane leading to deformation of its outline, pore formation, leakage of internal contents, cell lysis and finally death. Furthermore, variations in membrane composition of eukaryotic and microbial cells provide a key for colistin selectivity toward bacterial cells. Colistin selectively alters membrane permeability of pan-drug resistant isolates which leads to cell lysis. Colistin was proved to be an efficient last line treatment for pan-drug resistant infections which are hard to treat.

  13. Structural Studies of Bacterial Enzymes and their Relation to Antibiotic Resistance Mechanisms - Final Paper

    SciTech Connect

    Maltz, Lauren

    2015-08-27

    By using protein crystallography and X-ray diffraction, structures of bacterial enzymes were solved to gain a better understanding of how enzymatic modification acts as an antibacterial resistance mechanism. Aminoglycoside phosphotransferases (APHs) are one of three aminoglycoside modifying enzymes that confer resistance to the aminoglycoside antibiotics via enzymatic modification, rendering many drugs obsolete. Specifically, the APH(2”) family vary in their substrate specificities and also in their preference for the phosphate donor (ADP versus GDP). By solving the structures of members of the APH(2”) family of enzymes, we can see how domain movements are important to their substrate specificity. Our structure of the ternary complex of APH(2”)-IIIa with GDP and kanamycin, when compared to the known structures of APH(2”)-IVa, reveals that there are real physical differences between these two enzymes, a structural finding that explains why the two enzymes differ in their preferences for certain aminoglycosides. Another important group of bacterial resistance enzymes are the Class D β- lactamases. Oxacillinase carbapenemases (OXAs) are part of this enzyme class and have begun to confer resistance to ‘last resort’ drugs, most notably carbapenems. Our structure of OXA-143 shows that the conformational flexibility of a conserved hydrophobic residue in the active site (Val130) serves to control the entry of a transient water molecule responsible for a key step in the enzyme’s mechanism. Our results provide insight into the structural mechanisms of these two different enzymes

  14. In vitro assessment of antifungal drug resistance.

    PubMed

    Holmberg, K

    1986-01-01

    Several studies have documented the variability in the susceptibility pattern of fungi to antifungal drugs, and fungi possess resistance determinants to negate the effects of antifungal agents. In vitro assessment of both resistance and susceptibility are measured by suitable concentration endpoints of the antifungal drug, the minimal inhibitory concentration (MIC). MICs serve as the main parameter to define the fungistatic action on fungi growing in culture. For the antifungals used for treatment of local mycoses, the limit between a MIC value indicating susceptibility and one indicating resistance is usually determined empirically on the basis of the correlation between MIC values, and either positive or negative response to chemotherapy. The principles of susceptibility testing of fungi are essentially the same as those for bacteria. However, testing with fungi must deal with the fact that interpretation of the results is complicated by inherent differences in fungal morphology, growth rate, and optimal culture conditions. Several factors could adversely affect the test results and must be considered in the design of susceptibility testing of fungi. It is obvious when the present data on fungal susceptibility testing are reviewed that much more work on standardization of techniques and interpretation of results is necessary. This presentation will focus on the in vitro susceptibility testing for determining primary and secondary drug resistance of griseofulvin and azole antifungal agents, and the correlation between the activities of these antifungals in vitro and in vivo.

  15. Bacterial cheating limits the evolution of antibiotic resistance

    NASA Astrophysics Data System (ADS)

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

    2011-03-01

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

  16. Human Tuberculosis II. M. tuberculosis Mechanisms of Genetic and Phenotypic Resistance to Anti-Tuberculosis Drugs.

    PubMed

    Sgaragli, Giampietro; Frosini, Maria

    2016-01-01

    The great progress of knowledge of both M. tuberculosis physiology and how human host and bacilli interact has provided fertile ground for improving diagnosis and cure of TB infection. Once M. tuberculosis has infected humans, it elaborates strategies for evading the risk to killing by the cells of the host immune system and by the anti-tuberculosis (anti-TB) agents employed to cure infection. These strategies give rise to a bacterial multidrug resistance (MDR) status. This stems firstly from genetic mutations targeting a constellation of drug-processing mechanisms that still need full identification, as drug efflux pumps and drug activating/ inactivating enzymes (genetic resistance). Secondly, from the bacterial adaptation to stressful environmental conditions by adopting a temporary dormancy state lasting for decades and characterized by indifference to anti-TB drugs (phenotypic resistance or tolerance). The clarification of the strategies elaborated for surviving by M. tuberculosis has brought to the identification in the last few years of a number of mycobacterial molecular targets worth to exploitation for the development of novel and powerful anti-TB drugs. These targets include drug-efflux pump systems, considered partly responsible for genetic multi-drug resistance, and several enzymes and pump systems, as well, that sustain the metabolic adaptations of M. tuberculosis in the host and give rise to its phenotypic drug resistance.

  17. [The fight against bacterial resistance, a public health priority].

    PubMed

    Carlet, Jean

    2015-01-01

    The increase in the number of antibiotic resistant bacteria represents a major danger for the health of humans and animals. Combined with an almost complete absence of new antibiotics, it is one of the most alarming public health issues of our time. Measures must be taken in order to control the use of these drugs and safeguard their effectiveness.

  18. Fungal Biofilms, Drug Resistance, and Recurrent Infection

    PubMed Central

    Desai, Jigar V.; Mitchell, Aaron P.; Andes, David R.

    2014-01-01

    A biofilm is a surface-associated microbial community. Diverse fungi are capable of biofilm growth. The significance of this growth form for infection biology is that biofilm formation on implanted devices is a major cause of recurrent infection. Biofilms also have limited drug susceptibility, making device-associated infection extremely difficult to treat. Biofilm-like growth can occur during many kinds of infection, even when an implanted device is not present. Here we summarize the current understanding of fungal biofilm formation, its genetic control, and the basis for biofilm drug resistance. PMID:25274758

  19. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia.

    PubMed

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry.

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

    PubMed

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

    2011-10-01

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

  1. European recommendations on surveillance of antituberculosis drug resistance.

    PubMed

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

    2000-10-01

    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

  2. DDTRP: Database of Drug Targets for Resistant Pathogens

    PubMed Central

    Sundaramurthi, Jagadish Chandrabose; Ramanandan, Prabhakaran; Brindha, Sridharan; Subhasree, Chelladurai Ramarathnam; Prasad, Abhimanyu; Kumaraswami, Vasanthapuram; Hanna, Luke Elizabeth

    2011-01-01

    Emergence of drug resistance is a major threat to public health. Many pathogens have developed resistance to most of the existing antibiotics, and multidrug-resistant and extensively drug resistant strains are extremely difficult to treat. This has resulted in an urgent need for novel drugs. We describe a database called ‘Database of Drug Targets for Resistant Pathogens’ (DDTRP). The database contains information on drugs with reported resistance, their respective targets, metabolic pathways involving these targets, and a list of potential alternate targets for seven pathogens. The database can be accessed freely at http://bmi.icmr.org.in/DDTRP. PMID:21938213

  3. Antibiotic discovery: combatting bacterial resistance in cells and in biofilm communities.

    PubMed

    Penesyan, Anahit; Gillings, Michael; Paulsen, Ian T

    2015-03-24

    Bacterial resistance is a rapidly escalating threat to public health as our arsenal of effective antibiotics dwindles. Therefore, there is an urgent need for new antibiotics. Drug discovery has historically focused on bacteria growing in planktonic cultures. Many antibiotics were originally developed to target individual bacterial cells, being assessed in vitro against microorganisms in a planktonic mode of life. However, towards the end of the 20th century it became clear that many bacteria live as complex communities called biofilms in their natural habitat, and this includes habitats within a human host. The biofilm mode of life provides advantages to microorganisms, such as enhanced resistance towards environmental stresses, including antibiotic challenge. The community level resistance provided by biofilms is distinct from resistance mechanisms that operate at a cellular level, and cannot be overlooked in the development of novel strategies to combat infectious diseases. The review compares mechanisms of antibiotic resistance at cellular and community levels in the light of past and present antibiotic discovery efforts. Future perspectives on novel strategies for treatment of biofilm-related infectious diseases are explored.

  4. QTLs for Resistance to Major Rice Diseases Exacerbated by Global Warming: Brown Spot, Bacterial Seedling Rot, and Bacterial Grain Rot.

    PubMed

    Mizobuchi, Ritsuko; Fukuoka, Shuichi; Tsushima, Seiya; Yano, Masahiro; Sato, Hiroyuki

    2016-12-01

    In rice (Oryza sativa L.), damage from diseases such as brown spot, caused by Bipolaris oryzae, and bacterial seedling rot and bacterial grain rot, caused by Burkholderia glumae, has increased under global warming because the optimal temperature ranges for growth of these pathogens are relatively high (around 30 °C). Therefore, the need for cultivars carrying genes for resistance to these diseases is increasing to ensure sustainable rice production. In contrast to the situation for other important rice diseases such as blast and bacterial blight, no genes for complete resistance to brown spot, bacterial seedling rot or bacterial grain rot have yet been discovered. Thus, rice breeders have to use partial resistance, which is largely influenced by environmental conditions. Recent progress in molecular genetics and improvement of evaluation methods for disease resistance have facilitated detection of quantitative trait loci (QTLs) associated with resistance. In this review, we summarize the results of worldwide screening for cultivars with resistance to brown spot, bacterial seedling rot and bacterial grain rot and we discuss the identification of QTLs conferring resistance to these diseases in order to provide useful information for rice breeding programs.

  5. Drug Resistance in Malaria: Investigation of Mechanisms and Patterns of Drug Resistance and Cross Resistance in Malaria.

    DTIC Science & Technology

    1987-10-19

    sites of drugs (fefloquine, etc.) in erythrocytes and/or parasites, 2) investigation of bindihg of drugs ( mefloquine in particular) in malaria strains...resistant and suscePible to other drugs (chloroquine in particu- lar), 3) investigation of the echanism of action of drugs ( mefloquine in particular...binds to phospholipids (13). This observation is of particular interest because mefloquine binds with high affinity to phospholipids (14). It is

  6. Emerging issues in gram-negative bacterial resistance: an update for the practicing clinician.

    PubMed

    Vasoo, Shawn; Barreto, Jason N; Tosh, Pritish K

    2015-03-01

    The rapid and global spread of antimicrobial-resistant organisms in recent years has been unprecedented. Although resistant gram-positive infections have been concerning to clinicians, the increasing incidence of antibiotic-resistant gram-negative infections has become the most pressing issue in bacterial resistance. Indiscriminate antimicrobial use in humans and animals coupled with increased global connectivity facilitated the transmission of gram-negative infections harboring extended-spectrum β-lactamases in the 1990s. Carbapenemase-producing Enterobacteriaceae, such as those containing Klebsiella pneumoniae carbapenemases and New Delhi metallo-β-lactamases, have been the latest scourge since the late 1990s to 2000s. Besides β-lactam resistance, these gram-negative infections are often resistant to multiple drug classes, including fluoroquinolones, which are commonly used to treat community-onset infections. In certain geographic locales, these pathogens, which have been typically associated with health care-associated infections, are disseminating into the community, posing a significant dilemma for clinicians treating community-onset infections. In this Concise Review, we summarize emerging trends in antimicrobial resistance. We also review the current knowledge on the detection, treatment, and prevention of infection with these organisms, with a focus on the carbapenemase-producing gram-negative bacilli. Finally, we discuss emerging therapies and areas that need further research and effort to stem the spread of antimicrobial resistance.

  7. Rapid methods for detection of bacterial resistance to antibiotics.

    PubMed

    March-Rosselló, Gabriel Alberto

    2017-03-01

    The most widely used antibiotic susceptibility testing methods in Clinical Microbiology are based on the phenotypic detection of antibiotic resistance by measuring bacterial growth in the presence of the antibiotic being tested. These conventional methods take typically 24hours to obtain results. Here we review the main techniques for rapid determination of antibiotic susceptibility. Data obtained with different methods such as molecular techniques, microarrays, commercial methods used in work routine, immunochromatographic methods, colorimetric methods, image methods, nephelometry, MALDI-TOF mass spectrometry, flow cytometry, chemiluminescence and bioluminescence, microfluids and methods based on cell disruption are analysed in detail.

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

    PubMed

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

    2012-01-01

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

  9. Evaluation of Glyphosate-Resistant Soybean Cultivars for Resistance to Bacterial Pustule

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Xanthomonas axonopodis pv. glycines causes bacterial pustule of soybean, which is a common disease in many soybean-growing areas of the world and is controlled by a single recessive gene that was commonly found in many conventional glyphosate-sensitive soybean cultivars. Since glyphosate-resistant c...

  10. How to Measure Export via Bacterial Multidrug Resistance Efflux Pumps

    PubMed Central

    Blair, Jessica M. A.

    2016-01-01

    ABSTRACT Bacterial multidrug resistance (MDR) efflux pumps are an important mechanism of antibiotic resistance and are required for many pathogens to cause infection. They are also being harnessed to improve microbial biotechnological processes, including biofuel production. Therefore, scientists of many specialties must be able to accurately measure efflux activity. However, myriad methodologies have been described and the most appropriate method is not always clear. Within the scientific literature, many methods are misused or data arising are misinterpreted. The methods for measuring efflux activity can be split into two groups, (i) those that directly measure efflux and (ii) those that measure the intracellular accumulation of a substrate, which is then used to infer efflux activity. Here, we review the methods for measuring efflux and explore the most recent advances in this field, including single-cell or cell-free technologies and mass spectrometry, that are being used to provide more detailed information about efflux pump activity. PMID:27381291

  11. Sterilization Resistance of Bacterial Spores Explained with Water Chemistry.

    PubMed

    Friedline, Anthony W; Zachariah, Malcolm M; Middaugh, Amy N; Garimella, Ravindranath; Vaishampayan, Parag A; Rice, Charles V

    2015-11-05

    Bacterial spores can survive for long periods without nutrients and in harsh environmental conditions. This survival is influenced by the structure of the spore, the presence of protective compounds, and water retention. These compounds, and the physical state of water in particular, allow some species of bacterial spores to survive sterilization schemes with hydrogen peroxide and UV light. The chemical nature of the spore core and its water has been a subject of some contention and the chemical environment of the water impacts resistance paradigms. Either the spore has a glassy core, where water is immobilized along with other core components, or the core is gel-like with mobile water diffusion. These properties affect the movement of peroxide and radical species, and hence resistance. Deuterium solid-state NMR experiments are useful for examining the nature of the water inside the spore. Previous work in our lab with spores of Bacillus subtilis indicate that, for spores, the core water is in a more immobilized state than expected for the gel-like core theory, suggesting a glassy core environment. Here, we report deuterium solid-state NMR observations of the water within UV- and peroxide-resistant spores from Bacillus pumilus SAFR-032. Variable-temperature NMR experiments indicate no change in the line shape after heating to 50 °C, but an overall decrease in signal after heating to 100 °C. These results show glass-like core dynamics within B. pumilus SAFR-032 that may be the potential source of its known UV-resistance properties. The observed NMR traits can be attributed to the presence of an exosporium containing additional labile deuterons that can aid in the deactivation of sterilizing agents.

  12. Characterization and Expression of Drug Resistance Genes in MDROs Originating from Combat Wound Infections

    DTIC Science & Technology

    2014-10-01

    13. SUPPLEMENTARY NOTES 14. ABSTRACT Twenty-five multi-drug resistant organisms (MDROs) of high military importance were sequenced ...SUBJECT TERMS Antibiotic resistance, whole genome sequencing , bacterial confrontation assays, qPCR, MDROs 16. SECURITY CLASSIFICATION OF: 17...eukaryotic interactions likely to occur in the wound environment. Deep next-generation cDNA sequencing is being used as a tool to dissect the

  13. Drug resistance and adherence to human intestines of enteroaggregative Escherichia coli.

    PubMed

    Yamamoto, T; Echeverria, P; Yokota, T

    1992-04-01

    Clinical isolates of enteroaggregative Escherichia coli (EAggEC) were tested for their in vitro susceptibilities to 27 antimicrobial agents. Marked drug resistance was observed with sulfamethoxazole, ampicillin, and chloramphenicol in contrast to such antimicrobial agents as cefixime, sparfloxacin, and ciprofloxacin. One of the EAggEC strains carried a plasmid that conferred on its host resistance to ampicillin, tetracycline, sulfamethoxazole, streptomycin, and spectinomycin and an ability to adhere to child ileal villi or HeLa cells in the characteristic aggregative pattern. This plasmid also mediated D-mannose-resistant hemagglutinin production and bacterial clump formation (autoagglutination). The data demonstrate appearance of marked drug resistance and an intestine-adherence and drug-resistance plasmid in the newest category of diarrheagenic E. coli.

  14. Biophysics of cell membrane lipids in cancer drug resistance: Implications for drug transport and drug delivery with nanoparticles.

    PubMed

    Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

    2013-11-01

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

  15. Neurostimulation for Drug-Resistant Epilepsy

    PubMed Central

    DeGiorgio, Christopher M.; Krahl, Scott E.

    2013-01-01

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

  16. Management of multiple drug-resistant tuberculosis.

    PubMed

    Hutchison, D C S; Drobniewski, F A; Milburn, H J

    2003-01-01

    There has been a worldwide increase in multiple drug-resistant tuberculosis (MDR-TB) which has in the past been associated with a poor prognosis. In the U.K., about half of the cases live in the London area and we have set out to obtain further information on their treatment and outcome. We examined the risk factors, drug resistance, drug treatment, sputum conversion, and outcome in patients with MDR-TB at three hospitals in South London and diagnosed during the period June 1995-January 1999. Human Immunodeficiency Virus (HIV)-positive patients were excluded. There were 760 patients resident in Lambeth, Southwark and Lewisham Health Authority (LSLHA) who were notified as tuberculosis (TB) during the time period and who were of negative or unknown HIV status. (The population of LSLHA is approx.750,000.) There was a total of 13 patients with MDR-TB, known or presumed to be HlV negative. Their median age was 28 years (range 15-53); nine (69%) were born outside the U.K. and 11 had pulmonary disease; they had organisms resistant to a median of two first-line drugs (range 2-4) and to a median of four of all drugs tested (range 2-10). They received treatment with a median of six drugs (range 3-9). Eight were followed up for at least 3 years (range 3-6) after the completion of treatment; at their last assessment none had features of active TB and all were sputum negative (smear and culture). Two returned to their countries of origin during treatment; they were sputum negative at that time. Two patients are well and continue on treatment in the U.K. One patient (known HIV negative) died following treatment failure. In conclusion, we obtained disease-free survival in eight cases of MDR-TB, known or presumed to be HIV negative and followed up for 3 years or more. The prognosis for patients treated at specialised centres is good (and better than is generally believed). We describe a new protocol for the detection and management of MDR-TB.

  17. Why does drug resistance readily evolve but vaccine resistance does not?

    PubMed

    Kennedy, David A; Read, Andrew F

    2017-03-29

    Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced.

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

    PubMed Central

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

    2015-01-01

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

  19. A locked nucleic acid (LNA)-based real-time PCR assay for the rapid detection of multiple bacterial antibiotic resistance genes directly from positive blood culture.

    PubMed

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

    2015-01-01

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

  20. Limited Bacterial Diversity within a Treatment Plant Receiving Antibiotic-Containing Waste from Bulk Drug Production

    PubMed Central

    Shouche, Yogesh S.; Larsson, D. G. Joakim

    2016-01-01

    Biological treatment of waste water from bulk drug production, contaminated with high levels of fluoroquinolone antibiotics, can lead to massive enrichment of antibiotic resistant bacteria, resistance genes and associated mobile elements, as previously shown. Such strong selection may be boosted by the use of activated sludge (AS) technology, where microbes that are able to thrive on the chemicals within the wastewater are reintroduced at an earlier stage of the process to further enhance degradation of incoming chemicals. The microbial community structure within such a treatment plant is, however, largely unclear. In this study, Illumina-based 16S rRNA amplicon sequencing was applied to investigate the bacterial communities of different stages from an Indian treatment plant operated by Patancheru Environment Technology Limited (PETL) in Hyderabad, India. The plant receives waste water with high levels of fluoroquinolones and applies AS technology. A total of 1,019,400 sequences from samples of different stages of the treatment process were analyzed. In total 202, 303, 732, 652, 947 and 864 operational taxonomic units (OTUs) were obtained at 3% distance cutoff in the equilibrator, aeration tanks 1 and 2, settling tank, secondary sludge and old sludge samples from PETL, respectively. Proteobacteria was the most dominant phyla in all samples with Gammaproteobacteria and Betaproteobacteria being the dominant classes. Alcaligenaceae and Pseudomonadaceae, bacterial families from PETL previously reported to be highly multidrug resistant, were the dominant families in aeration tank samples. Despite regular addition of human sewage (approximately 20%) to uphold microbial activity, the bacterial diversity within aeration tanks from PETL was considerably lower than corresponding samples from seven, regular municipal waste water treatment plants. The strong selection pressure from antibiotics present may be one important factor in structuring the microbial community in PETL

  1. Signalling to drug resistance in CLL.

    PubMed

    Hertlein, Erin; Byrd, John C

    2010-03-01

    The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signalling pathway is constitutively active in a variety of cancers, including chronic lymphocytic leukaemia (CLL). The importance of this signalling pathway identifies it as a prime therapeutic target; however, the complexity and potential side effects of inhibiting NF-kappaB have thus far made the clinical use of NF-kappaB inhibitors a relatively unexplored resource in this disease. This article discusses the role of NF-kappaB in CLL as a common crossroad for pathways promoting drug resistance in CLL. We provide the background on how this pathway contributes to both spontaneous and drug-induced apoptosis. Potential new avenues to regulate this pathway in CLL are also discussed.

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

    PubMed Central

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

    1984-01-01

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

  3. Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance.

    PubMed

    Fernández, Lucía; Hancock, Robert E W

    2012-10-01

    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.

  4. On the Spread of Drug-Resistant Diseases

    NASA Astrophysics Data System (ADS)

    Schinazi, Rinaldo B.

    1999-10-01

    We introduce an interacting particle system to model the emergence of drug-resistant diseases, one of the most serious health problems in modern society. We are interested in diseases for which a natural strain may mutate into a drug-resistant strain. This happens, for instance, when antibiotics are misused. The main result of our analysis is that with an efficient drug against the natural strain, if there is even a small chance that the natural strain mutates into the drug-resistant one, then there will eventually be an outbreak of the drug-resistant strain throughout the population. In that case the natural strain disappears and is replaced by the drug-resistant strain. The disturbing part of this is that an efficient treatment of the natural strain gives an edge to the drug-resistant strain.

  5. Clinical treatment of pandrug-resistant bacterial infection consulted by clinical pharmacist

    PubMed Central

    Zhi-Wen, Yang; Yan-Li, Zhang; Man, Yuan; Wei-Jun, Fang

    2015-01-01

    Objective Pandrug-resistant (PDR) bacterial infections are associated with considerable prolongation of hospitalization and mortality in clinical practice. Method This case-series study was conducted during a 3-year period from 2011 to 2013. A total of 30 PDR patients consulted by clinical pharmacist were recorded to evaluate the anti-infection treatment. Results All isolates of PDR bacteria from patients were identified as pan-drug resistant acine-tobacter baumannii (63.3%), pan-drug resistant klebsiella pneumonia (20.0%), and pandrug-resistant pseudomonas aeruginosa (16.7%). Of the 30 patients, 96.7% therapeutic regimens supposed by clinical pharmacists were applied to treat the infectious patients up to 82.8% clinical cure rates. 30 patients completed the prescribed treatment, of which 19 underwent monotherapy that the clinical cure rate was 78.9%, and 10 underwent combination therapy that the clinical cure rate was 90.0%. In the following therapy, doxycycline, cefoperazone shubatan and amikacin have the certain effect on anti-infection therapy. Combination therapy combined with doxycycline was better treatment option for PDR infectious patients. Conclusion In a word, it appears to be effective for the successful therapy of PDR infections upon tetracyclines administration. PMID:27134538

  6. My Cousin, My Enemy: quasispecies suppression of drug resistance

    PubMed Central

    Kirkegaard, Karla; van Buuren, Nicholas J; Mateo, Roberto

    2017-01-01

    If a freshly minted genome contains a mutation that confers drug resistance, will it be selected in the presence of the drug? Not necessarily. During viral infections, newly synthesized viral genomes occupy the same cells as parent and other progeny genomes. If the antiviral target is chosen so that the drug-resistant progeny’s growth is dominantly inhibited by the drug-susceptible members of its intracellular family, its outgrowth can be suppressed. Precedent for ‘dominant drug targeting’ as a deliberate approach to suppress the outgrowth of inhibitor-resistant viruses has been established for envelope variants of vesicular stomatitis virus and for capsid variants of poliovirus and dengue virus. Small molecules that stabilize oligomeric assemblages are a promising means to an unfit family to destroy the effectiveness of a newborn drug-resistant relative due to the co-assembly of drug-susceptible and drug-resistant monomers. PMID:27764731

  7. Comprehensive Treatment of Extensively Drug-Resistant Tuberculosis

    PubMed Central

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

    2009-01-01

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

  8. Rhabdomyolysis associated with antimicrobial drug-resistant Mycoplasma pneumoniae.

    PubMed

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

    2012-05-01

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

  9. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    NASA Astrophysics Data System (ADS)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

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

    ERIC Educational Resources Information Center

    Silva, Roberta K.

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

  12. 2015 Update of the Drug Resistance Mutations in HIV-1.

    PubMed

    Wensing, Annemarie M; Calvez, Vincent; Günthard, Huldrych F; Johnson, Victoria A; Paredes, Roger; Pillay, Deenan; Shafer, Robert W; Richman, Douglas D

    2015-01-01

    The 2015 edition of the IAS-USA drug resistance mutations list updates the figures last published in July 2014. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The figures are designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs and, therefore, in making clinical decisions regarding antiretroviral therapy.

  13. 2017 Update of the Drug Resistance Mutations in HIV-1.

    PubMed

    Wensing, Annemarie M; Calvez, Vincent; Günthard, Huldrych F; Johnson, Victoria A; Paredes, Roger; Pillay, Deenan; Shafer, Robert W; Richman, Douglas D

    The 2017 edition of the IAS-USA drug resistance mutations list updates the figures last published in November 2015. The mutations listed are those that have been identified by specific criteria for evidence and drugs described. The figures are designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs and, therefore, in making clinical decisions regarding antiretroviral therapy.

  14. Antibiotic Resistance: New Challenge in the Management of Bacterial Eye Infections.

    PubMed

    Talukder, A K; Sultana, Z; Jahan, I; Khanam, M; Rahman, M; Rahman, M F; Rahman, M B

    2017-01-01

    Ophthalmologists are still facing difficulties in managing bacterial eye infections. The study was designed for the isolation and identification of bacteria from infected eyes and observation of the sensitivity and resistant pattern. This cross sectional study was performed among 160 patients of suspected bacterial eye infection at Dr. K. Zaman BNSB Eye Hospital, Mymensingh and Department of Microbiology and Hygiene, Bangladesh Agricultural University, Mymensingh from March, 2010 to June, 2014. After collection of the samples from suspected infected eyes, it was nourished into nutrient broth in shaking incubator for three hours and then cultured into nutrient agar media followed by Mannitol salt agar, MacConkey's agar and blood agar. Bacteria were categorized by colony characteristics and Gram staining. Antibiogram was performed by disc diffusion method on Mueller Hinton agar media. McFarland Equivalence Turbidity Standard was maintained. The efficacy of the drug was evaluated by measuring the diameter of the zone of inhibition surrounding the disc. Ten percent Staphylococcus species isolates was resistant to Gatifloxacin, Gentamicin, Tobramycin and Cloxacillin, 26.0% to Ciprofloxacin, 40.0% to Azythromycin and Moxifloxacin, 58.0% to Cefixime and 64.0% to Cephalexin. Methicillin resistant Staphylococcus aureus was 62.8%. About 24.0% Streptococcus species isolates was resistant to Gatifloxacin, 33.3% to Azythromycin, Ciprofloxacin, Gentamycin, Moxifloxacin and Tobramycin, 52.4% to Cefixime and 71.4% to Cephalexin. About 9.0% of Pseudomonas species was resistant to Gatifloxacin and Tobramycin, 14.7% to Ciprofloxacin, 26.5% to Cefixime, 29.4% to Gentamicin and Moxifloxacin, 44.1% to Azythromycin and 82.3% to Cephalexin and Cloxacillin. Rational use of antibiotics and proper attentions of concerned authorities are necessary to overcome the emergent ocular situation leaded by antibiotic resistant.

  15. GEAR: A database of Genomic Elements Associated with drug Resistance

    PubMed Central

    Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

    2017-01-01

    Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org. PMID:28294141

  16. GEAR: A database of Genomic Elements Associated with drug Resistance.

    PubMed

    Wang, Yin-Ying; Chen, Wei-Hua; Xiao, Pei-Pei; Xie, Wen-Bin; Luo, Qibin; Bork, Peer; Zhao, Xing-Ming

    2017-03-15

    Drug resistance is becoming a serious problem that leads to the failure of standard treatments, which is generally developed because of genetic mutations of certain molecules. Here, we present GEAR (A database of Genomic Elements Associated with drug Resistance) that aims to provide comprehensive information about genomic elements (including genes, single-nucleotide polymorphisms and microRNAs) that are responsible for drug resistance. Right now, GEAR contains 1631 associations between 201 human drugs and 758 genes, 106 associations between 29 human drugs and 66 miRNAs, and 44 associations between 17 human drugs and 22 SNPs. These relationships are firstly extracted from primary literature with text mining and then manually curated. The drug resistome deposited in GEAR provides insights into the genetic factors underlying drug resistance. In addition, new indications and potential drug combinations can be identified based on the resistome. The GEAR database can be freely accessed through http://gear.comp-sysbio.org.

  17. Antiplasmid activity: loss of bacterial resistance to antibiotics.

    PubMed

    Molnár, J; Földeák, S; Nakamura, M J; Rausch, H; Domonkos, K; Szabó, M

    1992-01-01

    The antiplasmid activity of tricyclic compounds, e.g. phenothiazines, dibenzoazepines, dibenzocykloheptene derivatives and some stereoisomers, was shown on E. coli in vitro. Some ring-substituted phenothiazine and cannabis derivatives had only an antibacterial effect. Promethazine, a selected phenothiazine, cured antibiotic resistance and lactose fermentation of E.coli, tumour inducing ability of Agrobacterium tumefaciens and nodule formation of Rhizobium meliloti. Plasmids of different E.coli strains were eliminated with varying frequency. The antiplasmid activity of the compounds can be due to the increased membrane permeability. Inhibition of DNA gyrase and complex formation with the supercoiled form of plasmid DNA can lead to the cessation of plasmid replication in the bacterial cells. In addition, in vivo plasmid curing was demonstrated at a low frequency.

  18. Monopoly pricing of an antibiotic subject to bacterial resistance.

    PubMed

    Herrmann, Markus

    2010-01-01

    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.

  19. 77 FR 60126 - Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment; Availability

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-10-02

    ...; Formerly 2008N-0004] Guidance for Industry on Acute Bacterial Otitis Media: Developing Drugs for Treatment... Media: Developing Drugs for Treatment.'' This guidance addresses FDA's current thinking regarding the... treatment of acute bacterial otitis media (ABOM). This guidance finalizes the revised draft guidance of...

  20. Discordant resistance to kanamycin and amikacin in drug-resistant Mycobacterium tuberculosis.

    PubMed

    Krüüner, Annika; Jureen, Pontus; Levina, Klavdia; Ghebremichael, Solomon; Hoffner, Sven

    2003-09-01

    It is generally thought that there is full cross-resistance in Mycobacterium tuberculosis between the aminoglycoside drugs kanamycin and amikacin. However, kanamycin resistance and amikacin susceptibility were seen in 43 of 79 (54%) multidrug-resistant Estonian isolates, indicating that there might be a need to test the resistance of M. tuberculosis isolates to both drugs.

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

    PubMed

    Dey, Diganta; Ray, Ratnamala; Hazra, Banasri

    2014-07-01

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

  2. Vitamin B3 confers resistance to sulfa drugs in Saccharomyces cerevisiae.

    PubMed

    Kornfeld, Olga; Nichols, Brian P

    2005-10-01

    Sulfa drugs are ubiquitous antibiotics used to treat bacterial infections and diseases caused by eukaryotes, such as Pneumocystis carinii, the leading cause of pneumonia (PCP) in HIV patients. A daily regimen of sulfonamides and multivitamins including vitamin B3 is also recommended for persons with HIV. We show that exogenous vitamin B3 (nicotinate) confers resistance to sulfa drugs in Saccharomyces cerevisiae, a model for P. carinii. We propose a model of metabolic rerouting in which increased nicotinate leads to increased intracellular concentration of p-aminobenzoate, thus leading to sulfonamide resistance.

  3. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides

    PubMed Central

    Almutairi, Mashal M.; Park, Sung Ryeol; Rose, Simon; Hansen, Douglas A.; Vázquez-Laslop, Nora; Douthwaite, Stephen; Sherman, David H.; Mankin, Alexander S.

    2015-01-01

    Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism. PMID:26438831

  4. Resistance to ketolide antibiotics by coordinated expression of rRNA methyltransferases in a bacterial producer of natural ketolides.

    PubMed

    Almutairi, Mashal M; Park, Sung Ryeol; Rose, Simon; Hansen, Douglas A; Vázquez-Laslop, Nora; Douthwaite, Stephen; Sherman, David H; Mankin, Alexander S

    2015-10-20

    Ketolides are promising new antimicrobials effective against a broad range of Gram-positive pathogens, in part because of the low propensity of these drugs to trigger the expression of resistance genes. A natural ketolide pikromycin and a related compound methymycin are produced by Streptomyces venezuelae strain ATCC 15439. The producer avoids the inhibitory effects of its own antibiotics by expressing two paralogous rRNA methylase genes pikR1 and pikR2 with seemingly redundant functions. We show here that the PikR1 and PikR2 enzymes mono- and dimethylate, respectively, the N6 amino group in 23S rRNA nucleotide A2058. PikR1 monomethylase is constitutively expressed; it confers low resistance at low fitness cost and is required for ketolide-induced activation of pikR2 to attain high-level resistance. The regulatory mechanism controlling pikR2 expression has been evolutionary optimized for preferential activation by ketolide antibiotics. The resistance genes and the induction mechanism remain fully functional when transferred to heterologous bacterial hosts. The anticipated wide use of ketolide antibiotics could promote horizontal transfer of these highly efficient resistance genes to pathogens. Taken together, these findings emphasized the need for surveillance of pikR1/pikR2-based bacterial resistance and the preemptive development of drugs that can remain effective against the ketolide-specific resistance mechanism.

  5. AN ELEMENTARY APPROACH TO MODELING DRUG RESISTANCE IN CANCER

    PubMed Central

    Tomasetti, Cristian; Levy, Doron

    2013-01-01

    Resistance to drugs has been an ongoing obstacle to a successful treatment of many diseases. In this work we consider the problem of drug resistance in cancer, focusing on random genetic point mutations. Most previous works on mathematical models of such drug resistance have been based on stochastic methods. In contrast, our approach is based on an elementary, compartmental system of ordinary differential equations. We use our very simple approach to derive results on drug resistance that are comparable to those that were previously obtained using much more complex mathematical techniques. The simplicity of our model allows us to obtain analytic results for resistance to any number of drugs. In particular, we show that the amount of resistance generated before the start of the treatment, and present at some given time afterward, always depends on the turnover rate, no matter how many drugs are simultaneously used in the treatment. PMID:21077714

  6. Drug resistance reversal--are we getting closer?

    PubMed

    Baird, R D; Kaye, S B

    2003-11-01

    Clinical drug resistance is a major barrier to overcome before chemotherapy can become curative for most patients presenting with metastatic cancer. Rational attempts to tackle clinical drug resistance need to be based on an understanding of the mechanisms involved; these are likely to be complex and multifactorial, and may be due to inadequate drug exposure or alterations in the cancer cell itself. This article reviews a number of strategies used to tackle drug resistance, focussing on work in our institution related to the treatment of ovarian cancer and resistance to platinum and taxane-based chemotherapy. Further progress towards drug resistance reversal will require a three-pronged approach, namely: the development of novel cytotoxics which exploit selectively expressed targets; modulation of resistance to conventional agents and, most importantly, a serious attempt to understand resistance mechanisms in tumour samples taken both pre- and post-chemotherapy.

  7. Bacterial Resistance to Antisense Peptide Phosphorodiamidate Morpholino Oligomers

    PubMed Central

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

    2012-01-01

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

  8. Bacterial resistance to antisense peptide phosphorodiamidate morpholino oligomers.

    PubMed

    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

    2012-12-01

    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 β-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 μM (14 μg/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 μM (224 μg/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.

  9. Inactivation of indispensable bacterial proteins by early proteins of bacteriophages: implication in antibacterial drug discovery.

    PubMed

    Sau, S; Chattoraj, P; Ganguly, T; Chanda, P K; Mandal, N C

    2008-06-01

    Bacteriophages utilize host bacterial cellular machineries for their own reproduction and completion of life cycles. The early proteins that phage synthesize immediately after the entry of their genomes into bacterial cells participate in inhibiting host macromolecular biosynthesis, initiating phage-specific replication and synthesizing late proteins. Inhibition of synthesis of host macromolecules that eventually leads to cell death is generally performed by the physical and/or chemical modification of indispensable host proteins by early proteins. Interestingly, most modified bacterial proteins were shown to take part actively in phage-specific transcription and replication. Research on phages in last nine decades has demonstrated such lethal early proteins that interact with or chemically modify indispensable host proteins. Among the host proteins inhibited by lethal phage proteins, several are not inhibited by any chemical inhibitor available today. Under the context of widespread dissemination of antibiotic-resistant strains of pathogenic bacteria in recent years, the information of lethal phage proteins and cognate host proteins could be extremely invaluable as they may lead to the identification of novel antibacterial compounds. In this review, we summarize the current knowledge about some early phage proteins, their cognate host proteins and their mechanism of action and also describe how the above interacting proteins had been exploited in antibacterial drug discovery.

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

    PubMed Central

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

    2013-01-01

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

  11. Covalently linked kanamycin - Ciprofloxacin hybrid antibiotics as a tool to fight bacterial resistance.

    PubMed

    Shavit, Michal; Pokrovskaya, Varvara; Belakhov, Valery; Baasov, Timor

    2017-03-16

    To address the growing problem of antibiotic resistance, a set of 12 hybrid compounds that covalently link fluoroquinolone (ciprofloxacin) and aminoglycoside (kanamycin A) antibiotics were synthesized, and their activity was determined against both Gram-negative and Gram-positive bacteria, including resistant strains. The hybrids were antagonistic relative to the ciprofloxacin, but were substantially more potent than the parent kanamycin against Gram-negative bacteria, and overcame most dominant resistance mechanisms to aminoglycosides. Selected hybrids were 42-640 fold poorer inhibitors of bacterial protein synthesis than the parent kanamycin, while they displayed similar inhibitory activity to that of ciprofloxacin against DNA gyrase and topoisomerase IV enzymes. The hybrids showed significant delay of resistance development in both E. coli and B. subtilis in comparison to that of component drugs alone or their 1:1 mixture. More generally, the data suggest that an antagonistic combination of aminoglycoside-fluoroquinolone hybrids can lead to new compounds that slowdown/prevent the emergence of resistance.

  12. EPIDEMIOLOGICAL AND GENETICAL STUDIES ON THE DRUG-RESISTANCE OF SHIGELLAE AND STAPHYLOCOCCI.

    DTIC Science & Technology

    ANTIBIOTICS , RESISTANCE (BIOLOGY)), (*SHIGELLA, RESISTANCE(BIOLOGY)), (*STAPHYLOCOCCUS, RESISTANCE(BIOLOGY)), EPIDEMIOLOGY, GENETICS, DRUGS, BACTERIOPHAGES, TETRACYCLINES, PENICILLINS, ESCHERICHIA COLI, JAPAN

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

    PubMed Central

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

    2003-01-01

    Resistance to therapeutic drugs encompasses a diverse range of biological systems, which all have a human impact. From the relative simplicity of bacterial cells, fungi and protozoa to the complexity of human cancer cells, resistance has become problematic. Stated in its simplest terms, drug resistance decreases the chance of providing successful treatment against a plethora of diseases. Worryingly, it is a problem that is increasing, and consequently there is a pressing need to develop new and effective classes of drugs. This has provided a powerful stimulus in promoting research on drug resistance and, ultimately, it is hoped that this research will provide novel approaches that will allow the deliberate circumvention of well understood resistance mechanisms. A major mechanism of resistance in both microbes and cancer cells is the membrane protein-catalysed extrusion of drugs from the cell. Resistant cells exploit proton-driven antiporters and/or ATP-driven ABC (ATP-binding cassette) transporters to extrude cytotoxic drugs that usually enter the cell by passive diffusion. Although some of these drug efflux pumps transport specific substrates, many are transporters of multiple substrates. These multidrug pumps can often transport a variety of structurally unrelated hydrophobic compounds, ranging from dyes to lipids. If we are to nullify the effects of efflux-mediated drug resistance, we must first of all understand how these efflux pumps can accommodate a diverse range of compounds and, secondly, how conformational changes in these proteins are coupled to substrate translocation. These are key questions that must be addressed. In this review we report on the advances that have been made in understanding the structure and function of drug efflux pumps. PMID:13678421

  14. What is Multidrug and Extensively Drug Resistant TB?

    MedlinePlus

    ... org > Lung Health and Diseases > Lung Disease Lookup > Tuberculosis (TB) What Is Multidrug and Extensively Drug Resistant TB? Multidrug-resistant tuberculosis ( MDR TB ) is a very dangerous form of ...

  15. Management of febrile neutropenia in the era of bacterial resistance

    PubMed Central

    Alp, Sehnaz

    2013-01-01

    Managing cancer patients with fever and neutropenia must be considered as a medical emergency since any delay in initiating appropriate empirical antibacterial therapy may result in high rates of mortality and morbidity. Emerging antibacterial resistance in bacterial pathogens infecting febrile neutropenic patients complicates management, and choosing the type of empirical antimicrobial therapy has become a challenge. To further complicate the decision process, not all neutropenic patients are in same category of susceptibility to develop severe infection. While low-risk patients may be treated with oral antibiotics in the outpatient setting, high-risk patients usually need to be admitted to hospital and receive parenteral broad-spectrum antibiotics until the neutrophil levels recover. These strategies have recently been addressed in two international guidelines from the Infectious Diseases Society of America (IDSA) and the European Conference on Infections in Leukaemia (ECIL). This review gives a brief overview of current antimicrobial resistance problems and their effects in febrile neutropenic cancer patients by summarizing the suggestions from the IDSA and ECIL guidelines. PMID:25165543

  16. Reengineering Antibiotics to Combat Bacterial Resistance: Click Chemistry [1,2,3]-Triazole Vancomycin Dimers with Potent Activity against MRSA and VRE.

    PubMed

    Silverman, Steven M; Moses, John E; Sharpless, K Barry

    2017-01-01

    Vancomycin has long been considered a drug of last resort. Its efficiency in treating multiple drug-resistant bacterial infections, particularly methicillin-resistant Staphylococcus aureus (MRSA), has had a profound effect on the treatment of life-threatening infections. However, the emergence of resistance to vancomycin is a cause for significant worldwide concern, prompting the urgent development of new effective treatments for antibiotic resistant bacterial infections. Harnessing the benefits of multivalency and cooperativity against vancomycin-resistant strains, we report a Click Chemistry approach towards reengineered vancomycin derivatives and the synthesis of a number of dimers with increased potency against MRSA and vancomycin resistant Enterococci (VRE; VanB). These semi-synthetic dimeric ligands were linked together with great efficiency using the powerful CuAAC reaction, demonstrating high levels of selectivity and purity.

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-10-01

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

  19. A new look at the drug-resistance investigation of uropathogenic E. coli strains.

    PubMed

    Adamus-Białek, Wioletta; Lechowicz, Łukasz; Kubiak-Szeligowska, Anna B; Wawszczak, Monika; Kamińska, Ewelina; Chrapek, Magdalena

    2017-02-01

    Bacterial drug resistance and uropathogenic tract infections are among the most important issues of current medicine. Uropathogenic Escherichia coli strains are the primary factor of this issue. This article is the continuation of the previous study, where we used Kohonen relations to predict the direction of drug resistance. The characterized collection of uropathogenic E. coli strains was used for microbiological (the disc diffusion method for antimicrobial susceptibility testing), chemical (ATR/FT-IR) and mathematical (artificial neural networks, Ward's hierarchical clustering method, the analysis of distributions of inhibition zone diameters for antibiotics, Cohen's kappa measure of agreement) analysis. This study presents other potential tools for the epidemiological differentiation of E. coli strains. It is noteworthy that ATR/FT-IR technique has turned out to be useful for the quick and simple identification of MDR strains. Also, diameter zones of resistance of this E. coli population were compared to the population of E. coli strains published by EUCAST. We observed the bacterial behaviors toward particular antibiotics in comparison to EUCAST bacterial collections. Additionally, we used Cohen's kappa to show which antibiotics from the same class are closely related to each other and which are not. The presented associations between antibiotics may be helpful in selecting the proper therapy directions. Here we present an adaptation of interdisciplinary studies of drug resistance of E. coli strains for epidemiological and clinical investigations. The obtained results may be some indication in deciding on antibiotic therapy.

  20. Packaging protein drugs as bacterial inclusion bodies for therapeutic applications

    PubMed Central

    2012-01-01

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

  1. Targeted cancer therapy; nanotechnology approaches for overcoming drug resistance.

    PubMed

    Gao, Yan; Shen, Jacson K; Milane, Lara; Hornicek, Francis J; Amiji, Mansoor M; Duan, Zhenfeng

    2015-01-01

    Recent advances in cancer molecular biology have resulted in parallel and unprecedented progress in the development of targeted cancer therapy. Targeted therapy can provide higher efficacy and lower toxicity than conventional chemotherapy for cancer. However, like traditional chemotherapy, molecularly targeted cancer therapy also faces the challenge of drug resistance. Multiple mechanisms are responsible for chemotherapy resistance in tumors, including over-expression of efflux transporters, somatic alterations of drug targets, deregulation of apoptosis, and numerous pharmacokinetic issues. Nanotechnology based approaches are proving to be efficacious in overcoming drug resistance in cancer. Combination of targeted therapies with nanotechnology approaches is a promising strategy to overcome targeted therapy drug resistance in cancer treatment. This review discusses the mechanisms of targeted drug resistance in cancer and discusses nanotechnology approaches to circumvent this resistance.

  2. Targeting efflux pumps to overcome antifungal drug resistance.

    PubMed

    Holmes, Ann R; Cardno, Tony S; Strouse, J Jacob; Ivnitski-Steele, Irena; Keniya, Mikhail V; Lackovic, Kurt; Monk, Brian C; Sklar, Larry A; Cannon, Richard D

    2016-08-01

    Resistance to antifungal drugs is an increasingly significant clinical problem. The most common antifungal resistance encountered is efflux pump-mediated resistance of Candida species to azole drugs. One approach to overcome this resistance is to inhibit the pumps and chemosensitize resistant strains to azole drugs. Drug discovery targeting fungal efflux pumps could thus result in the development of azole-enhancing combination therapy. Heterologous expression of fungal efflux pumps in Saccharomyces cerevisiae provides a versatile system for screening for pump inhibitors. Fungal efflux pumps transport a range of xenobiotics including fluorescent compounds. This enables the use of fluorescence-based detection, as well as growth inhibition assays, in screens to discover compounds targeting efflux-mediated antifungal drug resistance. A variety of medium- and high-throughput screens have been used to identify a number of chemical entities that inhibit fungal efflux pumps.

  3. Drug resistance in Leishmania: similarities and differences to other organisms.

    PubMed

    Papadopoulou, B; Kündig, C; Singh, A; Ouellette, M

    1998-01-01

    The main line of defense available against parasitic protozoa is chemotherapy. Drug resistance has emerged however, as a primary obstacle to the successful treatment and control of parasitic diseases. Leishmania spp., the causative agents of leishmaniasis, have served as a useful model for studying mechanisms of drug resistance in vitro. Antimonials and amphotericin B are the first line drugs to treat Leishmania followed by pentamidine and a number of other drugs. Parasites resistant against all these classes of drugs have been selected under laboratory conditions. A multiplicity of resistance mechanisms has been detected, the most prevalent being gene amplification and transport mutations. With the tools now available, it should be possible to elucidate the mechanisms that govern drug resistance in field isolates and develop more effective chemotherapeutic agents.

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

    PubMed Central

    GREENBERG, ROBERT M.

    2013-01-01

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

  5. Molecular structure and dynamics in bacterial mercury resistance

    SciTech Connect

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

    2008-01-01

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

  6. The non-medical use of antibiotics and the risk of causing microbial drug-resistance*

    PubMed Central

    Manten, A.

    1963-01-01

    One of the hazards involved in the use of antibiotics in animal feeds is that it may lead to the development of bacterial drug-resistance. An analysis of the phenomenon shows that this possibility largely depends on the size of the bacterial populations involved and on the possibility of selective multiplication of the resistant mutants that may be present. Additional factors involved in the development of resistance are the type of drug applied and the time during which the bacteria are in contact with it. Animal experiments and general practical experience show that resistance, especially in E. coli, Salm. typhimurium and Staph. aureus, may considerably increase as higher doses are added to the feed. Therefore, the lowest effective level for growth promotion (5-20 p.p.m. of penicillin or tetracycline) is to be preferred over higher levels. As to the practice of food preservation by means of antibiotics, a dangerous situation may arise if two factors combine: emergence of bacterial resistance in Salmonella and perhaps other pathogenic bacteria in the animal as a result of the addition of a certain antibiotic to feeds, and subsequent use of the same substance for preservation of the meat. PMID:14058230

  7. Understanding bacterial resistance to antimicrobial peptides: From the surface to deep inside.

    PubMed

    Maria-Neto, Simone; de Almeida, Keyla Caroline; Macedo, Maria Ligia Rodrigues; Franco, Octávio Luiz

    2015-11-01

    Resistant bacterial infections are a major health problem in many parts of the world. The major commercial antibiotic classes often fail to combat common bacteria. Although antimicrobial peptides are able to control bacterial infections by interfering with microbial metabolism and physiological processes in several ways, a large number of cases of resistance to antibiotic peptide classes have also been reported. To gain a better understanding of the resistance process various technologies have been applied. Here we discuss multiple strategies by which bacteria could develop enhanced antimicrobial peptide resistance, focusing on sub-cellular regions from the surface to deep inside, evaluating bacterial membranes, cell walls and cytoplasmic metabolism. Moreover, some high-throughput methods for antimicrobial resistance detection and discrimination are also examined. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

  8. Acute bacterial skin and skin structure infections in internal medicine wards: old and new drugs.

    PubMed

    Falcone, Marco; Concia, Ercole; Giusti, Massimo; Mazzone, Antonino; Santini, Claudio; Stefani, Stefania; Violi, Francesco

    2016-08-01

    Skin and soft tissue infections (SSTIs) are a common cause of hospital admission among elderly patients, and traditionally have been divided into complicated and uncomplicated SSTIs. In 2010, the FDA provided a new classification of these infections, and a new category of disease, named acute bacterial skin and skin structure infections (ABSSSIs), has been proposed as an independent clinical entity. ABSSSIs include three entities: cellulitis and erysipelas, wound infections, and major cutaneous abscesses This paper revises the epidemiology of SSTIs and ABSSSIs with regard to etiologies, diagnostic techniques, and clinical presentation in the hospital settings. Particular attention is owed to frail patients with multiple comorbidities and underlying significant disease states, hospitalized on internal medicine wards or residing in nursing homes, who appear to be at increased risk of infection due to multi-drug resistant pathogens and treatment failures. Management of ABSSSIs and SSTIs, including evaluation of the hemodynamic state, surgical intervention and treatment with appropriate antibiotic therapy are extensively discussed.

  9. Inhibition of bacterial carbonic anhydrases and zinc proteases: from orphan targets to innovative new antibiotic drugs.

    PubMed

    Supuran, C T

    2012-01-01

    Zinc-containing enzymes, such as carbonic anhydrases (CAs) and metalloproteases (MPs) play critical functions in bacteria, being involved in various steps of their life cycle, which are important for survival, colonization, acquisition of nutrients for growth and proliferation, facilitation of dissemination, invasion and pathogenicity. The development of resistance to many classes of clinically used antibiotics emphasizes the need of new antibacterial drug targets to be explored. There is a wealth of data regarding bacterial CAs and zinc MPs present in many pathogenic species, such as Neisseria spp., Helycobacter pylori Escherichia coli, Mycobacterium tuberculosis, Brucella spp., Streptococcus pneumoniae, Salmonella enterica, Haemophilus influenzae, Listeria spp, Vibrio spp., Pseudomonas aeruginosa, Legionella pneumophila, Streptomyces spp., Clostridium spp., Enterococcus spp., etc. Some of these enzymes have been cloned, purified and characterized by crystallographic techniques. However, for the moment, few potent and specific inhibitors for bacterial MPs have been reported except for Clostridium histolyticum collagenase, botulinum and tetanus neurotoxin and anthrax lethal factor, which will be reviewed in this article. Bacteria encode α-,β-, and/or γ-CA families, but up to now only the first two classes have been investigated in some detail in different species. The α-CAs from Neisseria spp. and H. pylori as well as the β-class enzymes from E. coli, H. pylori, M. tuberculosis, Brucella spp., S. pneumoniae, S. enterica and H. influenzae have been cloned and characterized. The catalytic/inhibition mechanisms of these CAs are well understood as X-ray crystal structures are available for some of them, but no adducts of these enzymes with inhibitors have been characterized so far. In vitro and in vivo studies with various classes of inhibitors, such as anions, sulfonamides and sulfamates have been reported. Only for Neisseria spp., H. pylori, B. suis and S

  10. Emergence of multi drug resistance among soil bacteria exposing to insecticides.

    PubMed

    Rangasamy, Kirubakaran; Athiappan, Murugan; Devarajan, Natarajan; Parray, Javid A

    2017-02-10

    Impacts of pesticide exposure on the soil microbial flora and cross resistance to antibiotics have not been well documented. Development of antibiotic resistance is a common issue among soil bacteria which are exposing to pesticides continuously at sub-lethal concentration. The present study was focused to evaluate the correlation between pesticide exposures and evolution of multi drug resistance among isolates collected from soil applied with insecticides. Twenty five insecticide (Monochrotophos) degrading bacteria were isolated from contaminated agricultural soil. The bacterial isolates Bacillus Sps, Bacillus cereus, Bacillus firmus and Bacillus thuringiensis were found to be resistant against chloramphenical, monochrotophos, ampicillin, cefotaxime, streptomycin and tetracycline antibiotics used. Involvement of plasmid in drug as well as insecticide resistant was confirmed through plasmid curing among selected bacterial strains. Bacillus Sps (MK-07), Bacillus cereus (MK-11), Bacillus firmus (MK-13) and Bacillus thuringiensis (MK-24) lost their resistant against insecticides and antibiotics once after removal of plasmid by exposing to 2% sodium dodecyl sulphate. The plasmid was transformed back to bacteria which produced similar derivatives when cultured in Minimal Salt medium (pH 7.0) supplemented with 0.4% of insecticide. Homology modeling was used to prove that organophosphorus hydrolase and able to metabolize all the antibiotics showed positive interaction with high docking score. The present study revealed that persistent of insecticides in the agricultural soil may lead to increasing development of multidrug resistance among soil bacteria.

  11. The dynamics of drug resistance: a mathematical perspective.

    PubMed

    Lavi, Orit; Gottesman, Michael M; Levy, Doron

    2012-01-01

    Resistance to chemotherapy is a key impediment to successful cancer treatment that has been intensively studied for the last three decades. Several central mechanisms have been identified as contributing to the resistance. In the case of multidrug resistance (MDR), the cell becomes resistant to a variety of structurally and mechanistically unrelated drugs in addition to the drug initially administered. Mathematical models of drug resistance have dealt with many of the known aspects of this field, such as pharmacologic sanctuary and location/diffusion resistance, intrinsic resistance, induced resistance and acquired resistance. In addition, there are mathematical models that take into account the kinetic/phase resistance, and models that investigate intracellular mechanisms based on specific biological functions (such as ABC transporters, apoptosis and repair mechanisms). This review covers aspects of MDR that have been mathematically studied, and explains how, from a methodological perspective, mathematics can be used to study drug resistance. We discuss quantitative approaches of mathematical analysis, and demonstrate how mathematics can be used in combination with other experimental and clinical tools. We emphasize the potential benefits of integrating analytical and mathematical methods into future clinical and experimental studies of drug resistance.

  12. Modeling of signaling crosstalk-mediated drug resistance and its implications on drug combination

    PubMed Central

    Sun, Xiaoqiang; Bao, Jiguang; You, Zhuhong; Chen, Xing; Cui, Jun

    2016-01-01

    The efficacy of pharmacological perturbation to the signaling transduction network depends on the network topology. However, whether and how signaling dynamics mediated by crosstalk contributes to the drug resistance are not fully understood and remain to be systematically explored. In this study, motivated by a realistic signaling network linked by crosstalk between EGF/EGFR/Ras/MEK/ERK pathway and HGF/HGFR/PI3K/AKT pathway, we develop kinetic models for several small networks with typical crosstalk modules to investigate the role of the architecture of crosstalk in inducing drug resistance. Our results demonstrate that crosstalk inhibition diminishes the response of signaling output to the external stimuli. Moreover, we show that signaling crosstalk affects the relative sensitivity of drugs, and some types of crosstalk modules that could yield resistance to the targeted drugs were identified. Furthermore, we quantitatively evaluate the relative efficacy and synergism of drug combinations. For the modules that are resistant to the targeted drug, we identify drug targets that can not only increase the relative drug efficacy but also act synergistically. In addition, we analyze the role of the strength of crosstalk in switching a module between drug-sensitive and drug-resistant. Our study provides mechanistic insights into the signaling crosstalk-mediated mechanisms of drug resistance and provides implications for the design of synergistic drug combinations to reduce drug resistance. PMID:27590512

  13. 78 FR 63220 - Guidance for Industry on Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... HUMAN SERVICES Food and Drug Administration Guidance for Industry on Acute Bacterial Skin and Skin... guidance for industry entitled ``Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for... drugs to treat acute bacterial skin and skin structure infections (ABSSSI). This guidance finalizes...

  14. Asynchronous magnetic bead rotation (AMBR) micro-viscometer for rapid, sensitive and label-free studies of bacterial growth and drug sensitivity

    PubMed Central

    Sinn, Irene; Albertson, Theodore; Kinnunen, Paivo; Breslauer, David N.; McNaughton, Brandon H.; Burns, Mark A.; Kopelman, Raoul

    2012-01-01

    The long turnaround time in antimicrobial susceptibility testing (AST) endangers patients and encourages the administration of wide spectrum antibiotics, thus resulting in alarming increases of multi-drug resistant pathogens. A method for faster detection of bacterial proliferation presents one avenue towards addressing this global concern. We report on a label-free asynchronous magnetic bead rotation (AMBR) based viscometry method that rapidly detects bacterial growth and determines drug sensitivity by measuring changes in the suspension’s viscosity. With this platform, we observed the growth of a uropathogenic Escherichia coli isolate, with an initial concentration of 50 cells per drop, within 20 minutes; in addition, we determined the gentamicin minimum inhibitory concentration (MIC) of the E. coli isolate within 100 minutes. We thus demonstrated a label-free, micro-viscometer platform that can measure bacterial growth and drug susceptibility more rapidly, with lower initial bacterial counts than existing commercial systems, and potentially with any microbial strains. PMID:22507307

  15. In Search of Alternative Antibiotic Drugs: Quorum-Quenching Activity in Sponges and their Bacterial Isolates

    PubMed Central

    Saurav, Kumar; Bar-Shalom, Rinat; Haber, Markus; Burgsdorf, Ilia; Oliviero, Giorgia; Costantino, Valeria; Morgenstern, David; Steindler, Laura

    2016-01-01

    Owing to the extensive development of drug resistance in pathogens against the available antibiotic arsenal, antimicrobial resistance is now an emerging major threat to public healthcare. Anti-virulence drugs are a new type of therapeutic agent aiming at virulence factors rather than killing the pathogen, thus providing less selective pressure for evolution of resistance. One promising example of this therapeutic concept targets bacterial quorum sensing (QS), because QS controls many virulence factors responsible for bacterial infections. Marine sponges and their associated bacteria are considered a still untapped source for unique chemical leads with a wide range of biological activities. In the present study, we screened extracts of 14 sponge species collected from the Red and Mediterranean Sea for their quorum-quenching (QQ) potential. Half of the species showed QQ activity in at least 2 out of 3 replicates. Six out of the 14 species were selected for bacteria isolation, to test for QQ activity also in isolates, which, once cultured, represent an unlimited source of compounds. We show that ≈20% of the isolates showed QQ activity based on a Chromobacterium violaceum CV026 screen, and that the presence or absence of QQ activity in a sponge extract did not correlate with the abundance of isolates with the same activity from the same sponge species. This can be explained by the unknown source of QQ compounds in sponge-holobionts (host or symbionts), and further by the possible non-symbiotic nature of bacteria isolated from sponges. The potential symbiotic nature of the isolates showing QQ activity was tested according to the distribution and abundance of taxonomically close bacterial Operational Taxonomic Units (OTUs) in a dataset including 97 sponge species and 178 environmental samples (i.e., seawater, freshwater, and marine sediments). Most isolates were found not to be enriched in sponges and may simply have been trapped in the filtration channels of the

  16. In Search of Alternative Antibiotic Drugs: Quorum-Quenching Activity in Sponges and their Bacterial Isolates.

    PubMed

    Saurav, Kumar; Bar-Shalom, Rinat; Haber, Markus; Burgsdorf, Ilia; Oliviero, Giorgia; Costantino, Valeria; Morgenstern, David; Steindler, Laura

    2016-01-01

    Owing to the extensive development of drug resistance in pathogens against the available antibiotic arsenal, antimicrobial resistance is now an emerging major threat to public healthcare. Anti-virulence drugs are a new type of therapeutic agent aiming at virulence factors rather than killing the pathogen, thus providing less selective pressure for evolution of resistance. One promising example of this therapeutic concept targets bacterial quorum sensing (QS), because QS controls many virulence factors responsible for bacterial infections. Marine sponges and their associated bacteria are considered a still untapped source for unique chemical leads with a wide range of biological activities. In the present study, we screened extracts of 14 sponge species collected from the Red and Mediterranean Sea for their quorum-quenching (QQ) potential. Half of the species showed QQ activity in at least 2 out of 3 replicates. Six out of the 14 species were selected for bacteria isolation, to test for QQ activity also in isolates, which, once cultured, represent an unlimited source of compounds. We show that ≈20% of the isolates showed QQ activity based on a Chromobacterium violaceum CV026 screen, and that the presence or absence of QQ activity in a sponge extract did not correlate with the abundance of isolates with the same activity from the same sponge species. This can be explained by the unknown source of QQ compounds in sponge-holobionts (host or symbionts), and further by the possible non-symbiotic nature of bacteria isolated from sponges. The potential symbiotic nature of the isolates showing QQ activity was tested according to the distribution and abundance of taxonomically close bacterial Operational Taxonomic Units (OTUs) in a dataset including 97 sponge species and 178 environmental samples (i.e., seawater, freshwater, and marine sediments). Most isolates were found not to be enriched in sponges and may simply have been trapped in the filtration channels of the

  17. Drug Resistance Mechanisms in Bacteria Causing Sexually Transmitted Diseases and Associated with Vaginosis

    PubMed Central

    Shaskolskiy, Boris; Dementieva, Ekaterina; Leinsoo, Arvo; Runina, Anastassia; Vorobyev, Denis; Plakhova, Xenia; Kubanov, Alexey; Deryabin, Dmitrii; Gryadunov, Dmitry

    2016-01-01

    Here, we review sexually transmitted diseases (STDs) caused by pathogenic bacteria and vaginal infections which result from an overgrowth of opportunistic bacterial microflora. First, we describe the STDs, the corresponding pathogens and the antimicrobials used for their treatment. In addition to the well-known diseases caused by single pathogens (i.e., syphilis, gonococcal infections, and chlamydiosis), we consider polymicrobial reproductive tract infections (especially those that are difficult to effectively clinically manage). Then, we summarize the biochemical mechanisms that lead to antimicrobial resistance and the most recent data on the emergence of drug resistance in STD pathogens and bacteria associated with vaginosis. A large amount of research performed in the last 10–15 years has shed light on the enormous diversity of mechanisms of resistance developed by bacteria. A detailed understanding of the mechanisms of antimicrobials action and the emergence of resistance is necessary to modify existing drugs and to develop new ones directed against new targets. PMID:27242760

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

    PubMed

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

    2010-10-01

    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.

  19. Diagnosis and Treatment of Drug-Resistant Tuberculosis.

    PubMed

    Caminero, José A; Cayla, Joan A; García-García, José-María; García-Pérez, Francisco J; Palacios, Juan J; Ruiz-Manzano, Juan

    2017-03-27

    In the last 2 decades, drug-resistant tuberculosis has become a threat and a challenge to worldwide public health. The diagnosis and treatment of these forms of tuberculosis are much more complex and prognosis clearly worsens as the resistance pattern intensifies. Nevertheless, it is important to remember that with the appropriatesystematic clinical management, most of these patients can be cured. These guidelines itemize the basis for the diagnosis and treatment of all tuberculosis patients, from those infected by strains that are sensitive to all drugs, to those who are extensively drug-resistant. Specific recommendations are given forall cases. The current and future role of new molecular methods for detecting resistance, shorter multi-drug-resistant tuberculosis regimens, and new drugs with activity against Mycobacterium tuberculosis are also addressed.

  20. Quantifying the Determinants of Evolutionary Dynamics Leading to Drug Resistance

    PubMed Central

    Chevereau, Guillaume; Dravecká, Marta; Batur, Tugce; Guvenek, Aysegul; Ayhan, Dilay Hazal; Toprak, Erdal; Bollenbach, Tobias

    2015-01-01

    The emergence of drug resistant pathogens is a serious public health problem. It is a long-standing goal to predict rates of resistance evolution and design optimal treatment strategies accordingly. To this end, it is crucial to reveal the underlying causes of drug-specific differences in the evolutionary dynamics leading to resistance. However, it remains largely unknown why the rates of resistance evolution via spontaneous mutations and the diversity of mutational paths vary substantially between drugs. Here we comprehensively quantify the distribution of fitness effects (DFE) of mutations, a key determinant of evolutionary dynamics, in the presence of eight antibiotics representing the main modes of action. Using precise high-throughput fitness measurements for genome-wide Escherichia coli gene deletion strains, we find that the width of the DFE varies dramatically between antibiotics and, contrary to conventional wisdom, for some drugs the DFE width is lower than in the absence of stress. We show that this previously underappreciated divergence in DFE width among antibiotics is largely caused by their distinct drug-specific dose-response characteristics. Unlike the DFE, the magnitude of the changes in tolerated drug concentration resulting from genome-wide mutations is similar for most drugs but exceptionally small for the antibiotic nitrofurantoin, i.e., mutations generally have considerably smaller resistance effects for nitrofurantoin than for other drugs. A population genetics model predicts that resistance evolution for drugs with this property is severely limited and confined to reproducible mutational paths. We tested this prediction in laboratory evolution experiments using the “morbidostat”, a device for evolving bacteria in well-controlled drug environments. Nitrofurantoin resistance indeed evolved extremely slowly via reproducible mutations—an almost paradoxical behavior since this drug causes DNA damage and increases the mutation rate. Overall

  1. Drug Response and Resistance in Advanced NF-1-Associated Cancers

    DTIC Science & Technology

    2015-07-01

    in Nf1 mutant mice and have investigated mechanisms of drug responses and resistance. Our studies of MEK inhibitors in Nf1 mutant mice unexpectedly...Nf1 inactivation; (4) implementing protocols for treating mice with CPX-351; and (5) performing in vivo studies of drug combinations in Nf1 mutant AML...MPN and AML in Nf1 mutant mice and have investigated mechanisms of drug response and resistance. Our studies of MEK inhibitors in Nf1 mutant mice

  2. Resistance to anti-influenza drugs: adamantanes and neuraminidase inhibitors.

    PubMed

    Hurt, Aeron C; Ho, Hui-Ting; Barr, Ian

    2006-10-01

    Development of effective drugs for the treatment or prevention of epidemic and pandemic influenza is important in order to reduce its impact. Adamantanes and neuraminidase inhibitors are two classes of anti-influenza drugs available for influenza therapy currently. However, emergence of resistance to these drugs has been detected, which raises concerns regarding their widespread use. In this review, resistance to the adamantanes and neuraminidase inhibitors will be discussed in relation to both epidemic and pandemic influenza viruses.

  3. Antitubercular Drug Resistance in Four Healthcare Facilities in North India

    PubMed Central

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

    2011-01-01

    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. PMID:22283032

  4. Overcome Cancer Cell Drug Resistance Using Natural Products

    PubMed Central

    Wang, Pu; Yang, Hua Li; Yang, Ying Juan; Wang, Lan; Lee, Shao Chin

    2015-01-01

    Chemotherapy is one of the major treatment methods for cancer. However, failure in chemotherapy is not uncommon, mainly due to dose-limiting toxicity associated with drug resistance. Management of drug resistance is important towards successful chemotherapy. There are many reports in the Chinese literature that natural products can overcome cancer cell drug resistance, which deserve sharing with scientific and industrial communities. We summarized the reports into four categories: (1) in vitro studies using cell line models; (2) serum pharmacology; (3) in vivo studies using animal models; and (4) clinical studies. Fourteen single compounds were reported to have antidrug resistance activity for the first time. In vitro, compounds were able to overcome drug resistance at nontoxic or subtoxic concentrations, in a dose-dependent manner, by inhibiting drug transporters, cell detoxification capacity, or cell apoptosis sensitivity. Studies in vivo showed that single compounds, herbal extract, and formulas had potent antidrug resistance activities. Importantly, many single compounds, herbal extracts, and formulas have been used clinically to treat various diseases including cancer. The review provides comprehensive data on use of natural compounds to overcome cancer cell drug resistance in China, which may facilitate the therapeutic development of natural products for clinical management of cancer drug resistance. PMID:26421052

  5. Cancer stem cells and drug resistance: the potential of nanomedicine

    PubMed Central

    Vinogradov, Serguei; Wei, Xin

    2012-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  7. Efflux-Mediated Drug Resistance in Bacteria: an Update

    PubMed Central

    Li, Xian-Zhi; Nikaido, Hiroshi

    2010-01-01

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

  8. On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy.

    PubMed

    Mattila, Sari; Ruotsalainen, Pilvi; Jalasvuori, Matti

    2015-01-01

    Bacteriophages are bacterial viruses, capable of killing even multi-drug resistant bacterial cells. For this reason, therapeutic use of phages is considered as a possible alternative to conventional antibiotics. However, phages are very host specific in comparison to wide-spectrum antibiotics and thus preparation of phage-cocktails beforehand against pathogens can be difficult. In this study, we evaluate whether it may be possible to isolate phages on-demand from environmental reservoir. We attempted to enrich infectious bacteriophages from sewage against nosocomial drug-resistant bacterial strains of different medically important species in order to evaluate the probability of discovering novel therapeutic phages. Stability and host-range were determined for the acquired phages. Our results suggest that on-demand isolation of phages is possible against Pseudomonas aeruginosa, Salmonella and extended spectrum beta-lactamase Escherichia coli and Klebsiella pneumoniae. The probability of finding suitable phages was less than 40% against vancomycin resistant Enterococcus and Acinetobacter baumannii strains. Furthermore, isolation of new phages against methicillin resistant Staphylococcus aureus strains was found to be very difficult.

  9. On-Demand Isolation of Bacteriophages Against Drug-Resistant Bacteria for Personalized Phage Therapy

    PubMed Central

    Mattila, Sari; Ruotsalainen, Pilvi; Jalasvuori, Matti

    2015-01-01

    Bacteriophages are bacterial viruses, capable of killing even multi-drug resistant bacterial cells. For this reason, therapeutic use of phages is considered as a possible alternative to conventional antibiotics. However, phages are very host specific in comparison to wide-spectrum antibiotics and thus preparation of phage-cocktails beforehand against pathogens can be difficult. In this study, we evaluate whether it may be possible to isolate phages on-demand from environmental reservoir. We attempted to enrich infectious bacteriophages from sewage against nosocomial drug-resistant bacterial strains of different medically important species in order to evaluate the probability of discovering novel therapeutic phages. Stability and host-range were determined for the acquired phages. Our results suggest that on-demand isolation of phages is possible against Pseudomonas aeruginosa, Salmonella and extended spectrum beta-lactamase Escherichia coli and Klebsiella pneumoniae. The probability of finding suitable phages was less than 40% against vancomycin resistant Enterococcus and Acinetobacter baumannii strains. Furthermore, isolation of new phages against methicillin resistant Staphylococcus aureus strains was found to be very difficult. PMID:26617601

  10. Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance.

    PubMed

    El-Halfawy, Omar M; Klett, Javier; Ingram, Rebecca J; Loutet, Slade A; Murphy, Michael E P; Martín-Santamaría, Sonsoles; Valvano, Miguel A

    2017-03-14

    The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins.IMPORTANCE Current research on antibiotic action and resistance focuses on targeting essential functions within bacterial cells. We discovered a previously unrecognized mode of general bacterial antibiotic resistance operating in the extracellular space, which depends on bacterial protein molecules called lipocalins. These molecules are highly conserved in most bacteria and have the ability to capture different classes of antibiotics outside bacterial cells. We also discovered that liposoluble vitamins, such as vitamin E, overcome in vitro and in vivo antibiotic resistance mediated by bacterial lipocalins, providing an unexpected new alternative to combat resistance by using this vitamin or its derivatives as antibiotic adjuvants.

  11. Totally drug-resistant tuberculosis and adjunct therapies.

    PubMed

    Parida, S K; Axelsson-Robertson, R; Rao, M V; Singh, N; Master, I; Lutckii, A; Keshavjee, S; Andersson, J; Zumla, A; Maeurer, M

    2015-04-01

    The first cases of totally drug-resistant (TDR) tuberculosis (TB) were reported in Italy 10 years ago; more recently, cases have also been reported in Iran, India and South Africa. Although there is no consensus on terminology, it is most commonly described as 'resistance to all first- and second-line drugs used to treat TB'. Mycobacterium tuberculosis (M.tb) acquires drug resistance mutations in a sequential fashion under suboptimal drug pressure due to monotherapy, inadequate dosing, treatment interruptions and drug interactions. The treatment of TDR-TB includes antibiotics with disputed or minimal effectiveness against M.tb, and the fatality rate is high. Comorbidities such as diabetes and infection with human immunodeficiency virus further impact on TB treatment options and survival rates. Several new drug candidates with novel modes of action are under late-stage clinical evaluation (e.g., delamanid, bedaquiline, SQ109 and sutezolid). 'Repurposed' antibiotics have also recently been included in the treatment of extensively drug resistant TB. However, because of mutations in M.tb, drugs will not provide a cure for TB in the long term. Adjunct TB therapies, including therapeutic vaccines, vitamin supplementation and/or repurposing of drugs targeting biologically and clinically relevant molecular pathways, may achieve better clinical outcomes in combination with standard chemotherapy. Here, we review broader perspectives of drug resistance in TB and potential adjunct treatment options.

  12. Is bacterial fatty acid synthesis a valid target for antibacterial drug discovery?

    PubMed

    Parsons, Joshua B; Rock, Charles O

    2011-10-01

    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 is not 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.

  13. Electrospinning polyvinylidene fluoride fibrous membranes containing anti-bacterial drugs used as wound dressing.

    PubMed

    He, Ting; Wang, Jingnan; Huang, Peilin; Zeng, Baozhen; Li, Haihong; Cao, Qingyun; Zhang, Shiying; Luo, Zhuo; Deng, David Y B; Zhang, Hongwu; Zhou, Wuyi

    2015-06-01

    The aim of this study was to synthesis drug-loaded fibrous membrane scaffolds for potential applications as wound dressing. Polyvinylidene fluoride (PVDF) fibrous membranes were loaded with enrofloxacin (Enro) drugs by using an electrospinning process, and their mechanical strength, drug release profile and anti-bacterial properties were evaluated. Enro drug-loaded PVDF membranes exhibited good elasticity, flexibility and excellent mechanical strength. The electrospinning Enro/PVDF membranes showed a burst drug release in the initial 12h, followed by sustained release for the next 3 days, which was an essential property for antibiotic drugs applied for wound healing. The drug-loaded PVDF fibrous membranes displayed excellent anti-bacterial activity toward Escherichia coli and Staphylococcus aureus. The results suggest that electrospinning PVDF membrane scaffolds loaded with drugs can be used as wound dressing.

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

    NASA Astrophysics Data System (ADS)

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

    2013-03-01

    Drug resistance in cancer is usually caused by the spatial drug gradients in tumor environment. Here, we culture multiple myeloma in a gradient from 0 to 20 nM of doxorubicin (genotoxic drug) across 2 mm wide region for 12 days. The myeloma cells grew rapidly and formed 3D colonies in the regions with less drug concentration. However, we have seen emergent colonies forming in regions with drug concentration above the minimal inhibitory concentration in less than one week. Once the cells have occupied the regions with less drug concentration, they tend to migrate toward the regions with higher drug concentration in a collective behavior. To characterize their resistance, we collect them from this microfluidic system, for further analysis of the dose response. We find that the IC50 (drug concentration that inhibits 50% of controlled population) of the cells, undergone a drug gradient, increase 16-fold of the wildtype cells. We further discover that these resistant cells express more Multidrug Resistance (mdr) protein, which pumps out the drugs and causes drug resistance, than the wildtype. Our current works on RNA-sequencing analysis may discover other biomolecular mechanisms that may confer the drug resistance.

  15. Increase in Antibiotic-Resistant Gram-Negative Bacterial Infections in Febrile Neutropenic Children

    PubMed Central

    2016-01-01

    Background The incidence of bacteremia caused by Gram-negative bacteria has increased recently in febrile neutropenic patients with the increase of antibiotic-resistant Gram-negative bacterial infections. This study aimed to identify the distribution of causative bacteria and the proportion of antibiotic-resistant bacteria in bacteremia diagnosed in febrile neutropenic children. Materials and Methods The medical records of febrile neutropenic children diagnosed with bacteremia between 2010 and 2014 were retrospectively reviewed. The causative bacteria and proportion of antibiotic-resistant bacteria were investigated and compared yearly during the study period. The clinical impact of antibiotic-resistant bacterial infections was also determined. Results A total of 336 bacteremia episodes were identified. During the entire study period, 181 (53.9%) and 155 (46.1%) episodes were caused by Gram-negative and Gram-positive bacteria, respectively. Viridans streptococci (25.9%), Klebsiella spp. (16.7%), and Escherichia coli (16.4%) were the most frequent causative bacteria. The overall distribution of causative bacteria was not significantly different annually. Antibiotic-resistant bacteria were identified in 85 (25.3%) episodes, and the proportion of antibiotic-resistant bacteria was not significantly different annually. Extended-spectrum β-lactamase-producing E. coli and Klebsiella spp. were most common among antibiotic-resistant Gram-negative bacteria, and they accounted for 30.6% (n = 34) of the identified E. coli and K. pneumoniae. Methicillin-resistant coagulase-negative staphylococci were most common among antibiotic-resistant Gram-positive bacteria, and it accounted for 88.5% (n = 23) of the identified coagulase-negative staphylococci. Antibiotic-resistant bacterial infections, especially antibiotic-resistant Gram-negative bacterial infections, caused significantly higher mortality due to bacteremia compared with non-antibiotic-resistant bacterial infections (P <0

  16. Antibiotic Capture by Bacterial Lipocalins Uncovers an Extracellular Mechanism of Intrinsic Antibiotic Resistance

    PubMed Central

    El-Halfawy, Omar M.; Klett, Javier; Ingram, Rebecca J.; Loutet, Slade A.; Murphy, Michael E. P.; Martín-Santamaría, Sonsoles

    2017-01-01

    ABSTRACT The potential for microbes to overcome antibiotics of different classes before they reach bacterial cells is largely unexplored. Here we show that a soluble bacterial lipocalin produced by Burkholderia cenocepacia upon exposure to sublethal antibiotic concentrations increases resistance to diverse antibiotics in vitro and in vivo. These phenotypes were recapitulated by heterologous expression in B. cenocepacia of lipocalin genes from Pseudomonas aeruginosa, Mycobacterium tuberculosis, and methicillin-resistant Staphylococcus aureus. Purified lipocalin bound different classes of bactericidal antibiotics and contributed to bacterial survival in vivo. Experimental and X-ray crystal structure-guided computational studies revealed that lipocalins counteract antibiotic action by capturing antibiotics in the extracellular space. We also demonstrated that fat-soluble vitamins prevent antibiotic capture by binding bacterial lipocalin with higher affinity than antibiotics. Therefore, bacterial lipocalins contribute to antimicrobial resistance by capturing diverse antibiotics in the extracellular space at the site of infection, which can be counteracted by known vitamins. PMID:28292982

  17. The mechanism of resistance to sulfa drugs in Plasmodium falciparum.

    PubMed

    Triglia, Tony; Cowman, Alan F.

    1999-02-01

    The sulfonamide and sulfone (sulfa) group of antimalarials has been used extensively throughout malaria endemic regions of the world to control this important infectious disease of humans. Sulfadoxine is the most extensively used drug of this group of drugs and is usually combined with pyrimethamine (Fansidar), particularly for the control of Plasmodium falciparum, the causative agent of the most lethal form of malaria. Resistance to the sulfadoxine/pyrimethamine combination is widespread. Analysis using molecular, genetic and biochemical approaches has shown that the mechanism of resistance to sulfadoxine involves mutation of dihydropteroate synthase, the enzyme target of this group of drugs. Understanding the mechanism of resistance of P. falciparum to sulfa drugs has allowed detailed analysis of the epidemiology of the spread of drug resistance alleles in the field(1)and, in the future, opens the way to the development of novel antimalarials to this target enzyme. Copyright 1999 Harcourt Publishers Ltd.

  18. Understanding Drug Resistance in Breast Cancer with Mathematical Oncology

    PubMed Central

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

    2014-01-01

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

  19. [New tuberculosis drugs in resistant and multiresistant tuberculosis].

    PubMed

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

    2013-10-05

    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.

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

    PubMed Central

    Williams, Julia J.; Hergenrother, Paul J.

    2008-01-01

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

  1. PfCRT and its role in antimalarial drug resistance

    PubMed Central

    Ecker, Andrea; Lehane, Adele M.; Clain, Jérôme; Fidock, David A.

    2012-01-01

    Plasmodium falciparum resistance to chloroquine, the former gold standard antimalarial drug, is mediated primarily by mutant forms of the ‘Chloroquine Resistance Transporter’ (PfCRT). These mutations impart upon PfCRT the ability to efflux chloroquine from the intracellular digestive vacuole, the site of drug action. Recent studies reveal that PfCRT variants can also affect parasite fitness, protect immature gametocytes against chloroquine action, and alter P. falciparum susceptibility to current first-line therapies. These results highlight the need to be vigilant in screening for the appearance of novel pfcrt alleles that could contribute to new multi-drug resistance phenotypes. PMID:23020971

  2. Microenvironment drug resistance in multiple myeloma: emerging new players

    PubMed Central

    Solimando, Antonio Giovanni; Ruggieri, Simona; Annese, Tiziana; Nico, Beatrice; Fumarulo, Ruggiero; Vacca, Angelo; Frassanito, Maria Antonia

    2016-01-01

    Multiple myeloma (MM) drug resistance (DR) is a multistep transformation process based on a powerful interplay between bone marrow stromal cells and MM cells that allows the latter to escape anti-myeloma therapies. Here we present an overview of the role of the bone marrow microenvironment in both soluble factors-mediated drug resistance (SFM-DR) and cell adhesion-mediated drug resistance (CAM-DR), focusing on the role of new players, namely miRNAs, exosomes and cancer-associated fibroblasts. PMID:27474171

  3. Prediction of Cancer Drug Resistance and Implications for Personalized Medicine

    PubMed Central

    Volm, Manfred; Efferth, Thomas

    2015-01-01

    Drug resistance still impedes successful cancer chemotherapy. A major goal of early concepts in individualized therapy was to develop in vitro tests to predict tumors’ drug responsiveness. We have developed an in vitro short-term test based on nucleic acid precursor incorporation to determine clinical drug resistance. This test detects inherent and acquired resistance in vitro and transplantable syngeneic and xenografted tumors in vivo. In several clinical trials, clinical resistance was predictable with more than 90% accuracy, while drug sensitivity was detected with less accuracy (~60%). Remarkably, clinical cross-resistance to numerous drugs (multidrug resistance, broad spectrum resistance) was detectable by a single compound, doxorubicin, due to its multifactorial modes of action. The results of this predictive test were in good agreement with predictive assays of other authors. As no predictive test has been established as yet for clinical diagnostics, the identification of sensitive drugs may not reach sufficiently high reliability for clinical routine. A meta-analysis of the literature published during the past four decades considering test results of more than 15,000 tumor patients unambiguously demonstrated that, in the majority of studies, resistance was correctly predicted with an accuracy between 80 and 100%, while drug sensitivity could only be predicted with an accuracy of 50–80%. This synopsis of the published literature impressively illustrates that prediction of drug resistance could be validated. The determination of drug resistance was reliable independent of tumor type, test assay, and drug used in these in vitro tests. By contrast, chemosensitivity could not be predicted with high reliability. Therefore, we propose a rethinking of the “chemosensitivity” concept. Instead, predictive in vitro tests may reliably identify drug-resistant tumors. The clinical consequence imply to subject resistant tumors not to chemotherapy, but to other new

  4. Suppression of bacterial blight on mustard greens with host plant resistance and Acibenzolar-S-Methyl

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial blight, caused by Pseudomonas cannabina pv. alisalensis, attacks the leaves of most brassica vegetables, including mustard greens (Brassica juncea). ‘Carolina Broadleaf,’ a new mustard cultivar, is resistant to bacterial blight. Acibenzolar-S-methyl (trade name Actigard) has been used to m...

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  6. Why does drug resistance readily evolve but vaccine resistance does not?

    PubMed Central

    2017-01-01

    Why is drug resistance common and vaccine resistance rare? Drugs and vaccines both impose substantial pressure on pathogen populations to evolve resistance and indeed, drug resistance typically emerges soon after the introduction of a drug. But vaccine resistance has only rarely emerged. Using well-established principles of population genetics and evolutionary ecology, we argue that two key differences between vaccines and drugs explain why vaccines have so far proved more robust against evolution than drugs. First, vaccines tend to work prophylactically while drugs tend to work therapeutically. Second, vaccines tend to induce immune responses against multiple targets on a pathogen while drugs tend to target very few. Consequently, pathogen populations generate less variation for vaccine resistance than they do for drug resistance, and selection has fewer opportunities to act on that variation. When vaccine resistance has evolved, these generalities have been violated. With careful forethought, it may be possible to identify vaccines at risk of failure even before they are introduced. PMID:28356449

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

    PubMed

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

    2015-05-07

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

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

    PubMed

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

    2015-05-01

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

  9. Origin of robustness in generating drug-resistant malaria parasites.

    PubMed

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

    2014-07-01

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

  10. Epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

    PubMed

    Issa, Mark E; Takhsha, Farnaz Sedigheh; Chirumamilla, Chandra Sekhar; Perez-Novo, Claudina; Vanden Berghe, Wim; Cuendet, Muriel

    2017-01-01

    Multiple myeloma (MM) is a hematological malignancy, which remains incurable because most patients eventually relapse or become refractory to current treatments. Due to heterogeneity within the cancer cell microenvironment, cancer cell populations employ a dynamic survival strategy to chemotherapeutic treatments, which frequently results in a rapid acquisition of therapy resistance. Besides resistance-conferring genetic alterations within a tumor cell population selected during drug treatment, recent findings also reveal non-mutational mechanisms of drug resistance, involving a small population of "cancer stem cells" (CSCs) which are intrinsically more refractory to the effects of a variety of anticancer drugs. Other studies have implicated epigenetic mechanisms in reversible drug tolerance to protect the population from eradication by potentially lethal exposures, suggesting that acquired drug resistance does not necessarily require a stable heritable genetic alteration. Clonal evolution of MM cells and the bone marrow microenvironment changes contribute to drug resistance. MM-CSCs may not be a static population and survive as phenotypically and functionally different cell types via the transition between stem-like and non-stem-like states in local microenvironments, as observed in other types of cancers. Targeting MM-CSCs is clinically relevant, and different approaches have been suggested to target molecular, metabolic and epigenetic signatures, and the self-renewal signaling characteristic of MM CSC-like cells. Here, we summarize epigenetic strategies to reverse drug resistance in heterogeneous multiple myeloma.

  11. Mechanisms of Resistance to Antibody-Drug Conjugates.

    PubMed

    Loganzo, Frank; Sung, Matthew; Gerber, Hans-Peter

    2016-12-01

    Drug resistance limits the effectiveness of cancer therapies. Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents. Antibody-drug conjugates (ADC) are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy; however, recent preclinical studies reveal potential mechanisms of resistance. Because ADCs are a combination of antibody and small molecule cytotoxin, multifactorial modes of resistance are emerging that are inherent to the structure and function of the ADC. Decreased cell-surface antigen reduces antibody binding, whereas elevated drug transporters such as MDR1 and MRP1 reduce effectiveness of the payload. Inherent to the uniqueness of the ADC, other novel resistance mechanisms are emerging, including altered antibody trafficking, ADC processing, and intracellular drug release. Most importantly, the modular nature of the ADC allows components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance. This review is intended to highlight recent progress in our understanding of ADC resistance, including approaches to create preclinical ADC-refractory models and to characterize their emerging mechanisms of resistance. Mol Cancer Ther; 15(12); 2825-34. ©2016 AACR.

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

    NASA Astrophysics Data System (ADS)

    Taitt, Chris Rowe; Leski, Tomasz; Stenger, David; Vora, Gary J.; House, Brent; Nicklasson, Matilda; Pimentel, Guillermo; Zurawski, Daniel V.; Kirkup, Benjamin C.; Craft, David; Waterman, Paige E.; Lesho, Emil P.; Bangurae, Umaru; Ansumana, Rashid

    2012-06-01

    The prevalence of multidrug-resistant infections in personnel wounded in Iraq and Afghanistan has made it challenging for physicians to choose effective therapeutics in a timely fashion. To address the challenge of identifying the potential for drug resistance, we have developed the Antimicrobial Resistance Determinant Microarray (ARDM) to provide DNAbased analysis for over 250 resistance genes covering 12 classes of antibiotics. Over 70 drug-resistant bacteria from different geographic regions have been analyzed on ARDM, with significant differences in patterns of resistance identified: genes for resistance to sulfonamides, trimethoprim, chloramphenicol, rifampin, and macrolide-lincosamidesulfonamide drugs were more frequently identified in isolates from sources in Iraq/Afghanistan. Of particular concern was the presence of genes responsible for resistance to many of the last-resort antibiotics used to treat war traumaassociated infections.

  13. Bedaquiline: A novel drug to combat multiple drug-resistant tuberculosis.

    PubMed

    Goel, Divya

    2014-01-01

    Tuberculosis (TB) is among the most common infectious diseases and continues as a major global health problem. The scenario is worsened by the emergence and spread of multiple drug-resistant tuberculosis (MDR-TB) and extensive drug-resistant tuberculosis (XDR-TB). Cure rates are high for drug sensitive strains of Myobacterium tuberculosis if treatment protocols are adhered to, but treatment of MDR-TB and extensive drug drug-resistant strains is virtually impossible. The treatment of MDR-TB and XDR-TB relies on the drugs, which are less potent, more toxic and more costly and have to be administered for the longer duration. No new drug had come in to market for last 40 years, but the emergence of MDR-TB and XDR-TB has spurred interest in the development of novel drugs. For the effective treatment outcome, there is a dire need of new drugs with a different mechanism of action that can tackle both drug sensitive as well as drug-resistant strains. Bedaquiline is one such new drug with unique mechanism of action. Food and Drug Administration has approved bedaquiline for MDR-TB in December 2012. This article reviews the available evidence of efficacy and safety of bedaquiline.

  14. Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage

    PubMed Central

    Lehtinen, Sonja; Blanquart, François; Croucher, Nicholas J.; Turner, Paul; Lipsitch, Marc; Fraser, Christophe

    2017-01-01

    Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance. PMID:28096340

  15. Evolution of antibiotic resistance is linked to any genetic mechanism affecting bacterial duration of carriage.

    PubMed

    Lehtinen, Sonja; Blanquart, François; Croucher, Nicholas J; Turner, Paul; Lipsitch, Marc; Fraser, Christophe

    2017-01-31

    Understanding how changes in antibiotic consumption affect the prevalence of antibiotic resistance in bacterial pathogens is important for public health. In a number of bacterial species, including Streptococcus pneumoniae, the prevalence of resistance has remained relatively stable despite prolonged selection pressure from antibiotics. The evolutionary processes allowing the robust coexistence of antibiotic sensitive and resistant strains are not fully understood. While allelic diversity can be maintained at a locus by direct balancing selection, there is no evidence for such selection acting in the case of resistance. In this work, we propose a mechanism for maintaining coexistence at the resistance locus: linkage to a second locus that is under balancing selection and that modulates the fitness effect of resistance. We show that duration of carriage plays such a role, with long duration of carriage increasing the fitness advantage gained from resistance. We therefore predict that resistance will be more common in strains with a long duration of carriage and that mechanisms maintaining diversity in duration of carriage will also maintain diversity in antibiotic resistance. We test these predictions in S. pneumoniae and find that the duration of carriage of a serotype is indeed positively correlated with the prevalence of resistance in that serotype. These findings suggest heterogeneity in duration of carriage is a partial explanation for the coexistence of sensitive and resistant strains and that factors determining bacterial duration of carriage will also affect the prevalence of resistance.

  16. Co-delivery of multiple drug resistance inhibitors by polymer/inorganic hybrid nanoparticles to effectively reverse cancer drug resistance.

    PubMed

    Wu, Cong; Gong, Meng-Qing; Liu, Bo-Ya; Zhuo, Ren-Xi; Cheng, Si-Xue

    2017-01-01

    To effectively reverse multiple drug resistance (MDR) in tumor treatments, a functional nano-sized drug delivery system with active targeting function and pH sensitivity was prepared for the co-delivery of multiple drug resistance inhibitors. Buthionine sulfoximine (BSO) to inhibit GSH synthesis and celecoxib (CXB) to down-regulate P-gp expression were co-loaded in polymer/inorganic hybrid nanoparticles to form buthionine sulfoximine/celecoxib@biotin-heparin/heparin/calcium carbonate/calcium phosphate nanoparticles (BSO/CXB@BNP). To investigate the reversal of MDR, the drug resistant cells (MCF-7/ADR) were pretreated by the dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) followed by the treatment of doxorubicin (DOX) loaded nanoparticles (DOX@BNP). The dual-inhibitor loaded nanoparticles (BSO/CXB@BNP) exhibited greatly enhanced efficiency in down-regulation of GSH and P-gp since BSO and CXB had combined effects on the reduction of GSH and P-gp in drug resistant tumor cells. As a result, BSO/CXB@BNP exhibited a significantly improved capability in reversal of MDR compared with mono-inhibitor loaded nanoparticles (CXB@BNP and BSO@BNP). As compared with free drug resistance inhibitors, delivery of drug resistance inhibitors by functional nanocarriers could obviously improve the therapeutic efficiency due to enhanced cellular uptake and increased intracellular drug accumulation. The study on immunostimulatory effects of different treatments showed that BSO/CXB@BNP treatment resulted in the lowest concentration of interleukin 10, a cytokine related to tumor development. These results suggest the nanoparticulate drug delivery platform developed in this study has promising applications in multiple drug delivery to overcome drug resistance in tumor treatments.

  17. Mechanisms of Drug Resistance in Plasmodium falciparum

    DTIC Science & Technology

    1992-09-11

    parasites. With the collaboration of Dr. Esther Orozco, we cloned two mdr-like genes from Entamoeba histolytica and demonstrated an association of...Orozco (1990). " Entamoeba histolytica : "Physiology of multidrug resistance." Exp Parasitol. 71:169-175. Buschman, E., and P. Gros. (1991). "Functional...Ayala, E. Orozco, and D. Wirth. (1990). "Emetine-resistant mutants of Entamoeba histolytica overexpress mRNAs for multidrug resistance." Mol Biochem

  18. Drug resistance and biochemical characteristics of Salmonella from turkeys.

    PubMed Central

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

    1995-01-01

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

  19. Structure-based drug design to overcome drug resistance: challenges and opportunities.

    PubMed

    Ferreira, Rafaela S; Andricopulo, Adriano D

    2014-01-01

    Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

  20. Pyramiding transgenic resistance in elite indica rice cultivars against the sheath blight and bacterial blight.

    PubMed

    Maruthasalam, S; Kalpana, K; Kumar, K K; Loganathan, M; Poovannan, K; Raja, J A J; Kokiladevi, E; Samiyappan, R; Sudhakar, D; Balasubramanian, P

    2007-06-01

    Elite indica rice cultivars were cotransformed with genes expressing a rice chitinase (chi11) and a thaumatin-like protein (tlp) conferring resistance to fungal pathogens and a serine-threonine kinase (Xa21) conferring bacterial blight resistance, through particle bombardment, with a view to pyramiding sheath blight and bacterial blight resistance. Molecular analyses of putative transgenic lines by polymerase chain reaction, Southern Blot hybridization, and Western Blotting revealed stable integration and expression of the transgenes in a few independent transgenic lines. Progeny analyses showed the stable inheritance of transgenes to their progeny. Coexpression of chitinase and thaumatin-like protein in the progenies of a transgenic Pusa Basmati1 line revealed an enhanced resistance to the sheath blight pathogen, Rhizoctonia solani, as compared to that in the lines expressing the individual genes. A transgenic Pusa Basmati1 line pyramided with chi11, tlp, and Xa21 showed an enhanced resistance to both sheath blight and bacterial blight.

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

    PubMed

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

    2013-03-01

    Melarsoprol and pentamidine represent the two main classes of drugs, the arsenicals and diamidines, historically used to treat the diseases caused by African trypanosomes: sleeping sickness in humans and Nagana in livestock. Cross-resistance to these drugs was first observed over 60 years ago and remains the only example of cross-resistance among sleeping sickness therapies. A Trypanosoma brucei adenosine transporter is well known for its role in the uptake of both drugs. More recently, aquaglyceroporin 2 (AQP2) loss of function was linked to melarsoprol-pentamidine cross-resistance. AQP2, a channel that appears to facilitate drug accumulation, may also be linked to clinical cases of resistance. Here, we review these findings and consider some new questions as well as future prospects for tackling the devastating diseases caused by these parasites.

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

    PubMed

    Friedman, Ran

    2016-03-15

    Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.

  3. Resistance of Aerosolized Bacterial Viruses to Four Germicidal Products

    PubMed Central

    Turgeon, Nathalie; Michel, Kevin; Ha, Thi-Lan; Robine, Enric; Moineau, Sylvain; Duchaine, Caroline

    2016-01-01

    Viral diseases can spread through a variety of routes including aerosols. Yet, limited data are available on the efficacy of aerosolized chemicals to reduce viral loads in the air. Bacteriophages (phages) are often used as surrogates for hazardous viruses in aerosol studies because they are inexpensive, easy to handle, and safe for laboratory workers. Moreover, several of these bacterial viruses display physical characteristics similar to pathogenic human and animal viruses, like morphological size, type of nucleic acids, capsid morphology, and the presence of an envelope. In this study, the efficacy of four chemicals was evaluated on four airborne phages at two different relative humidity levels. Non-tailed bacteriophages MS2 (single-stranded RNA), ϕ6 (double-stranded RNA, enveloped), PR772 (double-stranded DNA), and ϕX174 (single-stranded DNA) were first aerosolized in a 55L rotative environmental chamber at 19°C with 25% and 50% relative humidity. Then, hydrogen peroxide, Eugenol (phenylpropene used in commercial perfumes and flavorings), Mist® (automobile disinfectant containing Triethylene glycol), and Pledge® (multisurface disinfectant containing Isopropanol, n-Alkyl Dimethyl Benzyl Amonium Chlorides, and n-Alkyl Dimethyl Ethylbenzyl Ammonium Chloride) were nebulized with the phages using a separate nebulizer. Aerosols were maintained in suspension during 10 minutes, 1 hour, and 2 hours. Viral aerosols were sampled using an SKC BioSampler and samples were analyzed using qPCR and plaque assays. The resistance levels of the four phages varied depending on the relative humidity (RH) and germicidal products tested. Phage MS2 was the most stable airborne virus under the environmental conditions tested while phage PR772 was the least stable. Pledge® and Eugenol reduced the infectivity of all airborne phages tested. At 25% RH, Pledge® and Eugenol were more effective at reducing infectivity of RNA phages ϕ6 and MS2. At 50% RH, Pledge® was the most effective

  4. Diverse and abundant multi-drug resistant E. coli in Matang mangrove estuaries, Malaysia

    PubMed Central

    Ghaderpour, Aziz; Ho, Wing Sze; Chew, Li-Lee; Bong, Chui Wei; Chong, Ving Ching; Thong, Kwai-Lin; Chai, Lay Ching

    2015-01-01

    E.coli, an important vector distributing antimicrobial resistance in the environment, was found to be multi-drug resistant, abundant, and genetically diverse in the Matang mangrove estuaries, Malaysia. One-third (34%) of the estuarine E. coli was multi-drug resistant. The highest antibiotic resistance prevalence was observed for aminoglycosides (83%) and beta-lactams (37%). Phylogenetic groups A and B1, being the most predominant E. coli, demonstrated the highest antibiotic resistant level and prevalence of integrons (integron I, 21%; integron II, 3%). Detection of phylogenetic group B23 downstream of fishing villages indicates human fecal contamination as a source of E. coli pollution. Enteroaggregative E. coli (1%) were also detected immediately downstream of the fishing village. The results indicated multi-drug resistance among E. coli circulating in Matang estuaries, which could be reflective of anthropogenic activities and aggravated by bacterial and antibiotic discharges from village lack of a sewerage system, aquaculture farms and upstream animal husbandry. PMID:26483759

  5. Effect of Vibration on Bacterial Growth and Antibiotic Resistance

    NASA Technical Reports Server (NTRS)

    Juergensmeyer, Elizabeth A.; Juergensmeyer, Margaret A.

    2004-01-01

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

  6. Highly active ozonides selected against drug resistant malaria

    PubMed Central

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

    2016-01-01

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

  7. Highly active ozonides selected against drug resistant malaria.

    PubMed

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

    2016-06-07

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

  8. Multidrug Efflux Pumps at the Crossroad between Antibiotic Resistance and Bacterial Virulence.

    PubMed

    Alcalde-Rico, Manuel; Hernando-Amado, Sara; Blanco, Paula; Martínez, José L

    2016-01-01

    Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance. This overexpression can be transient, in the presence of an effector (phenotypic resistance), or constitutive when mutants in the regulatory elements of the expression of efflux pumps are selected (acquired resistance). Efflux pumps are present in all cells, from human to bacteria and are highly conserved, which indicates that they are ancient elements in the evolution of different organisms. Consequently, it has been suggested that, besides antibiotic resistance, bacterial multidrug efflux pumps would likely contribute to other relevant processes of the microbial physiology. In the current article, we discuss some specific examples of the role that efflux pumps may have in the bacterial virulence of animals' and plants' pathogens, including the processes of intercellular communication. Based in these evidences, we propose that efflux pumps are at the crossroad between resistance and virulence of bacterial pathogens. Consequently, the comprehensive study of multidrug efflux pumps requires addressing these functions, which are of relevance for the bacterial-host interactions during infection.

  9. Combined antiretroviral and anti-tuberculosis drug resistance following incarceration

    PubMed Central

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

    2013-01-01

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

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

    PubMed

    Wally, Owen; Punja, Zamir K

    2010-01-01

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

  11. An antibiotic protocol to minimize emergence of drug-resistant tuberculosis

    NASA Astrophysics Data System (ADS)

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

    2014-04-01

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

  12. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post-chemotherapy tissues.

    PubMed

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-12-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens.

  13. The challenges of multi-drug-resistance in hepatology.

    PubMed

    Fernández, Javier; Bert, Frédéric; Nicolas-Chanoine, Marie-Hélène

    2016-11-01

    Antimicrobial resistance has become a major global public health security problem that needs coordinated approaches at regional, national and international levels. Antibiotic overuse and the failure of control measures to prevent the spread of resistant bacteria in the healthcare environment have led to an alarming increase in the number of infections caused by resistant bacteria, organisms that resist many (multi-drug and extensively drug-resistant strains), if not all (pan-drug-resistant bacteria) currently available antibiotics. While Gram-positive cocci resistance (methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci) shows a heterogeneous geographical distribution, extended-spectrum β-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae have become pandemic worldwide and endemic in some parts of the world, respectively. Moreover, currently available therapeutic options for resistant bacteria are very limited, with very few new agents in development. Antimicrobial resistance is especially relevant in decompensated cirrhosis. Firstly, cirrhotic patients are highly susceptible to develop infections caused by resistant bacteria as risk factors of multiresistance concentrate in this population (mainly repeated hospitalizations and antibiotic exposure). Secondly, inappropriate empirical antibiotic schedules easily translate into increased morbidity (acute kidney injury, acute-on-chronic liver failure, septic shock) and hospital mortality in advanced cirrhosis. Therefore, hepatologists must face nowadays a complex clinical scenario that requires new empirical antibiotic strategies that may further spread resistance. Global, regional and local preventive measures should therefore be implemented to combat antimicrobial resistance in cirrhosis including the restriction of antibiotic prophylaxis to high-risk populations, investigation on non-antibiotic prophylaxis, stewardship programs on adequate antibiotic

  14. Extensively drug-resistant tuberculosis: epidemiology and management.

    PubMed

    Matteelli, Alberto; Roggi, Alberto; Carvalho, Anna Cc

    2014-01-01

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

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

    PubMed Central

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

    2009-01-01

    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. PMID:19416855

  16. Bacterial resistance and impetigo treatment trends: a review.

    PubMed

    Bangert, Scott; Levy, Moise; Hebert, Adelaide A

    2012-01-01

    Impetigo is a common cutaneous infection that is especially prevalent in children. The prevalence of colonization and infection with resistant strains is continually increasing, forcing clinicians to reevaluate treatment strategies. Newer topical agents are effective in treating infections with resistant strains and may help minimize resistance and adverse effects from systemic agents. Use of topical disinfectants to decrease colonization is an important adjunctive measure. Physicians should be aware of local resistance patterns in impetigo to help guide therapy.

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

    PubMed

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

    2013-01-01

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

  18. Pilot Screening to Determine Antimicrobial Synergies in a Multidrug-Resistant Bacterial Strain Library

    PubMed Central

    Kim, Si-Hyun; Park, Chulmin; Chun, Hye-Sun; Choi, Jae-Ki; Lee, Hyo-Jin; Cho, Sung-Yeon; Park, Sun Hee; Choi, Su-Mi; Choi, Jung-Hyun; Yoo, Jin-Hong

    2016-01-01

    With the rise in multidrug-resistant (MDR) bacterial infections, there has been increasing interest in combinations of ≥2 antimicrobial agents with synergistic effects. We established an MDR bacterial strain library to screen for in vitro antimicrobial synergy by using a broth microdilution checkerboard method and high-throughput luciferase-based bacterial cell viability assay. In total, 39 MDR bacterial strains, including 23 carbapenem-resistant gram-negative bacteria, 9 vancomycin-intermediate Staphylococcus aureus, and 7 vancomycin-resistant Enterococcus faecalis, were used to screen for potential antimicrobial synergies. Synergies were more frequently identified with combinations of imipenem plus trimethoprim–sulfamethoxazole for carbapenem-resistant Acinetobacter baumannii in the library. To verify this finding, we tested 34 A. baumannii clinical isolates resistant to both imipenem and trimethoprim–sulfamethoxazole by the checkerboard method. The imipenem plus trimethoprim–sulfamethoxazole combination showed synergy in the treatment of 21 (62%) of the clinical isolates. The results indicate that pilot screening for antimicrobial synergy in the MDR bacterial strain library could be valuable in the selection of combination therapeutic regimens to treat MDR bacterial infections. Further studies are warranted to determine whether this screening system can be useful to screen for the combined effects of conventional antimicrobials and new-generation antimicrobials or nonantimicrobials. PMID:26974861

  19. [Advances in molecular mechanisms of bacterial resistance caused by stress-induced transfer of resistance genes--a review].

    PubMed

    Sun, Dongchang; Wang, Bing; Zhu, Lihong

    2013-07-04

    The transfer of resistance gene is one of the most important causes of bacterial resistance. Recent studies reveal that stresses induce the transfer of antibiotic resistance gene through multiple mechanisms. DNA damage stresses trigger bacterial SOS response and induce the transfer of resistance gene mediated by conjugative DNA. Antibiotic stresses induce natural bacterial competence for transformation in some bacteria which lack the SOS system. In addition, our latest studies show that the general stress response regulator RpoS regulates a novel type of resistance gene transfer which is mediated by double-stranded plasmid DNA and occurs exclusively on the solid surface. In this review, we summarized recent advances in SOS dependent and independent stress-induced DNA transfer which is mediated by conjugation and transformation respectively, and the transfer of double-stranded plasmid DNA on the solid surface which is regulated by RpoS. We propose that future work should address how stresses activate the key regulators and how these regulators control the expression of gene transfer related genes. Answers to the above questions would pave the way for searching for candidate targets for controlling bacterial resistance resulted from the transfer of antibiotic genes.

  20. The interplay between drug resistance and fitness in malaria parasites.

    PubMed

    Rosenthal, Philip J

    2013-09-01

    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.

  1. Bacteremic pneumonia caused by extensively drug-resistant Streptococcus pneumoniae.

    PubMed

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

    2012-12-01

    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.

  2. A Research-Inspired Laboratory Sequence Investigating Acquired Drug Resistance

    ERIC Educational Resources Information Center

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

    2010-01-01

    Here, we present a six-session laboratory exercise designed to introduce students to standard biochemical techniques in the context of investigating a high impact research topic, acquired resistance to the cancer drug Gleevec. Students express a Gleevec-resistant mutant of the Abelson tyrosine kinase domain, the active domain of an oncogenic…

  3. An efficient system for intracellular delivery of beta-lactam antibiotics to overcome bacterial resistance

    PubMed Central

    Abed, Nadia; Saïd-Hassane, Fatouma; Zouhiri, Fatima; Mougin, Julie; Nicolas, Valérie; Desmaële, Didier; Gref, Ruxandra; Couvreur, Patrick

    2015-01-01

    The “Golden era” of antibiotics is definitely an old story and this is especially true for intracellular bacterial infections. The poor intracellular bioavailability of antibiotics reduces the efficency of many treatments and thereby promotes resistances. Therefore, the development of nanodevices coupled with antibiotics that are capable of targeting and releasing the drug into the infected-cells appears to be a promising solution to circumvent these complications. Here, we took advantage of two natural terpenes (farnesyl and geranyl) to design nanodevices for an efficient intracellular delivery of penicillin G. The covalent linkage between the terpene moieties and the antibiotic leads to formation of prodrugs that self-assemble to form nanoparticles with a high drug payload between 55–63%. Futhermore, the addition of an environmentally-sensitive bond between the antibiotic and the terpene led to an efficient antibacterial activity against the intracellular pathogen Staphylococcus aureus with reduced intracellular replication of about 99.9% compared to untreated infected cells. Using HPLC analysis, we demonstrated and quantified the intracellular release of PenG when this sensitive-bond (SB) was present on the prodrug, showing the success of this technology to deliver antibiotics directly into cells. PMID:26311631

  4. Past, Present, and Future of Antibacterial Economics: Increasing Bacterial Resistance, Limited Antibiotic Pipeline, and Societal Implications.

    PubMed

    Luepke, Katherine H; Suda, Katie J; Boucher, Helen; Russo, Rene L; Bonney, Michael W; Hunt, Timothy D; Mohr, John F

    2017-01-01

    Growing antimicrobial resistance and a dwindling antibiotic pipeline have resulted in an emerging postantibiotic era, as patients are now dying from bacterial infections that were once treatable. The fast-paced "Golden Age" of antibiotic development that started in the 1940s has lost momentum; from the 1980s to the early 2000s, there was a 90% decline in the approval of new antibiotics as well as the discovery of few new novel classes. Many companies have shifted away from development due to scientific, regulatory, and economic hurdles that proved antibiotic development to be less attractive compared with more lucrative therapeutic areas. National and global efforts are focusing attention toward potential solutions for reinvigorating the antibiotic pipeline and include "push" incentives such as public-private partnerships and "pull" incentives such as reimbursement reform and market exclusivity. Hybrid models of incentives, global coordination among stakeholders, and the appropriate balance of antibiotic pricing, volume of drug used, and proper antimicrobial stewardship are key to maximizing efforts toward drug development to ensure access to patients in need of these therapies.

  5. Effect of Lipid Materials on Heat Resistance of Bacterial Spores

    PubMed Central

    Molin, N.; Snygg, B. G.

    1967-01-01

    The apparent heat resistance of spores of Bacillus megaterium, B. subtilis, B. cereus, B. stearothermophilus, and Clostridium botulinum type E in lipids was investigated and compared with the resistance of the spores in phosphate buffer solution. The most pronounced increase in heat resistance was noted for B. subtilis and C. botulinum type E, the increase varying with the type of lipid used. A high water content of the lipids used as heating menstruum lowered the heat resistance of the spores. Possible explanations for the high heat resistance of spores in lipids are discussed. PMID:16349757

  6. Fungal naphtho-γ-pyrones: Potent antibiotics for drug-resistant microbial pathogens

    PubMed Central

    He, Yan; Tian, Jun; Chen, Xintao; Sun, Weiguang; Zhu, Hucheng; Li, Qin; Lei, Liang; Yao, Guangmin; Xue, Yongbo; Wang, Jianping; Li, Hua; Zhang, Yonghui

    2016-01-01

    Four naphtho-γ-pyrones (fonsecinones A and C and aurasperones A and E) were identified as potential antibacterial agents against Escherichia coli, extended-spectrum β-lactamase (ESBL)-producing E. coli, Pseudomonas aeruginosa, Enterococcus faecalis, and methicillin-resistant Staphylococcus aureus (MRSA) in an in vitro antibacterial screen of 218 fungal metabolites. Fonsecinone A (2) exhibited the most potent antibacterial activity, with minimum inhibitory concentrations (MICs) of 4.26, 17.04, and 4.26 μg/mL against ESBL-producing E. coli, P. aeruginosa, and E. faecalis, respectively. The inhibitory effects of fonsecinones A (2) and C (3) against E. coli and ESBL-producing E. coli were comparable to those of amikacin. Molecular docking-based target identification of naphtho-γ-pyrones 1–8 revealed bacterial enoyl-acyl carrier protein reductase (FabI) as an antibacterial target, which was further validated by FabI affinity and inhibition assays. Fonsecinones A (2) and C (3) and aurasperones A (6) and E (7) bound FabI specifically and produced concentration-dependent inhibition effects. This work is the first report of anti-drug-resistant bacterial activities of naphtho-γ-pyrones 1–8 and their possible antibacterial mechanism of action and provides an example of the successful application of in silico methods for drug target identification and validation and the identification of new lead antibiotic compounds against drug-resistant pathogens. PMID:27063778

  7. Analysis on the infections change and measures for the multiple drug-resistant bacteria of neurology.

    PubMed

    Zang, Wenju

    2016-05-01

    To analyze the bacterial infection situations and the separation situations of multiple drug-resistant bacteria of the neurology of Zhengzhou People's hospital from Feb. 2012 to Dec. 2014. The patients data of neurology were retrieved by means of the doctor workstation system. The infection sites, the classification and drug-resistant feature of bacteria were classified and summarized in Excel. Finally, Compared with the infection sites, the classification and drug-resistant feature of bacteria at different year. The data obtained use SPSS 19.0 software to do statistical analysis. The infection rate of bacteria in neurology from Year 2012 to 2014 declined from 4.99% to 3.41%. But the constitution of the infection sites of bacteria had no significant changes. Staphylococcus aureus still was the majority in the infections of gram-positive bacteria, and Escherichia coli was the majority in the infections of gram-negative bacteria, and there were no significant changes in the ranking of the past three years. The separation rate of Acihetobacter baumanii and Pseudomonas aeruginosa in gram-negative bacteria gradually escalated. There were definite efficiencies in the prevention and control of the bacterial infections in neurology in the past three years. But the situation of prevention and control was still severe at the same time.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  9. Phenotypic resistance and the dynamics of bacterial escape from phage control.

    PubMed

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

    2014-01-01

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

  10. New source of bacterial soft rot resistance in wild potato (Solanum chacoense) tubers

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bacterial soft rot caused by Pectobacterium and Dickeya species can cause major losses to the potato (Solanum tuberosum L.) industry, mostly due to tuber rot in storage. There are few germplasm resources for soft rot resistance breeding. Here, we introduce a resistant diploid wild potato relative, M...

  11. Antimicrobial resistance in bacterial isolates from a delhi hospital: one year outcomes.

    PubMed

    Jain, Sanjay; Sharma, Yukti; Arora, Vivek; Deka, Lopamudra; Singh, Sompal

    2013-01-01

    Antimicrobial resistance and hospital acquired infections have become an important public health issue. Data on pathogen and antibiotic resistance is important for physicians, microbiologists and infection control officials but limited information on antibiotic resistance prevents pathogen specific therapy and propels antibiotic misuse. A retrospective review of bacterial isolation and antimicrobial susceptibility profiles in the in- and outpatients of a Delhi hospital between January 2009-December 2009 was performed. A total of 1772 pathogens causing bacterial infections were recorded during the study period January 2009-December 2009. The most frequently encountered bacterial pathogens were Escherichia coli (40.51%), Klebsiella spp. (14.84%) and Staphylococcus aureus (13.99%). We encountered high resistance to ciprofloxacin in Enterobactereaceae family, i.e., 32.5%. Aminoglycosides, once considered optimum for broad spectrum coverage of pathogens for almost all systemic infections, are now showing high rate of resistance as was noted in Acinetobacter sp. (57.14%) and Pseudomonas aeruginosa (69.2%). Antibiotic susceptibility results show a higher level of resistance to cotrimoxazole, cephalosporins and ciprofloxacin which are easily available, orally administered and cheaper and thus are considered a better option for the patients. This study provides insight into the problem of resistance in bacterial pathogens in Delhi. Our results demonstrated that, in general, isolates have high rates of resistance to antibiotics commonly used in developing countries. Guidelines for surveillance and prevention of nosocomial infections must be implemented in order to reduce the rate of hospital acquired infections.

  12. Infectious Multiple Drug Resistance in the Enterobacteriaceae

    DTIC Science & Technology

    1982-03-01

    Enterotoxigenic E . coli were identified with the Y-1 adrenal and suckling mouse assays. All were homologous and thus identifiable with radiolabled...technique detected DNA homologous with the three probes in bacterial growth of all stools from patients with diarrhea from whom enterotoxigenic E . coli were...isolated and in enterotoxigenic E . coli -inoculated water containing other species of bacteria. The DNA hybridization assay is a useful technique for

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

    PubMed Central

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

    2012-01-01

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

  14. [Mobile ISCR elements: structure, functions, and role in the emergence, increasing and spreading of blocks of bacterial genes of multiple antibiotic resistance].

    PubMed

    Il'ina, T S

    2012-01-01

    The recently discovered method of horizontal distribution of bacterial genes with atypical ISCR sequences is reviewed using an example of drug resistance genes. The adjacent DNA segment mobilization is provided by the transposition of such elements, including rolling circle replication, formation of autonomous nonreplicable circular structures, and homological recombination. The gene distribution capacity with the ISCR elements is more significant than the capacity of transposons and integrons, thereby providing formation of groups of mobile genes, including antibiotic-resistance genes of pathogenic bacteria. The structure and functions of the ISCR elements were discussed together with their similarity and dissimilarity with the group of IS91-similar elements and their role in the emergence of blocks of bacterial genes encoding of multiple antibiotic resistance and their contribution to evolution of bacterial and plasmid genes.

  15. New Role for FDA-Approved Drugs in Combating Antibiotic-Resistant Bacteria

    PubMed Central

    Andersson, Jourdan A.; Fitts, Eric C.; Kirtley, Michelle L.; Ponnusamy, Duraisamy; Peniche, Alex G.; Dann, Sara M.; Motin, Vladimir L.; Chauhan, Sadhana; Rosenzweig, Jason A.; Sha, Jian

    2016-01-01

    Antibiotic resistance in medically relevant bacterial pathogens, coupled with a paucity of novel antimicrobial discoveries, represents a pressing global crisis. Traditional drug discovery is an inefficient and costly process; however, systematic screening of Food and Drug Administration (FDA)-approved therapeutics for other indications in humans offers a rapid alternative approach. In this study, we screened a library of 780 FDA-approved drugs to identify molecules that rendered RAW 264.7 murine macrophages resistant to cytotoxicity induced by the highly virulent Yersinia pestis CO92 strain. Of these compounds, we identified 94 not classified as antibiotics as being effective at preventing Y. pestis-induced cytotoxicity. A total of 17 prioritized drugs, based on efficacy in in vitro screens, were chosen for further evaluation in a murine model of pneumonic plague to delineate if in vitro efficacy could be translated in vivo. Three drugs, doxapram (DXP), amoxapine (AXPN), and trifluoperazine (TFP), increased animal survivability despite not exhibiting any direct bacteriostatic or bactericidal effect on Y. pestis and having no modulating effect on crucial Y. pestis virulence factors. These findings suggested that DXP, AXPN, and TFP may modulate host cell pathways necessary for disease pathogenesis. Finally, to further assess the broad applicability of drugs identified from in vitro screens, the therapeutic potential of TFP, the most efficacious drug in vivo, was evaluated in murine models of Salmonella enterica serovar Typhimurium and Clostridium difficile infections. In both models, TFP treatment resulted in increased survivability of infected animals. Taken together, these results demonstrate the broad applicability and potential use of nonantibiotic FDA-approved drugs to combat respiratory and gastrointestinal bacterial pathogens. PMID:27067323

  16. Defensive remodeling: How bacterial surface properties and biofilm formation promote resistance to antimicrobial peptides.

    PubMed

    Nuri, Reut; Shprung, Tal; Shai, Yechiel

    2015-11-01

    Multidrug resistance bacteria are a major concern worldwide. These pathogens cannot be treated with conventional antibiotics and thus alternative therapeutic agents are needed. Antimicrobial peptides (AMPs) are considered to be good candidates for this purpose. Most AMPs are short and positively charged amphipathic peptides, which are found in all known forms of life. AMPs are known to kill bacteria by binding to the negatively charged bacterial surface, and in most cases cause membrane disruption. Resistance toward AMPs can be developed, by modification of bacterial surface molecules, secretion of protective material and up-regulation or elimination of specific proteins. Because of the general mechanisms of attachment and action of AMPs, bacterial resistance to AMPs often involves biophysical and biochemical changes such as surface rigidity, cell wall thickness, surface charge, as well as membrane and cell wall modification. Here we focus on the biophysical, surface and surrounding changes that bacteria undergo in acquiring resistance to AMPs. In addition we discuss the question of whether bacterial resistance to administered AMPs might compromise our innate immunity to endogenous AMPs. This article is part of a Special Issue entitled: Bacterial Resistance to Antimicrobial Peptides.

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

    PubMed Central

    2011-01-01

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

  18. The Warburg effect and drug resistance

    PubMed Central

    Mohd Omar, Mohd Feroz; Soong, Richie

    2016-01-01

      The Warburg effect describes the increased utilization of glycolysis rather than oxidative phosphorylation by tumour cells for their energy requirements under physiological oxygen conditions. This effect has been the basis for much speculation on the survival advantage of tumour cells, tumourigenesis and the microenvironment of tumours. More recently, studies have begun to reveal how the Warburg effect could influence drug efficacy and how our understanding of tumour energetics could be exploited to improve drug development. In particular, evidence is emerging demonstrating how better modelling of the tumour metabolic microenvironment could lead to a better prediction of drug efficacy and the identification of new combination strategies. This review will provide details of the current understanding of the complex interplay between glucose metabolism and pharmacology and discuss opportunities for utilizing the Warburg effect in future drug development. PMID:26750865

  19. Identification of pyruvate kinase in methicillin-resistant Staphylococcus aureus as a novel antimicrobial drug target.

    PubMed

    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

    2011-05-01

    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 μM) 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 μg/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.

  20. Effects of antibiotic resistance alleles on bacterial evolutionary responses to viral parasites.

    PubMed

    Arias-Sánchez, Flor I; Hall, Alex R

    2016-05-01

    Antibiotic resistance has wide-ranging effects on bacterial phenotypes and evolution. However, the influence of antibiotic resistance on bacterial responses to parasitic viruses remains unclear, despite the ubiquity of such viruses in nature and current interest in therapeutic applications. We experimentally investigated this by exposing various Escherichia coli genotypes, including eight antibiotic-resistant genotypes and a mutator, to different viruses (lytic bacteriophages). Across 960 populations, we measured changes in population density and sensitivity to viruses, and tested whether variation among bacterial genotypes was explained by their relative growth in the absence of parasites, or mutation rate towards phage resistance measured by fluctuation tests for each phage. We found that antibiotic resistance had relatively weak effects on adaptation to phages, although some antibiotic-resistance alleles impeded the evolution of resistance to phages via growth costs. By contrast, a mutator allele, often found in antibiotic-resistant lineages in pathogenic populations, had a relatively large positive effect on phage-resistance evolution and population density under parasitism. This suggests costs of antibiotic resistance may modify the outcome of phage therapy against pathogenic populations previously exposed to antibiotics, but the effects of any co-occurring mutator alleles are likely to be stronger.

  1. Distribution of drug-resistant bacteria and rational use of clinical antimicrobial agents.

    PubMed

    Zhou, Chenliang; Chen, Xiaobing; Wu, Liwen; Qu, Jing

    2016-06-01

    Open wound may lead to infection in patients. Due to overuse of medication, certain bacteria have become resistant to drugs currently available. The aim of the present study was to provide a guide to ameliorate the appropriate and rational use of clinical antimicrobial agents by analyzing the distribution of drug-resistant pathogenic bacteria in patients. Between October 2013 and January 2015, 126 patients were selected at the Department of Orthopedics. Wound secretion samples were collected, and the pathogen bacteria isolated and identified. Identification was performed using an automated identification instrument and the Kirby-Bauer antibiotic method was used to evaluate the bacterial resistance. Of the 126 patients, 118 patients were infected (infection rate, 93.65%). Additionally, 47 strains of gram-positive pathogenic bacteria (39.83%) and 71 strains of pathogenic-gram negative bacteria (60.17%) were identified. The bacteria were most likely to be resistant to penicillin while sensitive to vancomycin and imipenem. Some bacteria were resistant to several antibacterial agents. The results showed that existing risk factors at the Department of Orthopedics were complex and any non-standard procedures were able to cause bacterial infection. There were obvious dissimilarities among infectious bacteria with regard to their sensitivity to various antibacterial agents. Manipulation techniques during the treatment process were performed in a sterile manner and the use of antibacterial agents was required to be strictly in accordance with the results of drug sensitivity tests to provide effective etiologic information and a treatment plan for clinical trials and to reduce the risk of infection by multi-resistant bacteria.

  2. Human APOBEC3 proteins, retrovirus restriction, and HIV drug resistance.

    PubMed

    Haché, Guylaine; Mansky, Louis M; Harris, Reuben S

    2006-01-01

    Over 40 million people worldwide currently have HIV/AIDS. Many antiretroviral drugs have proven effective, but drug-resistant HIV variants frequently emerge to thwart treatment efforts. Reverse transcription errors undoubtedly contribute to drug resistance, but additional significant sources of viral genetic variation are debatable. The human APOBEC3F and APOBEC3G proteins can potently inhibit retrovirus infection by a mechanism that involves retroviral cDNA cytosine deamination. Here we review the current knowledge on the mechanism of APOBEC3-dependent retrovirus restriction and discuss whether this innate host-defense system actively contributes to HIV genetic variation.

  3. Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.

    PubMed

    McKie, J H; Douglas, K T; Chan, C; Roser, S A; Yates, R; Read, M; Hyde, J E; Dascombe, M J; Yuthavong, Y; Sirawaraporn, W

    1998-04-23

    Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

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

    PubMed Central

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

    2014-01-01

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

  5. Learning the ABC of oral fungal drug resistance.

    PubMed

    Cannon, R D; Holmes, A R

    2015-12-01

    ATP-binding cassette (ABC) proteins are ubiquitous in prokaryotes and eukaryotes. They are involved in energy-dependent transport of molecules across membranes. ABC proteins are often promiscuous transporters that can translocate a variety of substrates. In oral fungi, especially in Candida species, they have been implicated as major contributors to the high-level azole resistance of clinical isolates from infections that do not respond to drug therapy. Although this is predominantly due to efflux of azoles from the cells, ABC proteins can contribute to fungal drug resistance in other ways as well. Cells in biofilms are notoriously resistant to antifungal agents. ABC proteins can contribute to this resistance through the efflux of drugs. Biofilms are complex communities of myriad microorganisms which, to survive in such a milieu, need to communicate with, and respond to, other microorganisms and their products. ABC proteins are involved in the secretion of fungal mating factors and quorum sensing molecules. These molecules affect biofilm structure and behavior that can result in increased drug resistance. Hence, ABC proteins make multiple contributions to oral fungal drug resistance through a variety of responses to environmental signals.

  6. Indoleamides are active against drug-resistant Mycobacterium tuberculosis

    PubMed Central

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

    2014-01-01

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

  7. Molecular Biology of Drug Resistance in Mycobacterium tuberculosis

    PubMed Central

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

    2014-01-01

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

  8. The priorities for antiviral drug resistance surveillance and research.

    PubMed

    Pillay, Deenan

    2007-08-01

    The number of available antiviral drugs is growing fast. The emergence of drug-resistant viruses is well documented as a cause for drug failure. Such viruses also carry the potential for transmission, the risks for which vary according to specific viral transmission dynamics. This potential is best described for HIV and influenza. Resistance to the new generation of hepatitis C virus inhibitors is also likely to become a cause for concern. The priorities for future action to limit resistance include application of sophisticated surveillance mechanisms linked to detailed virological data, development of optimal treatment regimens (e.g. combination therapies) to limit emergence of resistance, and a focus on prevention strategies to prevent transmission.

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

    PubMed

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

    2013-03-01

    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 β-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.

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

    PubMed

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

    2014-10-15

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

  11. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005-2014.

    PubMed

    Hu, F-P; Guo, Y; Zhu, D-M; Wang, F; Jiang, X-F; Xu, Y-C; Zhang, X-J; Zhang, C-X; Ji, P; Xie, Y; Kang, M; Wang, C-Q; Wang, A-M; Xu, Y-H; Shen, J-L; Sun, Z-Y; Chen, Z-J; Ni, Y-X; Sun, J-Y; Chu, Y-Z; Tian, S-F; Hu, Z-D; Li, J; Yu, Y-S; Lin, J; Shan, B; Du, Y; Han, Y; Guo, S; Wei, L-H; Wu, L; Zhang, H; Kong, J; Hu, Y-J; Ai, X-M; Zhuo, C; Su, D-H; Yang, Q; Jia, B; Huang, W

    2016-03-01

    With the aim of gathering temporal trends on bacterial epidemiology and resistance from multiple laboratories in China, the CHINET surveillance system was organized in 2005. Antimicrobial susceptibility testing was carried out according to a unified protocol using the Kirby-Bauer method or automated systems. Results were analyzed according to Clinical and Laboratory Standards Institute (CLSI) 2014 definitions. Between 2005 and 2014, the number of bacterial isolates ranged between 22,774 and 84,572 annually. Rates of extended-spectrum β-lactamase production among Escherichia coli isolates were stable, between 51.7 and 55.8%. Resistance of E. coli and Klebsiella pneumoniae to amikacin, ciprofloxacin, piperacillin/tazobactam and cefoperazone/sulbactam decreased with time. Carbapenem resistance among K. pneumoniae isolates increased from 2.4 to 13.4%. Resistance of Pseudomonas aeruginosa strains against all of antimicrobial agents tested including imipenem and meropenem decreased with time. On the contrary, resistance of Acinetobacter baumannii strains to carbapenems increased from 31 to 66.7%. A marked decrease of methicillin resistance from 69% in 2005 to 44.6% in 2014 was observed for Staphylococcus aureus. Carbapenem resistance rates in K. pneumoniae and A. baumannii in China are high. Our results indicate the importance of bacterial surveillance studies.

  12. Antifungal drug resistance evoked via RNAi-dependent epimutations.

    PubMed

    Calo, Silvia; Shertz-Wall, Cecelia; Lee, Soo Chan; Bastidas, Robert J; Nicolás, Francisco E; Granek, Joshua A; Mieczkowski, Piotr; Torres-Martínez, Santiago; Ruiz-Vázquez, Rosa M; Cardenas, Maria E; Heitman, Joseph

    2014-09-25

    Microorganisms evolve via a range of mechanisms that may include or involve sexual/parasexual reproduction, mutators, aneuploidy, Hsp90 and even prions. Mechanisms that may seem detrimental can be repurposed to generate diversity. Here we show that the human fungal pathogen Mucor circinelloides develops spontaneous resistance to the antifungal drug FK506 (tacrolimus) via two distinct mechanisms. One involves Mendelian mutations that confer stable drug resistance; the other occurs via an epigenetic RNA interference (RNAi)-mediated pathway resulting in unstable drug resistance. The peptidylprolyl isomerase FKBP12 interacts with FK506 forming a complex that inhibits the protein phosphatase calcineurin. Calcineurin inhibition by FK506 blocks M. circinelloides transition to hyphae and enforces yeast growth. Mutations in the fkbA gene encoding FKBP12 or the calcineurin cnbR or cnaA genes confer FK506 resistance and restore hyphal growth. In parallel, RNAi is spontaneously triggered to silence the fkbA gene, giving rise to drug-resistant epimutants. FK506-resistant epimutants readily reverted to the drug-sensitive wild-type phenotype when grown without exposure to the drug. The establishment of these epimutants is accompanied by generation of abundant fkbA small RNAs and requires the RNAi pathway as well as other factors that constrain or reverse the epimutant state. Silencing involves the generation of a double-stranded RNA trigger intermediate using the fkbA mature mRNA as a template to produce antisense fkbA RNA. This study uncovers a novel epigenetic RNAi-based epimutation mechanism controlling phenotypic plasticity, with possible implications for antimicrobial drug resistance and RNAi-regulatory mechanisms in fungi and other eukaryotes.

  13. Bacterial Contamination of Anaesthetic and Vasopressor Drugs in the Operating Theatres

    PubMed Central

    Rueangchira-Urai, Rongrong; Rujirojindakul, Panthila; Geater, Alan Frederick; McNeil, Edward

    2017-01-01

    Objective The aim of this study was to determine the incidence of bacterial and fungal contamination in anaesthetic and vasopressor drugs before and after use in operating theatres. Methods A cross-sectional study was conducted in the operating theatres of a university hospital. We collected 945 samples of three different drugs, namely, propofol, vecuronium and ephedrine, from 20 operating rooms and refrigerators where the unused drugs were stored. Each drug was divided into two groups, the pre-use group and the post-use group. The pre-use drugs were cultured before the patient received the drug. The post-use drugs were cultured after the patient had received the drug or after the drugs had been transferred to other syringes. The culture results were reported as either positive or negative. Results Out of the 945 drug samples, 26 (2.8%, 95% confidence interval=1.8%–4.0%) gave a positive culture. Of the 317 propofol samples, 20 (6.3%) were found to have bacterial contamination, 11 in the pre-use group and 9 in the post-use group. Of the 318 ephedrine samples, 6 (1.9%) were found to be positive on culture, one in the pre-use group and five in the post-use group. Vecuronium gave no positive cultures. All organisms were non-pathogenic, and no fungal contamination was found. Conclusion The incidence of bacterial contamination in anaesthetic and vasopressor drugs was 2.8%. Anaesthetic teams must be aware of contamination issues in anaesthetic drugs that have been prepared for later use and, in order to reduce the risk of contamination, they must improve the methods of administering drugs to patients. PMID:28377840

  14. Multidrug Efflux Pumps at the Crossroad between Antibiotic Resistance and Bacterial Virulence

    PubMed Central

    Alcalde-Rico, Manuel; Hernando-Amado, Sara; Blanco, Paula; Martínez, José L.

    2016-01-01

    Multidrug efflux pumps can be involved in bacterial resistance to antibiotics at different levels. Some efflux pumps are constitutively expressed at low levels and contribute to intrinsic resistance. In addition, their overexpression may allow higher levels of resistance. This overexpression can be transient, in the presence of an effector (phenotypic resistance), or constitutive when mutants in the regulatory elements of the expression of efflux pumps are selected (acquired resistance). Efflux pumps are present in all cells, from human to bacteria and are highly conserved, which indicates that they are ancient elements in the evolution of different organisms. Consequently, it has been suggested that, besides antibiotic resistance, bacterial multidrug efflux pumps would likely contribute to other relevant processes of the microbial physiology. In the current article, we discuss some specific examples of the role that efflux pumps may have in the bacterial virulence of animals’ and plants’ pathogens, including the processes of intercellular communication. Based in these evidences, we propose that efflux pumps are at the crossroad between resistance and virulence of bacterial pathogens. Consequently, the comprehensive study of multidrug efflux pumps requires addressing these functions, which are of relevance for the bacterial–host interactions during infection. PMID:27708632

  15. Multidrug resistance pattern of bacterial agents isolated from patient with chronic sinusitis

    PubMed Central

    Rezai, Mohammad Sadegh; Pourmousa, Rostam; Dadashzadeh, Roksana; Ahangarkani, Fatemeh

    2016-01-01

    Background: Treatment of chronic sinusitis is complicated due to increase of antibiotic-resistant bacteria. The aim of this study was to determine the multidrug resistance (MDR) pattern of the bacteria causing chronic sinusitis in north of Iran. Methods: This cross-sectional study was carried out on patients with chronic sinusitis. Bacterial susceptibility to antimicrobial agents was determined according to the CLSI 2013 standards. Double-disk synergy (DDS) test was performed for the detection of extended-spectrum beta-lactamase (ESBL) producing bacteria; also methicillin-resistant Staphylococcus (MRSA) strains were identified by MRSA screen agar. The MDR isolates were defined as resistant to 3 or more antibiotics. Data were analyzed using SPSS 17 software. Descriptive statistics was used to describe the features of the data in this study. Results: The rate of ESBL-producing bacteria was 28.75-37.03% among enterobacteriaceae and the rate of MRSA was 42.75%-60% among Staphylococcus strains. The most detectable rate of the MDR bacterial isolates was Gram-negative bacteria 39 (76.47%) and Enterobacter spp. 19(70.37%) was the most multidrug resistant isolate among Gram negative bacteria. Also 36 (73.46%) of the gram positive bacterial isolated were multidrug resistance and Staphylococcus aureus 9(90%) was the most MDR among Gram positive bacteria. Conclusion: Antimicrobial resistance is increasing in chronic bacterial sinusitis. The emergence of MRSA and ESBL bacteria causing chronic sinusitis is increasing. PMID:27386063

  16. Non-toxic antimicrobials that evade drug resistance

    PubMed Central

    Davis, Stephen A.; Vincent, Benjamin M.; Endo, Matthew M.; Whitesell, Luke; Marchillo, Karen; Andes, David R.; Lindquist, Susan; Burke, Martin D.

    2015-01-01

    Drugs that act more promiscuously provide fewer routes for the emergence of resistant mutants. But this benefit often comes at the cost of serious off-target and dose-limiting toxicities. The classic example is the antifungal amphotericin B (AmB), which has evaded resistance for more than half a century. We report dramatically less toxic amphotericins that nevertheless evade resistance. They are scalably accessed in just three steps from the natural product, and bind their target (the fungal sterol, ergosterol) with far greater selectivity than AmB. Hence, they are less toxic and far more effective in a mouse model of systemic candidiasis. Surprisingly, exhaustive efforts to select for mutants resistant to these more selective compounds revealed that they are just as impervious to resistance as AmB. Thus, highly selective cytocidal action and the evasion of resistance are not mutually exclusive, suggesting practical routes to the discovery of less toxic, resistance-evasive therapies. PMID:26030729

  17. Induction of anti-actin drug resistance in Tetrahymena.

    PubMed

    Zackroff, Robert V; Hufnagel, Linda A

    2002-01-01

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

  18. Modeling the evolution of drug resistance in malaria

    NASA Astrophysics Data System (ADS)

    Hecht, David; Fogel, Gary B.

    2012-12-01

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

  19. Antimicrobial Action of Water-Soluble β-Chitosan against Clinical Multi-Drug Resistant Bacteria

    PubMed Central

    Park, Seong-Cheol; Nam, Joung-Pyo; Kim, Jun-Ho; Kim, Young-Min; Nah, Jae-Woon; Jang, Mi-Kyeong

    2015-01-01

    Recently, the number of patients infected by drug-resistant pathogenic microbes has increased remarkably worldwide, and a number of studies have reported new antibiotics from natural sources. Among them, chitosan, with a high molecular weight and α-conformation, exhibits potent antimicrobial activity, but useful applications as an antibiotic are limited by its cytotoxicity and insolubility at physiological pH. In the present study, the antibacterial activity of low molecular weight water-soluble (LMWS) α-chitosan (α1k, α5k, and α10k with molecular masses of 1, 5, and 10 kDa, respectively) and β-chitosan (β1k, β5k, and β10k) was compared using a range of pathogenic bacteria containing drug-resistant bacteria isolated from patients at different pH. Interestingly, β5k and β10k exhibited potent antibacterial activity, even at pH 7.4, whereas only α10k was effective at pH 7.4. The active target of β-chitosan is the bacterial membrane, where the leakage of calcein is induced in artificial PE/PG vesicles, bacterial mimetic membrane. Moreover, scanning electron microscopy showed that they caused significant morphological changes on the bacterial surfaces. An in vivo study utilizing a bacteria-infected mouse model found that LMWS β-chitosan could be used as a candidate in anti-infective or wound healing therapeutic applications. PMID:25867474

  20. Population-Based Drug Resistance Surveillance of Multidrug-Resistant Tuberculosis in Taiwan, 2007-2014

    PubMed Central

    Fan, Shin-Yuan; Lin, Keng-Yu; Jou, Ruwen

    2016-01-01

    Objective To determine the extent of drug resistance in multidrug-resistant tuberculosis (MDR-TB) cases, we conducted a retrospective, population-based analysis using drug susceptibility testing (DST) results of MDR Mycobacterium tuberculosis complex isolates obtained from 2007–2014 in Taiwan. Methods M. tuberculosis isolates collected from 1,331 MDR-TB cases were included in this survey. Treatment histories, age, sex, chest radiograph and bacteriological results of patients were analyzed. Standard DST was performed to assess resistance to the following drugs: isoniazid (INH), rifampicin (RIF), streptomycin (SM), ethambutol (EMB), amikacin (AM), kanamycin (KM), capreomycin (CAP), ofloxacin (OFX), moxifloxacin (MOX), levofloxacin (LVX), gatifloxacin (GAT), para-aminosalicylate (PAS), ethionamide (EA), and pyrazinamide (PZA). The Cochran-Armitage trend test was used for statistical analysis. Results We observed a significant increasing trend in portion of new MDR-TB cases, from 59.5% to 80.2% (p < 0.0001), and significant decreasing trend of portion in the 15-44-year-old age group (p < 0.05). Of the MDR M. tuberculosis isolates tested, 6.2% were resistant to AM, 8.6% were resistant to KM, 4.6% were resistant to CAP, 19.5% were resistant to OFX, 17.1% were resistant to MOX, 16.0% were resistant to LVX, 5.8% were resistant to GAT, 9.5% were resistant to PAS, 28.5% were resistant to EA and 33.3% were resistant to PZA. Fifty (3.8%) extensively drug-resistant TB cases were identified. No significant differences were found in drug resistance frequencies between new and previously treated MDR cases. However, we observed significant decreases in the rates of AM resistance (p < 0.05), OFX resistance (p < 0.00001), PAS resistance (p < 0.00001), EA resistance (p < 0.05) and PZA resistance (p < 0.05). Moreover, younger age groups had higher rates of resistance to fluoroquinolones. Conclusion A policy implemented in 2007 to restrict the prescription of fluoroquinolones was

  1. Establishing Drug Resistance in Microorganisms by Mass Spectrometry

    NASA Astrophysics Data System (ADS)

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

    2013-08-01

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

  2. Establishing drug resistance in microorganisms by mass spectrometry.

    PubMed

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

    2013-08-01

    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.

  3. Efflux pump-mediated drug resistance in Burkholderia

    PubMed Central

    Podnecky, Nicole L.; Rhodes, Katherine A.; Schweizer, Herbert P.

    2015-01-01

    Several members of the genus Burkholderia are prominent pathogens. Infections caused by these bacteria are difficult to treat because of significant antibiotic resistance. Virtually all Burkholderia species are also resistant to polymyxin, prohibiting use of drugs like colistin that are available for treatment of infections caused by most other drug resistant Gram-negative bacteria. Despite clinical significance and antibiotic resistance of Burkholderia species, characterization of efflux pumps lags behind other non-enteric Gram-negative pathogens such as Acinetobacter baumannii and Pseudomonas aeruginosa. Although efflux pumps have been described in several Burkholderia species, they have been best studied in Burkholderia cenocepacia and B. pseudomallei. As in other non-enteric Gram-negatives, efflux pumps of the resistance nodulation cell division (RND) family are the clinically most significant efflux systems in these two species. Several efflux pumps were described in B. cenocepacia, which when expressed confer resistance to clinically significant antibiotics, including aminoglycosides, chloramphenicol, fluoroquinolones, and tetracyclines. Three RND pumps have been characterized in B. pseudomallei, two of which confer either intrinsic or acquired resistance to aminoglycosides, macrolides, chloramphenicol, fluoroquinolones, tetracyclines, trimethoprim, and in some instances trimethoprim+sulfamethoxazole. Several strains of the host-adapted B. mallei, a clone of B. pseudomallei, lack AmrAB-OprA, and are therefore aminoglycoside and macrolide susceptible. B. thailandensis is closely related to B. pseudomallei, but non-pathogenic to humans. Its pump repertoire and ensuing drug resistance profile parallels that of B. pseudomallei. An efflux pump in B. vietnamiensis plays a significant role in acquired aminoglycoside resistance. Summarily, efflux pumps are significant players in Burkholderia drug resistance. PMID:25926825

  4. Oncolytic Virotherapy Targeting Lung Cancer Drug Resistance

    DTIC Science & Technology

    2014-10-01

    Resistance PRINCIPAL INVESTIGATOR: Dr John Hiscott CONTRACTING ORGANIZATION: Vaccine & Gene Therapy Institute of Florida...NAME(S) AND ADDRESS(ES) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER Vaccine & Gene Therapy Institute of Florida Port St...highly immunogenic platform for gene delivery, it cured established prostate tumors of the same histological type (8). Suboptimal vaccination , on the

  5. Bcl-2–Mediated Drug Resistance

    PubMed Central

    Srivastava, Rakesh K.; Sasaki, Carl Y.; Hardwick, J. Marie; Longo, Dan L.

    1999-01-01

    Bcl-2 inhibits apoptosis induced by a variety of stimuli, including chemotherapy drugs and glucocorticoids. It is generally accepted that Bcl-2 exerts its antiapoptotic effects mainly by dimerizing with proapoptotic members of the Bcl-2 family such as Bax and Bad. However, the mechanism of the antiapoptotic effects is unclear. Paclitaxel and other drugs that disturb microtubule dynamics kill cells in a Fas/Fas ligand (FasL)-dependent manner; antibody to FasL inhibits paclitaxel-induced apoptosis. We have found that Bcl-2 overexpression leads to the prevention of chemotherapy (paclitaxel)-induced expression of FasL and blocks paclitaxel-induced apoptosis. The mechanism of this effect is that Bcl-2 prevents the nuclear translocation of NFAT (nuclear factor of activated T lymphocytes, a transcription factor activated by microtubule damage) by binding and sequestering calcineurin, a calcium-dependent phosphatase that must dephosphorylate NFAT to move to the nucleus. Without NFAT nuclear translocation, the FasL gene is not transcribed. Thus, it appears that paclitaxel and other drugs that disturb microtubule function kill cells at least in part through the induction of FasL. Furthermore, Bcl-2 antagonizes drug-induced apoptosis by inhibiting calcineurin activation, blocking NFAT nuclear translocation, and preventing FasL expression. The effects of Bcl-2 can be overcome, at least partially, through phosphorylation of Bcl-2. Phosphorylated Bcl-2 cannot bind calcineurin, and NFAT activation, FasL expression, and apoptosis can occur after Bcl-2 phosphorylation. PMID:10432288

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

    PubMed Central

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

    2016-01-01

    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

  7. Drug Repurposing Identifies Inhibitors of Oseltamivir-Resistant Influenza Viruses.

    PubMed

    Bao, Ju; Marathe, Bindumadhav; Govorkova, Elena A; Zheng, Jie J

    2016-03-01

    The neuraminidase (NA) inhibitor, oseltamivir, is a widely used anti-influenza drug. However, oseltamivir-resistant H1N1 influenza viruses carrying the H275Y NA mutation spontaneously emerged as a result of natural genetic drift and drug treatment. Because H275Y and other potential mutations may generate a future pandemic influenza strain that is oseltamivir-resistant, alternative therapy options are needed. Herein, we show that a structure-based computational method can be used to identify existing drugs that inhibit resistant viruses, thereby providing a first line of pharmaceutical defense against this possible scenario. We identified two drugs, nalidixic acid and dorzolamide, that potently inhibit the NA activity of oseltamivir-resistant H1N1 viruses with the H275Y NA mutation at very low concentrations, but have no effect on wild-type H1N1 NA even at a much higher concentration, suggesting that the oseltamivir-resistance mutation itself caused susceptibility to these drugs.

  8. Bacterial resistance to tetracycline: mechanisms, transfer, and clinical significance.

    PubMed Central

    Speer, B S; Shoemaker, N B; Salyers, A A

    1992-01-01

    Tetracycline has been a widely used antibiotic because of its low toxicity and broad spectrum of activity. However, its clinical usefulness has been declining because of the appearance of an increasing number of tetracycline-resistant isolates of clinically important bacteria. Two types of resistance mechanisms predominate: tetracycline efflux and ribosomal protection. A third mechanism of resistance, tetracycline modification, has been identified, but its clinical relevance is still unclear. For some tetracycline resistance genes, expression is regulated. In efflux genes found in gram-negative enteric bacteria, regulation is via a repressor that interacts with tetracycline. Gram-positive efflux genes appear to be regulated by an attenuation mechanism. Recently it was reported that at least one of the ribosome protection genes is regulated by attenuation. Tetracycline resistance genes are often found on transmissible elements. Efflux resistance genes are generally found on plasmids, whereas genes involved in ribosome protection have been found on both plasmids and self-transmissible chromosomal elements (conjugative transposons). One class of conjugative transposon, originally found in streptococci, can transfer itself from streptococci to a variety of recipients, including other gram-positive bacteria, gram-negative bacteria, and mycoplasmas. Another class of conjugative transposons has been found in the Bacteroides group. An unusual feature of the Bacteroides elements is that their transfer is enhanced by preexposure to tetracycline. Thus, tetracycline has the double effect of selecting for recipients that acquire a resistance gene and stimulating transfer of the gene. PMID:1423217

  9. Identification, characterization and antibiotic resistance of bacterial isolates obtained from waterpipe device hoses.

    PubMed

    Masadeh, Majed M; Hussein, Emad I; Alzoubi, Karem H; Khabour, Omar; Shakhatreh, Muhamad Ali K; Gharaibeh, Mahmoud

    2015-05-13

    The general lack of knowledge about the health effects of waterpipe smoking is among the reasons for its global spread. In this study, bacterial contamination of waterpipe hoses was investigated. Twenty hoses were collected from waterpipe cafés and screened for bacterial pathogens using standard culture and isolation techniques. Additionally, resistance of isolated bacteria to common antibiotics was determined by identifying the minimum inhibitory concentration (MIC) of each isolate. Forty eight bacterial isolates were detected. Isolates included both Gram-positive and Gram-negative pathogens from species that included Micrococcus (12), Corynebacterium (13) and Bacillus (9). In addition, some of the detected pathogens were found to be resistant to aztreonam (79%), cefixime (79%), norfloxacin, amoxicillin (47%), clarithromycin (46%) and enrofloxacin (38%). In conclusion, the hose of the waterpipe device is a good environment for the growth of bacterial pathogens, which can then be transmitted to users.

  10. Resistance to drug by different isolates Trypanosoma evansi in China.

    PubMed

    Zhou, Jinlin; Shen, Jie; Liao, Dangjin; Zhou, Yongzhi; Lin, Jiaojiao

    2004-05-01

    In order to understand drug resistance in Chinese Trypanosoma evansi isolates, the in vitro growth inhibition test was carried out to detect the sensitivities to suramin and antrycide of 12 T. evansi isolates. For suramin, 50% inhibitory concentrations (IC(50)) ranged from 0.041 to 0.752 microg/ml; for antrycide, the IC(50) values ranged from 0.00151 to 0.06694 microg/ml. In vivo experiments in mice with selected isolates showed that the isolate most resistant to suramin was not cured at a dosage of 10 mg/kg, while the isolate that was most resistant to antrycide showed only 50% cure rate at a dose rate of 5 mg/kg. The data presented here indicate that T. evansi isolates from China had differences in drug resistance, with some isolates exhibiting low sensitivity to suramin or antrycide, while a few isolates showed complete drug resistance to curative dosages of suramin or antrycide. No drug cross-resistance was observed between suramin and antrycide.

  11. Additional Drug Resistance Patterns among Multidrug-Resistant Tuberculosis Patients in Korea: Implications for Regimen Design

    PubMed Central

    2017-01-01

    Detailed information on additional drug resistance patterns of multidrug-resistant tuberculosis (MDR-TB) is essential to build an effective treatment regimen; however, such data are scarce in Korea. We retrospectively analyzed the results of phenotypic drug susceptibility testing (DST) of culture confirmed-TB patients from January 2010 to December 2014 in 7 university hospitals in Korea. MDR-TB was identified among 6.8% (n = 378) of 5,599 isolates. A total of 57.1% (n = 216) of the MDR-TB patients had never been treated for TB. Strains from MDR-TB patients showed additional resistance to pyrazinamide (PZA) (35.7%), any second-line injectable drug (19.3%), and any fluoroquinolone (26.2%). Extensively drug resistant TB comprised 12.4% (n = 47) of the MDR-TB patients. Of 378 MDR-TB patients, 50.3% (n = 190) were eligible for the shorter MDR-TB regimen, and 50.0% (n = 189) were fully susceptible to the 5 drugs comprising the standard conventional regimen (PZA, kanamycin, ofloxoacin, prothionamide, and cycloserine). In conclusion, the proportion of new patients and the levels of additional drug resistance were high in MDR-TB patients. Considering the high levels of drug resistance, the shorter MDR-TB treatment regimen may not be feasible; instead, an individually tailored regimen based on the results of molecular and phenotypic DST may be more appropriate in MDR-TB patients in Korea. PMID:28244290

  12. Extensively Drug-Resistant Tuberculosis: Principles of Resistance, Diagnosis, and Management.

    PubMed

    Wilson, John W; Tsukayama, Dean T

    2016-04-01

    Extensively drug-resistant (XDR) tuberculosis (TB) is an unfortunate by-product of mankind's medical and pharmaceutical ingenuity during the past 60 years. Although new drug developments have enabled TB to be more readily curable, inappropriate TB management has led to the emergence of drug-resistant disease. Extensively drug-resistant TB describes Mycobacterium tuberculosis that is collectively resistant to isoniazid, rifampin, a fluoroquinolone, and an injectable agent. It proliferates when established case management and infection control procedures are not followed. Optimized treatment outcomes necessitate time-sensitive diagnoses, along with expanded combinations and prolonged durations of antimicrobial drug therapy. The challenges to public health institutions are immense and most noteworthy in underresourced communities and in patients coinfected with human immunodeficiency virus. A comprehensive and multidisciplinary case management approach is required to optimize outcomes. We review the principles of TB drug resistance and the risk factors, diagnosis, and managerial approaches for extensively drug-resistant TB. Treatment outcomes, cost, and unresolved medical issues are also discussed.

  13. Evolution of drug resistance in Salmonella panama isolates in Chile.

    PubMed Central

    Cordano, A M; Virgilio, R

    1996-01-01

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

  14. Sunitinib treatment enhances metastasis of innately drug resistant breast tumors

    PubMed Central

    Wragg, Joseph W; Heath, Victoria L; Bicknell, Roy

    2017-01-01

    Anti-angiogenic therapies have failed to confer survival benefits in patients with metastatic breast cancer (mBC). However, to date there has not been an inquiry into roles for acquired versus innate drug resistance in this setting. In this study, we report roles for these distinct phenotypes in determining therapeutic response in a murine model of mBC resistance to the anti-angiogenic tyrosine kinase inhibitor sunitinib. Using tumor measurement and vascular patterning approaches, we differentiated tumors displaying innate versus acquired resistance. Bioluminescent imaging of tumor metastases to the liver, lungs and spleen revealed that sunitinib administration enhances metastasis, but only in tumors displaying innate resistance to therapy. Transcriptomic analysis of tumors displaying acquired versus innate resistance allowed the identification of specific biomarkers, many of which have a role in angiogenesis. In particular, aquaporin-1 upregulation occurred in acquired resistance, mTOR in innate resistance, and pleiotrophin in both settings, suggesting their utility as candidate diagnostics to predict drug response or to design tactics to circumvent resistance. Our results unravel specific features of antiangiogenic resistance, with potential therapeutic implications. PMID:28011623

  15. Bacterial Community Shift Drives Antibiotic Resistance Promotion during Drinking Water Chlorination.

    PubMed

    Jia, Shuyu; Shi, Peng; Hu, Qing; Li, Bing; Zhang, Tong; Zhang, Xu-Xiang

    2015-10-20

    For comprehensive insights into the effects of chlorination, a widely used disinfection technology, on bacterial community and antibiotic resistome in drinking water, this study applied high-throughput sequencing and metagenomic approaches to investigate the changing patterns of antibiotic resistance genes (ARGs) and bacterial community in a drinking water treatment and distribution system. At genus level, chlorination could effectively remove Methylophilus, Methylotenera, Limnobacter, and Polynucleobacter, while increase the relative abundance of Pseudomonas, Acidovorax, Sphingomonas, Pleomonas, and Undibacterium in the drinking water. A total of 151 ARGs within 15 types were detectable in the drinking water, and chlorination evidently increased their total relative abundance while reduced their diversity in the opportunistic bacteria (p < 0.05). Residual chlorine was identified as the key contributing factor driving the bacterial community shift and resistome alteration. As the dominant persistent ARGs in the treatment and distribution system, multidrug resistance genes (mainly encoding resistance-nodulation-cell division transportation system) and bacitracin resistance gene bacA were mainly carried by chlorine-resistant bacteria Pseudomonas and Acidovorax, which mainly contributed to the ARGs abundance increase. The strong correlation between bacterial community shift and antibiotic resistome alteration observed in this study may shed new light on the mechanism behind the chlorination effects on antibiotic resistance.

  16. Overcoming target-mediated quinolone resistance in topoisomerase IV by introducing metal-ion-independent drug-enzyme interactions.

    PubMed

    Aldred, Katie J; Schwanz, Heidi A; Li, Gangqin; McPherson, Sylvia A; Turnbough, Charles L; Kerns, Robert J; Osheroff, Neil

    2013-12-20

    Quinolones, which target gyrase and topoisomerase IV, are the most widely prescribed antibacterials worldwide. Unfortunately, their use is threatened by the increasing prevalence of target-mediated drug resistance. Greater than 90% of mutations that confer quinolone resistance act by disrupting enzyme-drug interactions coordinated by a critical water-metal ion bridge. Quinazolinediones are quinolone-like drugs but lack the skeletal features necessary to support the bridge interaction. These compounds are of clinical interest, however, because they retain activity against the most common quinolone resistance mutations. We utilized a chemical biology approach to determine how quinazolinediones overcome quinolone resistance in Bacillus anthracis topoisomerase IV. Quinazolinediones that retain activity against quinolone-resistant topoisomerase IV do so primarily by establishing novel interactions through the C7 substituent, rather than the drug skeleton. Because some quinolones are highly active against human topoisomerase IIα, we also determined how clinically relevant quinolones discriminate between the bacterial and human enzymes. Clinically relevant quinolones display poor activity against topoisomerase IIα because the human enzyme cannot support drug interactions mediated by the water-metal ion bridge. However, the inclusion of substituents that allow quinazolinediones to overcome topoisomerase IV-mediated quinolone resistance can cause cross-reactivity against topoisomerase IIα. Therefore, a major challenge in designing drugs that overcome quinolone resistance lies in the ability to identify substituents that mediate strong interactions with the bacterial, but not the human, enzymes. On the basis of our understanding of quinolone-enzyme interactions, we have identified three compounds that display high activity against quinolone-resistant B. anthracis topoisomerase IV but low activity against human topoisomerase IIα.

  17. Bacterial antibiotic resistance in soils irrigated with reclaimed municipal wastewater

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  18. The role of photodynamic therapy in overcoming cancer drug resistance

    PubMed Central

    Spring, Bryan Q.; Rizvi, Imran; Xu, Nan; Hasan, Tayyaba

    2015-01-01

    Many modalities of cancer therapy induce mechanisms of treatment resistance and escape pathways during chronic treatments, including photodynamic therapy (PDT). It is conceivable that resistance induced by one treatment might be overcome by another treatment. Emerging evidence suggests that the unique mechanisms of tumor cell and microenvironment damage produced by PDT could be utilized to overcome cancer drug resistance, to mitigate the compensatory induction of survival pathways and even to re-sensitize resistant cells to standard therapies. Approaches that capture the unique features of PDT, therefore, offer promising factors for increasing the efficacy of a broad range of therapeutic modalities. Here, we highlight key preclinical findings utilizing PDT to overcome classical drug resistance or escape pathways and thus enhance the efficacy of many pharmaceuticals, possibly explaining the clinical observations of the PDT response to otherwise treatment-resistant diseases. With the development of nanotechnology, it is possible that light activation may be used not only to damage and sensitize tumors but also to enable controlled drug release to inhibit escape pathways that may lead to resistance or cell proliferation. PMID:25856800

  19. Nanomechanics of Drug-target Interactions and Antibacterial Resistance Detection

    PubMed Central

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

    2013-01-01

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

  20. Approved Glycopeptide Antibacterial Drugs: Mechanism of Action and Resistance.

    PubMed

    Zeng, Daina; Debabov, Dmitri; Hartsell, Theresa L; Cano, Raul J; Adams, Stacy; Schuyler, Jessica A; McMillan, Ronald; Pace, John L

    2016-12-01

    The glycopeptide antimicrobials are a group of natural product and semisynthetic glycosylated peptides that show antibacterial activity against Gram-positive organisms through inhibition of cell-wall synthesis. This is achieved primarily through binding to the d-alanyl-d-alanine terminus of the lipid II bacterial cell-wall precursor, preventing cross-linking of the peptidoglycan layer. Vancomycin is the foundational member of the class, showing both clinical longevity and a still preferential role in the therapy of methicillin-resistant Staphylococcus aureus and of susceptible Enterococcus spp. Newer lipoglycopeptide derivatives (telavancin, dalbavancin, and oritavancin) were designed in a targeted fashion to increase antibacterial activity, in some cases through secondary mechanisms of action. Resistance to the glycopeptides emerged in delayed fashion and occurs via a spectrum of chromosome- and plasmid-associated elements that lead to structural alteration of the bacterial cell-wall precursor substrates.

  1. A recent evaluation of empirical cephalosporin treatment and antibiotic resistance of changing bacterial profiles in spontaneous bacterial peritonitis.

    PubMed

    Yakar, Tolga; Güçlü, Mustafa; Serin, Ender; Alişkan, Hikmet; Husamettin, Erdamar

    2010-04-01

    The aim of this research is to evaluate the recent changes in microorganisms causing spontaneous bacterial peritonitis in cirrhotic patients, antibiotic resistance, and response to empirical cephalosporin therapy. A total of 218 patients with ascites secondary to cirrhosis were enrolled. Parenteral cefotaxime or cefepime was given to patients who had a neutrophil count of 250/mm(3) or more or a positive bacterial culture of ascitic fluid. Antibiotic failure was defined by an absence of clinical improvement and an insufficient decrease in neutrophil count of ascites (<25% of initial value) by the third day of therapy. Of all the patients, 44.6% had culture-negative neutrocytic ascites, 24.8% had spontaneous bacterial peritonitis, and 10.1% had monomicrobial nonneutrocytic bacterascites. Growth in culture was observed in 76 patients (34.9%). The two most common isolated bacteria were Escherichia coli (33.8%) and coagulase-negative Staphylococcus (CoNS; 19.7%). The two cephalosporins were effective against E. coli (82%) and but not against CoNS (44%), while levofloxacin showed reasonable activity against both E. coli (71%) and CoNS (90%) in vitro. We confirmed a recent increased incidence of spontaneous bacterial peritonitis caused by Gram-positive bacteria. Levofloxacin seems to be a good alternative treatment for patients with uncomplicated spontaneous ascites infections.

  2. Development of a Protocol for Predicting Bacterial Resistance to Microbicides

    PubMed Central

    Knapp, Laura; Amézquita, Alejandro; McClure, Peter; Stewart, Sara

    2015-01-01

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

  3. Seeking Goldilocks During Evolution of Drug Resistance

    PubMed Central

    Petrov, Dmitri A.

    2017-01-01

    Speciation can occur when a population is split and the resulting subpopulations evolve independently, accumulating mutations over time that make them incompatible with one another. It is thought that such incompatible mutations, known as Bateson–Dobzhansky–Muller (BDM) incompatibilities, may arise when the two populations face different environments, which impose different selective pressures. However, a new study in PLOS Biology by Ono et al. finds that the first-step mutations selected in yeast populations evolving in parallel in the presence of the antifungal drug nystatin are frequently incompatible with one another. This incompatibility is environment dependent, such that the combination of two incompatible alleles can become advantageous under increasing drug concentrations. This suggests that the activity for the affected pathway must have an optimum level, the value of which varies according to the drug concentration. It is likely that many biological processes similarly have an optimum under a given environment and many single-step adaptive ways to reach it; thus, not only should BDM incompatibilities commonly arise during parallel evolution, they might be virtually inevitable, as the combination of two such steps is likely to overshoot the optimum. PMID:28158184

  4. Structure-based methods for predicting target mutation-induced drug resistance and rational drug design to overcome the problem.

    PubMed

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

    2012-10-01

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

  5. Enhanced transmission of drug-resistant parasites to mosquitoes following drug treatment in rodent malaria.

    PubMed

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

    2012-01-01

    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.

  6. New strategies against drug resistance to herpes simplex virus

    PubMed Central

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

    2016-01-01

    Herpes simplex virus (HSV), a member of the Herpesviridae family, is a significant human pathogen that results in mucocutaneous lesions in the oral cavity or genital infections. Acyclovir (ACV) and related nucleoside analogues can successfully treat HSV infections, but the emergence of drug resistance to ACV has created a barrier for the treatment of HSV infections, especially in immunocompromised patients. There is an urgent need to explore new and effective tactics to circumvent drug resistance to HSV. This review summarises the current strategies in the development of new targets (the DNA helicase/primase (H/P) complex), new types of molecules (nature products) and new antiviral mechanisms (lethal mutagenesis of Janus-type nucleosides) to fight the drug resistance of HSV. PMID:27025259

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2011-11-01

    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.

  10. Effects of temperature on biochemical reactions and drug resistance of virulent and avirulent Aeromonas salmonicida

    USGS Publications Warehouse

    Hahnel, G.B.; Gould, R.W.

    1982-01-01

    Incubation temperatures of 11°, 18° and 28° did not substantially affect biochemical reactions of either virulent or avirulent forms of Aeromonas salmonicida subspecies salmonicida. The only change observed, amygdalin fermentation, was positive at 11° and 18° but negative at 28°C. Several isolates utilized sucrose, a characteristic not normally recognized for A. salmonicida subspecies salmonicida.Antimicrobial susceptibility screening indicated resistance to novobiocin increased at the higher incubation temperatures. Standardized drug sensitivity testing procedures and precise zone diameter interpretive standards for bacterial fish pathogens are needed.

  11. A new common bacterial blight resistance QTL in VAX 1 common bean and interaction of the new QTL, SAP6 and SU91 with bacterial strains

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common bacterial blight (CBB) is a severe disease in common bean. New resistance QTL should facilitate development of cultivars with high levels of resistance. Our objectives were to (i) identify new resistance QTL in VAX 1 and verify presence in VAX 3, (ii) determine interaction of new QTL with exi...

  12. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase.

    PubMed

    Aldred, Katie J; Blower, Tim R; Kerns, Robert J; Berger, James M; Osheroff, Neil

    2016-02-16

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrA(A90) and GyrA(D94). M. tuberculosis gyrase lacks a conserved serine that anchors a water-metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrA(A90)) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone-gyrase interactions. Clinically relevant mutations at GyrA(A90) and GyrA(D94) cause quinolone resistance by disrupting the bridge-enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone-enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrA(A90V) and GyrA(D94G). 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug-enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis.

  13. The role of enzymology in a structure-based drug discovery program: bacterial DNA gyrase.

    PubMed

    Cunningham, Mark L

    2012-01-01

    The capability to accurately, rapidly, and reproducibly determine the affinity of a ligand for a target protein or enzyme is a vital component for a successful structure-based drug design effort. In order to successfully drive a structure-based drug design (SBDD) project forward, multiple distinct assays, each with particular strengths and weaknesses, need to be employed. Using bacterial DNA gyrase as an example, a range of assays are described that will fully support an SBDD program.

  14. Trends in bacterial resistance in a tertiary university hospital over one decade.

    PubMed

    Rubio, Fernando Góngora; Oliveira, Viviane Decicera Colombo; Rangel, Regina Mara Custódio; Nogueira, Mara Corrêa Lelles; Almeida, Margarete Teresa Gottardo

    2013-01-01

    The objective of this study was to investigate bacterial resistance trends, infection sites and the relationship between resistance and admittance to the intensive care unit (ICU). A total of 53,316 bacteria identified between 1999 and 2008 were evaluated. Multidrug resistance was characterized when gram-negative bacilli (GNB) presented resistance to two or more classes of antibiotics. Gram-positive cocci (CPC) were assessed for resistance to penicillin, oxacillin and vancomycin. GNB were the most common (66.1%) isolate. There was a 3.7-fold overall increase in multidrug resistant GNB over the study period; Acinetobacter baumanii and Staphylococcus aureus were the most prevalent. Highest increases were recorded for Klebsiella pneumoniae (14.6-fold) and enterococci (73-fold). The resistance rates for GNB and GPC were 36% and 51.7%, respectively. Most multidrug resistant GNB and GPC were recovered from ICU patients (p-value<0.001). Vancomycin-resistant enterococci were isolated during this decade with an increase of 18.7% by 2008. These data confirm the worldwide trend in multidrug bacterial resistance.

  15. Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis.

    PubMed

    Tho, Dau Quang; Török, M Estée; Yen, Nguyen Thi Bich; Bang, Nguyen Duc; Lan, Nguyen Thi Ngoc; Kiet, Vo Sy; van Vinh Chau, Nguyen; Dung, Nguyen Huy; Day, Jeremy; Farrar, Jeremy; Wolbers, Marcel; Caws, Maxine

    2012-06-01

    HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.

  16. Persistence of HIV-1 transmitted drug resistance mutations.

    PubMed

    Castro, Hannah; Pillay, Deenan; Cane, Patricia; Asboe, David; Cambiano, Valentina; Phillips, Andrew; Dunn, David T

    2013-11-01

    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.

  17. Dynamic optical tweezers based assay for monitoring early drug resistance

    NASA Astrophysics Data System (ADS)

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

    2013-06-01

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

  18. [Drug-resistant tuberculosis. Epidemiology, diagnostics and therapy].

    PubMed

    Grobusch, M P; Schaumburg, F; Altpeter, E; Bélard, S

    2016-02-01

    Drug-resistant tuberculosis (DR-TB) is one of the serious problems in the fight against tuberculosis on a global scale. This review article describes in brief the global epidemiology, diagnostics and treatment of DR-TB. The situation in Germany, Switzerland and Austria is addressed in detail. The article concludes with a presentation of current research topics in the field of resistant TB.

  19. Interferon in resistance to bacterial and protozoan infections

    NASA Technical Reports Server (NTRS)

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

    1986-01-01

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

  20. Safety and effectiveness of home intravenous antibiotic therapy for multidrug-resistant bacterial infections.

    PubMed

    Mujal, A; Sola, J; Hernandez, M; Villarino, M-A; Machado, M-L; Baylina, M; Tajan, J; Oristrell, J

    2015-06-01

    Home intravenous antibiotic therapy is an alternative to hospital admission for moderately severe infections. However, few studies have analyzed its safety and effectiveness in the treatment of infections caused by multidrug-resistant bacteria. The purpose of this study is to analyze the safety and effectiveness of home intravenous antibiotic therapy in multidrug-resistant bacterial infections. We analyzed prospectively all patients admitted to our service who underwent home intravenous antibiotic therapy during the period 2008-2012. All the treatments were administered by caretakers or self-administered by patients, through elastomeric infusion devices. Effectiveness was evaluated by analyzing the readmission rate for poor infection control. Safety was evaluated by analyzing adverse events, catheter-related complications, and readmissions not related to poor infection control. There were 433 admissions (in 355 patients) for home intravenous antibiotic therapy during the study period. There were 226 (52.2 %) admissions due to multidrug-resistant bacterial infections and 207 (47.8 %) due to non-multidrug-resistant infections. Hospital readmissions in patients with multidrug-resistant infections were uncommon. Multidrug-resistant enterococcal infections, healthcare-associated infections, and carbapenem therapy were independent variables associated with increased readmissions due to poor infection control. Readmissions not related to poor infection control, adverse events, and catheter-related complications were similar in multidrug-resistant compared to non-multidrug-resistant bacterial infections. Home intravenous therapy, administered by patients or their caretakers using elastomeric infusion pumps, was safe and effective for the treatment of most multidrug-resistant bacterial infections.

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

    PubMed Central

    Beceiro, Alejandro; Tomás, María

    2013-01-01

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

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

    PubMed

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

    2014-10-01

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

  3. Ecology and evolution as targets: the need for novel eco-evo drugs and strategies to fight antibiotic resistance.

    PubMed

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

    2011-08-01

    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.

  4. PREVALENCE OF BACTERIAL RESISTANCE IN HOSPITALIZED CIRRHOTIC PATIENTS IN SOUTHERN BRAZIL: A NEW CHALLENGE

    PubMed Central

    COSTABEBER, Ane Micheli; de MATTOS, Angelo Alves; SUKIENNIK, Teresa Cristina Teixeira

    2016-01-01

    Background & Aims: An increased frequency of infections by multiresistant bacteria has been described in hospitalized patients. The aim of this study was to evaluate the bacterial resistance profile in cirrhotic patients. Methods: This is a retrospective observational study. We assessed the antimicrobial susceptibility of 5,839 bacterial isolates from patients with and without cirrhosis. Regarding the multidrug resistance, we evaluated 4,505 bacterial isolates from 2,180 patients. Results: Two hundred and fifty-one patients had cirrhosis (mean age 57.6 ± 11 years; 61.8% were male, 47.8% of cases associated with hepatitis C virus). Of the isolates of patients with and without cirrhosis, 174/464 (37.5%) and 1,783/4,041 (44.1%) were multiresistant, respectively (p = 0.007). E. coli was the most common multiresistant bacteria in both groups. Approximately 20% of E. coli and Klebsiella sp. isolates were ESBL-producers and 44% of S. aureus isolates were methicillin-resistant in cirrhotic patients. In cirrhotic patients admitted to the emergency department, hospital ward, and intensive care unit, 28.3%, 50% and 40% had multiresistant isolates, respectively. In patients with and without cirrhosis, 36.2% and 33.5% of isolates were resistant to third-generation cephalosporins, respectively. Conclusions: The empirical treatment of infections in hospitalized patients using broad-spectrum antibiotics should consider the observed pattern of bacterial resistance. PMID:27253738

  5. Methylfolate Trap Promotes Bacterial Thymineless Death by Sulfa Drugs

    PubMed Central

    Pham, Thanh H.; Jakubowski, Hieronim; Wolff, Kerstin A.; Ogwang, Sam; Timpona, Joseph L.; Gogula, Soumya; Jacobs, Michael R.; Ruetz, Markus; Kräutler, Bernhard; Jacobsen, Donald W.; Zhang, Guo-Fang; Nguyen, Liem

    2016-01-01

    The methylfolate trap, a metabolic blockage associated with anemia, neural tube defects, Alzheimer’s dementia, cardiovascular diseases, and cancer, was discovered in the 1960s, linking the metabolism of folate, vitamin B12, methionine and homocysteine. However, the existence or physiological significance of this phenomenon has been unknown in bacteria, which synthesize folate de novo. Here we identify the methylfolate trap as a novel determinant of the bacterial intrinsic death by sulfonamides, antibiotics that block de novo folate synthesis. Genetic mutagenesis, chemical complementation, and metabolomic profiling revealed trap-mediated metabolic imbalances, which induced thymineless death, a phenomenon in which rapidly growing cells succumb to thymine starvation. Restriction of B12 bioavailability, required for preventing trap formation, using an “antivitamin B12” molecule, sensitized intracellular bacteria to sulfonamides. Since boosting the bactericidal activity of sulfonamides through methylfolate trap induction can be achieved in Gram-negative bacteria and mycobacteria, it represents a novel strategy to render these pathogens more susceptible to existing sulfonamides. PMID:27760199

  6. Multiple drug resistance genes in malaria -- from epistasis to epidemiology.

    PubMed

    Duraisingh, Manoj T; Refour, Philippe

    2005-08-01

    A decline in our ability to successfully treat patients with malaria infections of the parasitic protozoan Plasmodium falciparum with cheap quinoline drugs has led to a huge escalation in morbidity and mortality in recent years. Many approaches have been taken, including classical genetics, reverse genetics and molecular epidemiology, to identify the molecular determinants underlying this resistance. The contribution of the P. falciparum multidrug resistance gene, pfmdr1, to antimalarial resistance has been a source of controversy for over a decade since it was first identified. In the current issue of Molecular Microbiology, Sidhu and colleagues use powerful reverse genetics to demonstrate the importance of commonly occurring alleles of pfmdr1 in conferring resistance to the second-line drugs quinine and sensitivity to the new alternatives mefloquine and artemisinin. They also elegantly highlight the importance of genetic background and epistasis between pfmdr1 and other potential modulators of drug resistance. Such molecular knowledge will facilitate surveillance/monitoring and aid the development of strategies for the reversal of resistance.

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

    PubMed Central

    Lee, Jinsoo; Son, Kwanghyun; Hwang, Gwiseo

    2016-01-01

    Objective. Herbal medicine has been widely used to treat drug resistant epilepsy. Shihogyejitang (SGT) has been commonly used to treat epilepsy. We investigated the effect and safety of SGT in children with drug resistant epilepsy. Design. We reviewed medical records of 54 patients with epilepsy, who failed to respond to at least two antiepileptic drugs and have been treated with SGT between April 2006 and June 2014 at the Department of Pediatric Neurology, I-Tomato Hospital, Korea. Effect was measured by the response rate, seizure-free rate, and retention rate at six months. We also checked adverse events, change in antiepileptic drugs use, and the variables related to the outcome. Results. Intent-to-treat analysis showed that, after six months, 44.4% showed a >50% seizure reduction, 24.1% including seizure-free, respectively, and 53.7% remained on SGT. Two adverse events were reported, mild skin rash and fever. Focal seizure type presented significantly more positive responses when compared with other seizure types at six months (p = 0.0284, Fisher's exact test). Conclusion. SGT is an effective treatment with excellent tolerability for drug resistant epilepsy patients. Our data provide evidence that SGT may be used as alternative treatment option when antiepileptic drug does not work in epilepsy children. PMID:27047568

  8. Induced Bacterial Cross-Resistance toward Host Antimicrobial Peptides: A Worrying Phenomenon

    PubMed Central

    Fleitas, Osmel; Franco, Octávio L.

    2016-01-01

    Bacterial resistance to conventional antibiotics has reached alarming levels, threatening to return to the pre-antibiotic era. Therefore, the search for new antimicrobial compounds that overcome the resistance phenomenon has become a priority. Antimicrobial peptides (AMPs) appear as one of the most promising antibiotic medicines. However, in recent years several AMP-resistance mechanisms have been described. Moreover, the AMP-resistance phenomenon has become more complex due to its association with cross-resistance toward AMP effectors of the host innate immune system. In this context, the use of AMPs as a therapeutic option could be potentially hazardous, since bacteria could develop resistance toward our innate immune system. Here, we review the findings of major studies that deal with the AMP cross-resistance phenomenon. PMID:27047486

  9. Induced Bacterial Cross-Resistance toward Host Antimicrobial Peptides: A Worrying Phenomenon.

    PubMed

    Fleitas, Osmel; Franco, Octávio L

    2016-01-01

    Bacterial resistance to conventional antibiotics has reached alarming levels, threatening to return to the pre-antibiotic era. Therefore, the search for new antimicrobial compounds that overcome the resistance phenomenon has become a priority. Antimicrobial peptides (AMPs) appear as one of the most promising antibiotic medicines. However, in recent years several AMP-resistance mechanisms have been described. Moreover, the AMP-resistance phenomenon has become more complex due to its association with cross-resistance toward AMP effectors of the host innate immune system. In this context, the use of AMPs as a therapeutic option could be potentially hazardous, since bacteria could develop resistance toward our innate immune system. Here, we review the findings of major studies that deal with the AMP cross-resistance phenomenon.

  10. pncA Gene Mutations Associated with Pyrazinamide Resistance in Drug-Resistant Tuberculosis, South Africa and Georgia.

    PubMed

    Allana, Salim; Shashkina, Elena; Mathema, Barun; Bablishvili, Nino; Tukvadze, Nestani; Shah, N Sarita; Kempker, Russell R; Blumberg, Henry M; Moodley, Pravi; Mlisana, Koleka; Brust, James C M; Gandhi, Neel R

    2017-03-01

    Although pyrazinamide is commonly used for tuberculosis treatment, drug-susceptibility testing is not routinely available. We found polymorphisms in the pncA gene for 70% of multidrug-resistant and 96% of extensively drug-resistant Mycobacterium tuberculosis isolates from South Africa and Georgia. Assessment of pyrazinamide susceptibility may be prudent before using it in regimens for drug-resistant tuberculosis.

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

    PubMed Central

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

    2012-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2013-01-01

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

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

    PubMed Central

    Karuppiah, Ponmurugan; Rajaram, Shyamkumar

    2012-01-01

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

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

    PubMed

    Padwal, Priyanka; Bandyopadhyaya, Rajdip; Mehra, Sarika

    2014-12-23

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

  16. Use of phenotype microarrays to study the effect of acquisition of resistance to antimicrobials in bacterial physiology.

    PubMed

    Reales-Calderon, Jose A; Blanco, Paula; Alcalde-Rico, Manuel; Corona, Fernando; Lira, Felipe; Hernando-Amado, Sara; Bernardini, Alejandra; Sánchez, María B; Martínez, José L

    It is widely accepted that the acquisition of resistance to antimicrobials confers a fitness cost. Different works have shown that the effect of acquiring resistance in bacterial physiology may be more specific than previously thought. Study of these specific changes may help to predict the outcome of resistant organisms in different ecosystems. In addition to changing bacterial physiology, acquisition of resistance either increases or reduces susceptibility to other antimicrobials. In the current article, we review recent information on the effect of acquiring resistance upon bacterial physiology, with a specific focus on studies using phenotype microarray technology.

  17. Hepatitis C Virus and Antiviral Drug Resistance

    PubMed Central

    Kim, Seungtaek; Han, Kwang-Hyub; Ahn, Sang Hoon

    2016-01-01

    Since its discovery in 1989, hepatitis C virus (HCV) has been intensively investigated to understand its biology and develop effective antiviral therapies. The efforts of the previous 25 years have resulted in a better understanding of the virus, and this was facilitated by the development of in vitro cell culture systems for HCV replication. Antiviral treatments and sustained virological responses have also improved from the early interferon monotherapy to the current all-oral regimens using direct-acting antivirals. However, antiviral resistance has become a critical issue in the treatment of chronic hepatitis C, similar to other chronic viral infections, and retreatment options following treatment failure have become important questions. Despite the clinical challenges in the management of chronic hepatitis C, substantial progress has been made in understanding HCV, which may facilitate the investigation of other closely related flaviviruses and lead to the development of antiviral agents against these human pathogens. PMID:27784846

  18. Microvesicle removal of anticancer drugs contributes to drug resistance in human pancreatic cancer cells

    PubMed Central

    Muralidharan-Chari, Vandhana; Kohan, Hamed Gilzad; Asimakopoulos, Alexandros G.; Sudha, Thangirala; Sell, Stewart; Kannan, Kurunthachalam; Boroujerdi, Mehdi; Davis, Paul J.; Mousa, Shaker A.

    2016-01-01

    High mortality in pancreatic cancer patients is partly due to resistance to chemotherapy. We describe that human pancreatic cancer cells acquire drug resistance by a novel mechanism in which they expel and remove chemotherapeutic drugs from the microenvironment via microvesicles (MVs). Using human pancreatic cancer cells that exhibit varied sensitivity to gemcitabine (GEM), we show that GEM exposure triggers the cancer cells to release MVs in an amount that correlates with that cell line's sensitivity to GEM. The importance of MV-release in gaining drug resistance in GEM-resistant pancreatic cancer cells was confirmed when the inhibition of MV-release sensitized the cells to GEM treatment, both in vitro and in vivo. Mechanistically, MVs remove drugs that are internalized into the cells and that are in the microenvironment. The differences between the drug-resistant and drug-sensitive pancreatic cancer cell lines tested here are explained based on the variable content of influx/efflux proteins present on MVs, which directly dictates the ability of MVs either to trap GEM or to allow GEM to flow back to the microenvironment. PMID:27391262

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

    PubMed

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

    2014-11-01

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

  20. Interfamily transfer of a plant pattern-recognition receptor confers broad-spectrum bacterial resistance.

    PubMed

    Lacombe, Séverine; Rougon-Cardoso, Alejandra; Sherwood, Emma; Peeters, Nemo; Dahlbeck, Douglas; van Esse, H Peter; Smoker, Matthew; Rallapalli, Ghanasyam; Thomma, Bart P H J; Staskawicz, Brian; Jones, Jonathan D G; Zipfel, Cyril

    2010-04-01

    Plant diseases cause massive losses in agriculture. Increasing the natural defenses of plants may reduce the impact of phytopathogens on agricultural productivity. Pattern-recognition receptors (PRRs) detect microbes by recognizing conserved pathogen-associated molecular patterns (PAMPs). Although the overall importance of PAMP-triggered immunity for plant defense is established, it has not been used to confer disease resistance in crops. We report that activity of a PRR is retained after its transfer between two plant families. Expression of EFR (ref. 4), a PRR from the cruciferous plant Arabidopsis thaliana, confers responsiveness to bacterial elongation factor Tu in the solanaceous plants Nicotiana benthamiana and tomato (Solanum lycopersicum), making them more resistant to a range of phytopathogenic bacteria from different genera. Our results in controlled laboratory conditions suggest that heterologous expression of PAMP recognition systems could be used to engineer broad-spectrum disease resistance to important bacterial pathogens, potentially enabling more durable and sustainable resistance in the field.

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

    PubMed

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

    2014-07-03

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

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

    PubMed

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

    2016-09-01

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

  3. Biophysical principles predict fitness landscapes of drug resistance

    PubMed Central

    Bershtein, Shimon; Li, Annabel; Lozovsky, Elena R.; Hartl, Daniel L.; Shakhnovich, Eugene I.

    2016-01-01

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

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

    PubMed Central

    Zhang, Gao; Frederick, Dennie T.; Wu, Lawrence; Wei, Zhi; Krepler, Clemens; Srinivasan, Satish; Chae, Young Chan; Xu, Xiaowei; Choi, Harry; Dimwamwa, Elaida; Shannan, Batool; Basu, Devraj; Zhang, Dongmei; Guha, Manti; Xiao, Min; Randell, Sergio; Sproesser, Katrin; Xu, Wei; Liu, Jephrey; Karakousis, Giorgos C.; Schuchter, Lynn M.; Gangadhar, Tara C.; Amaravadi, Ravi K.; Gu, Mengnan; Xu, Caiyue; Ghosh, Abheek; Xu, Weiting; Tian, Tian; Zhang, Jie; Zha, Shijie; Brafford, Patricia; Weeraratna, Ashani; Davies, Michael A.; Wargo, Jennifer A.; Avadhani, Narayan G.; Lu, Yiling; Mills, Gordon B.; Altieri, Dario C.; Flaherty, Keith T.

    2016-01-01

    Targeting multiple components of the MAPK pathway can prolong the survival of patients with BRAFV600E melanoma. This approach is not curative, as some BRAF-mutated melanoma cells are intrinsically resistant to MAPK inhibitors (MAPKi). At the systemic level, our knowledge of how signaling pathways underlie drug resistance needs to be further expanded. Here, we have shown that intrinsically resistant BRAF-mutated melanoma cells with a low basal level of mitochondrial biogenesis depend on this process to survive MAPKi. Intrinsically resistant cells exploited an integrated stress response, exhibited an increase in mitochondrial DNA content, and required oxidative phosphorylation to meet their bioenergetic needs. We determined that intrinsically resistant cells rely on the genes encoding TFAM, which controls mitochondrial genome replication and transcription, and TRAP1, which regulates mitochondrial protein folding. Therefore, we targeted mitochondrial biogenesis with a mitochondrium-targeted, small-molecule HSP90 inhibitor (Gamitrinib), which eradicated intrinsically resistant cells and augmented the efficacy of MAPKi by inducing mitochondrial dysfunction and inhibiting tumor bioenergetics. A subset of tumor biopsies from patients with disease progression despite MAPKi treatment showed increased mitochondrial biogenesis and tumor bioenergetics. A subset of acquired drug-resistant melanoma cell lines was sensitive to Gamitrinib. Our study establishes mitochondrial biogenesis, coupled with aberrant tumor bioenergetics, as a potential therapy escape mechanism and paves the way for a rationale-based combinatorial strategy to improve the efficacy of MAPKi. PMID:27043285

  5. Antimicrobial drug resistance of Staphylococcus aureus in dairy products

    PubMed Central

    Sasidharan, S; Prema, B; Yoga, Latha L

    2011-01-01

    Objective To evaluate the prevalence of multidrug resistant Staphylococcus aureus (S. aureus) in dairy products. Methods Isolation and identification of S. aureus were performed in 3 dairy-based food products. The isolates were tested for their susceptibility to 5 different common antimicrobial drugs. Results Of 50 samples examined, 5 (10%) were contaminated with S. aureus. Subsequently, the 5 isolates were subjected to antimicrobial resistance pattern using five antibiotic discs (methicillin, vancomycin, kanamycin, chloramphenicol and tetracycline). Sample 29 showed resistance to methicillin and vancomycin. Sample 18 showed intermediate response to tetracycline. The other samples were susceptible to all the antibiotics tested. Conclusions The results provide preliminary data on sources of food contamination which may act as vehicles for the transmission of antimicrobial-resistant Staphylococcus. Therefore, it enables us to develop preventive strategies to avoid the emergence of new strains of resistant S. aureus. PMID:23569742

  6. Drug Targets and Mechanisms of Resistance in the Anaerobic Protozoa

    PubMed Central

    Upcroft, Peter; Upcroft, Jacqueline A.

    2001-01-01

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

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

    PubMed

    Charles, J F; Nielsen-LeRoux, C

    2000-01-01

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

  8. Insights into the amplification of bacterial resistance to erythromycin in activated sludge.

    PubMed

    Guo, Mei-Ting; Yuan, Qing-Bin; Yang, Jian

    2015-10-01

    Wastewater treatment plants are significant reservoirs for antimicrobial resistance. However, little is known about wastewater treatment effects on the variation of antibiotic resistance. The shifts of bacterial resistance to erythromycin, a macrolide widely used in human medicine, on a lab-scale activated sludge system fed with real wastewater was investigated from levels of bacteria, community and genes, in this study. The resistance variation of total heterotrophic bacteria was studied during the biological treatment process, based on culture dependent method. The alterations of bacterial community resistant to erythromycin and nine typical erythromycin resistance genes were explored with molecular approaches, including high-throughput sequencing and quantitative polymerase chain reaction. The results revealed that the total heterotrophs tolerance level to erythromycin concentrations (higher than 32 mg/L) was significantly amplified during the activated sludge treatment, with the prevalence increased from 9.6% to 21.8%. High-throughput sequencing results demonstrated an obvious increase of the total heterotrophic bacterial diversity resistant to erythromycin. Proteobacteria and Bacteroidetes were the two dominant phyla in the influent and effluent of the bioreactor. However, the prevalence of Proteobacteria decreased from 76% to 59% while the total phyla number increased greatly from 18 to 29 through activated sludge treatment. The gene proportions of erm(A), mef(E) and erm(D) were greatly amplified after biological treatment. It is proposed that the transfer of antibiotic resistance genes through the variable mixtures of bacteria in the activated sludge might be the reason for the antibiotic resistance amplification. The amplified risk of antibiotic resistance in wastewater treatment needs to be paid more attention.

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

    PubMed

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

    2013-04-01

    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.

  10. Recent developments in genomics, bioinformatics and drug discovery to combat emerging drug-resistant tuberculosis.

    PubMed

    Swaminathan, Soumya; Sundaramurthi, Jagadish Chandrabose; Palaniappan, Alangudi Natarajan; Narayanan, Sujatha

    2016-12-01

    Emergence of drug-resistant tuberculosis (DR-TB) is a big challenge in TB control. The delay in diagnosis of DR-TB leads to its increased transmission, and therefore prevalence. Recent developments in genomics have enabled whole genome sequencing (WGS) of Mycobacterium tuberculosis (M. tuberculosis) from 3-day-old liquid culture and directly from uncultured sputa, while new bioinformatics tools facilitate to determine DR mutations rapidly from the resulting sequences. The present drug discovery and development pipeline is filled with candidate drugs which have shown efficacy against DR-TB. Furthermore, some of the FDA-approved drugs are being evaluated for repurposing, and this approach appears promising as several drugs are reported to enhance efficacy of the standard TB drugs, reduce drug tolerance, or modulate the host immune response to control the growth of intracellular M. tuberculosis. Recent developments in genomics and bioinformatics along with new drug discovery collectively have the potential to result in synergistic impact leading to the development of a rapid protocol to determine the drug resistance profile of the infecting strain so as to provide personalized medicine. Hence, in this review, we discuss recent developments in WGS, bioinformatics and drug discovery to perceive how they would transform the management of tuberculosis in a timely manner.

  11. Resistance of Aerosolized Bacterial Viruses to Relative Humidity and Temperature.

    PubMed

    Verreault, Daniel; Marcoux-Voiselle, Mélissa; Turgeon, Nathalie; Moineau, Sylvain; Duchaine, Caroline

    2015-10-01

    The use of aerosolized bacteriophages as surrogates for hazardous viruses might simplify and accelerate the discovery of links between viral components and their persistence in the airborne state under diverse environmental conditions. In this study, four structurally distinct lytic phages, MS2 (single-stranded RNA [ssRNA]), ϕ6 (double-stranded RNA [dsRNA]), ϕX174 (single-stranded DNA [ssDNA]), and PR772 (double-stranded DNA [dsDNA]), were nebulized into a rotating chamber and exposed to various levels of relative humidity (RH) and temperature as well as to germicidal UV radiation. The aerosolized viral particles were allowed to remain airborne for up to 14 h before being sampled for analysis by plaque assays and quantitative PCRs. Phages ϕ6 and MS2 were the most resistant at low levels of relative humidity, while ϕX174 was more resistant at 80% RH. Phage ϕ6 lost its infectivity immediately after exposure to 30°C and 80% RH. The infectivity of all tested phages rapidly declined as a function of the exposure time to UVC radiation, phage MS2 being the most resistant. Taken altogether, our data indicate that these aerosolized phages behave differently under various environmental conditions and highlight the necessity of carefully selecting viral simulants in bioaerosol studies.

  12. Resistance of Aerosolized Bacterial Viruses to Relative Humidity and Temperature

    PubMed Central

    Verreault, Daniel; Marcoux-Voiselle, Mélissa; Turgeon, Nathalie; Moineau, Sylvain

    2015-01-01

    The use of aerosolized bacteriophages as surrogates for hazardous viruses might simplify and accelerate the discovery of links between viral components and their persistence in the airborne state under diverse environmental conditions. In this study, four structurally distinct lytic phages, MS2 (single-stranded RNA [ssRNA]), ϕ6 (double-stranded RNA [dsRNA]), ϕX174 (single-stranded DNA [ssDNA]), and PR772 (double-stranded DNA [dsDNA]), were nebulized into a rotating chamber and exposed to various levels of relative humidity (RH) and temperature as well as to germicidal UV radiation. The aerosolized viral particles were allowed to remain airborne for up to 14 h before being sampled for analysis by plaque assays and quantitative PCRs. Phages ϕ6 and MS2 were the most resistant at low levels of relative humidity, while ϕX174 was more resistant at 80% RH. Phage ϕ6 lost its infectivity immediately after exposure to 30°C and 80% RH. The infectivity of all tested phages rapidly declined as a function of the exposure time to UVC radiation, phage MS2 being the most resistant. Taken altogether, our data indicate that these aerosolized phages behave differently under various environmental conditions and highlight the necessity of carefully selecting viral simulants in bioaerosol studies. PMID:26253683

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

    ERIC Educational Resources Information Center

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

    2011-01-01

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

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

    ERIC Educational Resources Information Center

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

    2010-01-01

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

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

    PubMed Central

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

    2014-01-01

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

  16. Fluoroquinolone interactions with Mycobacterium tuberculosis gyrase: Enhancing drug activity against wild-type and resistant gyrase

    PubMed Central

    Aldred, Katie J.; Kerns, Robert J.; Berger, James M.; Osheroff, Neil

    2016-01-01

    Mycobacterium tuberculosis is a significant source of global morbidity and mortality. Moxifloxacin and other fluoroquinolones are important therapeutic agents for the treatment of tuberculosis, particularly multidrug-resistant infections. To guide the development of new quinolone-based agents, it is critical to understand the basis of drug action against M. tuberculosis gyrase and how mutations in the enzyme cause resistance. Therefore, we characterized interactions of fluoroquinolones and related drugs with WT gyrase and enzymes carrying mutations at GyrAA90 and GyrAD94. M. tuberculosis gyrase lacks a conserved serine that anchors a water–metal ion bridge that is critical for quinolone interactions with other bacterial type II topoisomerases. Despite the fact that the serine is replaced by an alanine (i.e., GyrAA90) in M. tuberculosis gyrase, the bridge still forms and plays a functional role in mediating quinolone–gyrase interactions. Clinically relevant mutations at GyrAA90 and GyrAD94 cause quinolone resistance by disrupting the bridge–enzyme interaction, thereby decreasing drug affinity. Fluoroquinolone activity against WT and resistant enzymes is enhanced by the introduction of specific groups at the C7 and C8 positions. By dissecting fluoroquinolone–enzyme interactions, we determined that an 8-methyl-moxifloxacin derivative induces high levels of stable cleavage complexes with WT gyrase and two common resistant enzymes, GyrAA90V and GyrAD94G. 8-Methyl-moxifloxacin was more potent than moxifloxacin against WT M. tuberculosis gyrase and displayed higher activity against the mutant enzymes than moxifloxacin did against WT gyrase. This chemical biology approach to defining drug–enzyme interactions has the potential to identify novel drugs with improved activity against tuberculosis. PMID:26792518

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

    PubMed

    Hricová, Kristýna; Kolář, Milan

    2014-12-01

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

  18. Community-acquired methicillin-resistant Staphylococcus aureus: an emerging cause of acute bacterial parotitis.

    PubMed

    Nicolasora, Nelson P; Zacharek, Mark A; Malani, Anurag N

    2009-02-01

    Staphylococcus aureus has long been recognized as a cause of acute bacterial parotitis. A case of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) parotitis is presented, highlighting the emergence of this increasingly important pathogen to cause a wide variety of infections. Also reviewed are the salient clinical and microbiologic features of this novel infection.

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

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

  20. Antibiotic exposure can induce various bacterial virulence phenotypes in multidrug-resistant Salmonella enterica serovar Typhimurium

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Salmonella is one of the most prevalent bacterial foodborne diseases in the United States and causes an estimated 1 million human cases every year. Multidrug-resistant (MDR) Salmonella has emerged as a public health issue as it has been associated with increased morbidity in humans and mortality in...

  1. Development of candidate gene markers associated to common bacterial blight resistance in common bean

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Common bacterial blight (CBB), caused by Xanthomonas axonopodis pv. phaseoli (Xap), is a major yield-limiting factor of common bean (Phaseolus vulgaris L.) production around the world. Two major CBB-resistant quantitative trait loci (QTL), linked to the sequence characterized amplified region marker...

  2. Multi-scale model of drug induced adaptive resistance of Gram-negative bacteria to polymyxin B

    PubMed Central

    Krzyzanski, Wojciech

    2017-01-01

    The purpose of this report is to apply multi-scale modeling using the theory of physiologically structured populations (PSP) to develop a mathematical model for antimicrobial resistance based on a heterogeneous distribution of receptors and affinities among bacterial cells. The theory has been tested on data obtained from an in vitro static time-kill infection model analyzing the pharmacodynamics of polymyxin B against Gram-negative bacteria. The drug binding parameter KD (dissociation equilibrium constant) is assumed to vary between the bacterial cells. The PSP model describes the time course of the density distribution of KD upon exposure to cytotoxic drug concentrations. The drug increases the hazard of cell death as a function of receptor occupancy. The initial distribution of KD is described by the Weibull function. Time-kill data were used for model qualification. In vitro static time-kill experiments to evaluate the rate and extent of killing due to polymyxin B against two Klebsiella pneumoniae clinical isolates with differing susceptibilities to polymyxin B were performed over 48 h. The time-kill kinetics data of bacterial load cfu (colony forming units)/mL was used for model qualification. The resistant bacterial population is determined by the balance between growth rate and hazard of cell death controlled by polymyxin B concentrations. There exists a critical KD value below which cells continue to grow. Estimates of shape parameters for distributions of KD yielded unimodal distributions with the modes at 0 nM and the right tails containing approximately 25% of the bacteria. Our findings support a hypothesis that resistance of Klebsiella pneumoniae to polymyxin B can be at least partially attributed to a drug-induced selection of a subpopulation due to heterogeneity of polymyxin B receptor binding in the bacterial population. PMID:28334005

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

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid...

  4. 21 CFR 866.3950 - In vitro human immunodeficiency virus (HIV) drug resistance genotype assay.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... resistance genotype assay. 866.3950 Section 866.3950 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT... Serological Reagents § 866.3950 In vitro human immunodeficiency virus (HIV) drug resistance genotype assay. (a) Identification. The in vitro HIV drug resistance genotype assay is a device that consists of nucleic acid...

  5. Mechanisms of Drug Resistance in Relapse and Refractory Multiple Myeloma

    PubMed Central

    Yang, Wen-Chi; Lin, Sheng-Fung

    2015-01-01

    Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients eventually relapse or become refractory to current treatments. Although the treatments have improved, the major problem in MM is resistance to therapy. Clonal evolution of MM cells and bone marrow microenvironment changes contribute to drug resistance. Some mechanisms affect both MM cells and microenvironment, including the up- and downregulation of microRNAs and programmed death factor 1 (PD-1)/PD-L1 interaction. Here, we review the pathogenesis of MM cells and bone marrow microenvironment and highlight possible drug resistance mechanisms. We also review a potential molecular targeting treatment and immunotherapy for patients with refractory or relapse MM. PMID:26649299

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

    PubMed Central

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

    2016-01-01

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

  7. Modeling mass drug treatment and resistant filaria disease transmission

    NASA Astrophysics Data System (ADS)

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

    2014-03-01

    It has been indicated that a long term application of combined mass drug treatment may contribute to the development of drug resistance in lymphatic filariasis. This phenomenon is not well understood due to the complexity of filaria life cycle. In this paper we formulate a mathematical model for the spread of mass drug resistant in a filaria endemic region. The model is represented in a 13-dimensional Host-Vector system. The basic reproductive ratio of the system which is obtained from the next generation matrix, and analysis of stability of both the disease free equilibrium and the coexistence equilibria are shown. Numerical simulation for long term dynamics for possible field conditions is also shown.

  8. Drug interactions with Bacillus anthracis topoisomerase IV: biochemical basis for quinolone action and resistance.

    PubMed

    Aldred, Katie J; McPherson, Sylvia A; Wang, Pengfei; Kerns, Robert J; Graves, David E; Turnbough, Charles L; Osheroff, Neil

    2012-01-10

    Bacillus anthracis, the causative agent of anthrax, is considered a serious threat as a bioweapon. The drugs most commonly used to treat anthrax are quinolones, which act by increasing the levels of DNA cleavage mediated by topoisomerase IV and gyrase. Quinolone resistance most often is associated with specific serine mutations in these enzymes. Therefore, to determine the basis for quinolone action and resistance, we characterized wild-type B. anthracis topoisomerase IV, the GrlA(S81F) and GrlA(S81Y) quinolone-resistant mutants, and the effects of quinolones and a related quinazolinedione on these enzymes. Ser81 is believed to anchor a water-Mg(2+) bridge that coordinates quinolones to the enzyme through the C3/C4 keto acid. Consistent with this hypothesized bridge, ciprofloxacin required increased Mg(2+) concentrations to support DNA cleavage by GrlA(S81F) topoisomerase IV. The three enzymes displayed similar catalytic activities in the absence of drugs. However, the resistance mutations decreased the affinity of topoisomerase IV for ciprofloxacin and other quinolones, diminished quinolone-induced inhibition of DNA religation, and reduced the stability of the enzyme-quinolone-DNA ternary complex. Wild-type DNA cleavage levels were generated by mutant enzymes at high quinolone concentrations, suggesting that increased drug potency could overcome resistance. 8-Methyl-quinazoline-2,4-dione, which lacks the quinolone keto acid (and presumably does not require the water-Mg(2+) bridge to mediate protein interactions), was more potent than quinolones against wild-type topoisomerase IV and was equally efficacious. Moreover, it maintained high potency and efficacy against the mutant enzymes, effectively inhibited DNA religation, and formed stable ternary complexes. Our findings provide an underlying biochemical basis for the ability of quinazolinediones to overcome clinically relevant quinolone resistance mutations in bacterial type II topoisomerases.

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

    PubMed Central

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

    2013-01-01

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

  10. Fast and Inexpensive Detection of Bacterial Viability and Drug Effectiveness through Metabolic Monitoring

    PubMed Central

    Ayyash, Sondos; Wu, Wen-I; Selvaganapathy, Ponnambalam Ravi

    2016-01-01

    Conventional methods for the detection of bacterial infection such as DNA or immunoassays are expensive, time consuming, or not definitive and thus may not provide all the information sought by medical professionals. In particular, it is difficult to obtain information about viability or drug effectiveness, which is crucial to formulate a treatment. Bacterial culture tests are the “gold standard” because they are inexpensive and do not require extensive sample preparation, and most importantly, provide all the necessary information sought by healthcare professionals, such as bacterial presence, viability and drug effectiveness. These conventional culture methods, however, have a long turnaround time, anywhere between 1 day and 4 weeks. Here, we solve this problem by monitoring the growth of bacteria in thousands of nanowells simultaneously to more quickly identify their presence in the sample and their viability. The segmentation of a sample with low bacterial concentration into thousands of nanoliter wells digitizes the samples and increases the effective concentration in those wells that contain bacteria. We monitor the metabolism of aerobic bacteria by using an oxygen-sensitive fluorophore, ruthenium tris (2,2’-diprydl) dichloride hexahydrate (RTDP), which allows us to monitor the dissolved oxygen concentration in the nanowells. Using E. coli K12 as a model pathogen, we demonstrate that the detection time of E. coli can be as fast as 35–60 min with sample concentrations varying from 104 (62 min for detection), 106 (42 min) and 108 cells/mL (38 min). More importantly, we also demonstrate that reducing the well size can reduce the detection time. Finally we show that drug effectiveness information can be obtained in this format by loading the wells with the drug and monitoring the metabolism of the bacteria. The method that we have developed is low cost, simple, requires minimal sample preparation and can potentially be used with a wide variety of samples

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

    PubMed

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

    2012-09-04

    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.

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

    PubMed

    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

    2008-11-01

    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.

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

    NASA Astrophysics Data System (ADS)

    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.

    2008-11-01

    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.

  14. Balancing drug resistance and growth rates via compensatory mutations in the Plasmodium falciparum chloroquine resistance transporter.

    PubMed

    Petersen, Ines; Gabryszewski, Stanislaw J; Johnston, Geoffrey L; Dhingra, Satish K; Ecker, Andrea; Lewis, Rebecca E; de Almeida, Mariana Justino; Straimer, Judith; Henrich, Philipp P; Palatulan, Eugene; Johnson, David J; Coburn-Flynn, Olivia; Sanchez, Cecilia; Lehane, Adele M; Lanzer, Michael; Fidock, David A

    2015-07-01

    The widespread use of chloroquine to treat Plasmodium falciparum infections has resulted in the selection and dissemination of variant haplotypes of the primary resistance determinant PfCRT. These haplotypes have encountered drug pressure and within-host competition with wild-type drug-sensitive parasites. To examine these selective forces in vitro, we genetically engineered P. falciparum to express geographically diverse PfCRT haplotypes. Variant alleles from the Philippines (PH1 and PH2, which differ solely by the C72S mutation) both conferred a moderate gain of chloroquine resistance and a reduction in growth rates in vitro. Of the two, PH2 showed higher IC50 values, contrasting with reduced growth. Furthermore, a highly mutated pfcrt allele from Cambodia (Cam734) conferred moderate chloroquine resistance and enhanced growth rates, when tested against wild-type pfcrt in co-culture competition assays. These three alleles mediated cross-resistance to amodiaquine, an antimalarial drug widely used in Africa. Each allele, along with the globally prevalent Dd2 and 7G8 alleles, rendered parasites more susceptible to lumefantrine, the partner drug used in the leading first-line artemisinin-based combination therapy. These data reveal ongoing region-specific evolution of PfCRT that impacts drug susceptibility and relative fitness in settings of mixed infections, and raise important considerations about optimal agents to treat chloroquine-resistant malaria.

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

    PubMed Central

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

    2014-01-01

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

  16. Prevalence and genetic characterization of second-line drug-resistant and extensively drug-resistant Mycobacterium tuberculosis in Rural China.

    PubMed

    Hu, Yi; Hoffner, Sven; Wu, Linlin; Zhao, Qi; Jiang, Weili; Xu, Biao

    2013-08-01

    This study aimed to investigate the prevalence of resistance to second-line antituberculosis (anti-TB) drugs and its association with resistance-related mutations in Mycobacterium tuberculosis isolated in China. In the present study, we collected 380 isolates from a population-based study in China and tested the drug susceptibility to first- and selected second-line drugs. These results were compared with polymorphisms in the DNA sequences of genes associated with drug resistance and MIC values of the studied second-line drugs. Of 43 multidrug-resistant M. tuberculosis isolates, 13 showed resistance to fluoroquinolones or injectable second-line drugs (preextensively drug-resistant TB [pre-XDR-TB]), and 4 were resistant to both and thus defined as extensively drug-resistant TB (XDR-TB). Age and previous TB therapy, including use of second-line drugs, were two independent factors associated with increased resistance to both first- and second-line drugs. Molecular analysis identified the most frequent mutations in the resistance-associated genes: D94G in gyrA (29.1%) and A1401G in rrs (30.8%). Meanwhile, all 4 XDR-TB isolates had a mutation in gyrA, and 3 of them carried the A1401G mutation in rrs. Mutations in gyrA and rrs were associated with high-level resistance to fluoroquinolones and the second-line injectable drugs. In addition to the identification of resistance-associated mutations and development of a rapid molecular test to diagnose the second-line drug resistance, it should be a priority to strictly regulate the administration of second-line drugs to maintain their efficacy to treat multidrug-resistant TB.

  17. Antifungal drug resistance among Candida species: mechanisms and clinical impact.

    PubMed

    Sanguinetti, Maurizio; Posteraro, Brunella; Lass-Flörl, Cornelia

    2015-06-01

    The epidemiology of Candida infections has changed in recent years. Although Candida albicans is still the main cause of invasive candidiasis in most clinical settings, a substantial proportion of patients is now infected with non-albicans Candida species. The various Candida species vary in their susceptibility to the most commonly used antifungal agents, and the intrinsic resistance to antifungal therapy seen in some species, along with the development of acquired resistance during treatment in others, is becoming a major problem in the management of Candida infection. A better understanding of the mechanisms and clinical impact of antifungal drug resistance is essential for the efficient treatment of patients with Candida infection and for improving treatment outcomes. Herein, we report resistance to the azoles and echinocandins among Candida species.

  18. Production of putrescine-capped stable silver nanoparticle: its characterization and antibacterial activity against multidrug-resistant bacterial strains

    NASA Astrophysics Data System (ADS)

    Saha, Saswati; Gupta, Bhaskar; Gupta, Kamala; Chaudhuri, Mahua Ghosh

    2016-11-01

    Integration of biology with nanotechnology is now becoming attention-grabbing area of research. The antimicrobial potency of silver has been eminent from antiquity. Due to the recent desire for the enhancement of antibacterial efficacy of silver, various synthesis methods of silver in their nano dimensions are being practiced using a range of capping material. The present work highlights a facile biomimetic approach for production of silver nanoparticle being capped and stabilized by putrescine, possessing a diameter of 10-25 ± 1.5 nm. The synthesized nanoparticles have been analyzed spectrally and analytically. Morphological studies are carried out by high-resolution transmission electron microscopy and crystallinity by selected area electron diffraction patterns. Moreover, the elemental composition of the capped nanoparticles was confirmed by energy-dispersive X-ray spectroscopy analysis. A comparative study (zone of inhibition and minimum inhibitory concentration) regarding the interactions and antibacterial potentiality of the capped silver nanoparticles with respect to the bare ones reveal the efficiency of the capped one over the bare one. The bacterial kinetic study was executed to monitor the interference of nanoparticles with bacterial growth rate. The results also highlight the efficacy of putrescine-capped silver nanoparticles as effective growth inhibitors against multi-drug resistant human pathogenic bacterial strains, which may, thus, potentially be applicable as an effective antibacterial control system to fight diseases.

  19. Evaluation of the in vivo efficacy of novel monosubstituted sulfonylureas against H37Rv and extensively drug-resistant tuberculosis.

    PubMed

    Liu, Yu; Bao, Pengtao; Wang, Di; Li, Zhengming; Li, Yun; Tang, Liping; Zhou, Yi; Zhao, Weiguo

    2014-01-01

    Sulfonylureas have been regarded as potential drug candidates against tuberculosis (TB) because they can inhibit the biosynthesis of branched-chain amino acids by targeting acetohydroxyacid synthase (AHAS). We demonstrated previously that novel monosubstituted sulfonylureas showed potent in vitro activities against TB. In the current study, we further explored the anti-TB activity of monosubstituted sulfonylureas in a mouse model. Compounds 30 and 31 exhibited the most efficacy: a single intragastric administration at a dose of 250 mg/kg led to a reduced lung bacterial count, and the dose of 500 mg/kg achieved a >99% reduction in bacterial load for both H37Rv and extensively drug-resistant isolates. These results indicate that these compounds are more potent than commercial sulfonylureas in vivo and may provide insight into the potential implications for the design of novel drugs to combat TB by targeting AHAS.

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

    PubMed

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

    2014-09-01

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

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

    PubMed

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

    2012-01-20

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

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

    NASA Astrophysics Data System (ADS)

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

    2015-03-01

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

  3. Modeling HIV-1 Drug Resistance as Episodic Directional Selection

    PubMed Central

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

    2012-01-01

    The evolution of substitutions conferring drug resistance to HIV-1 is both episodic, occurring when patients are on antiretroviral therapy, and strongly directional, with site-specific resistant residues increasing in frequency over time. While methods exist to detect episodic diversifying selection and continuous directional selection, no evolutionary model combining these two properties has been proposed. We present two models of episodic directional selection (MEDS and EDEPS) which allow the a priori specification of lineages expected to have undergone directional selection. The models infer the sites and target residues that were likely subject to directional selection, using either codon or protein sequences. Compared to its null model of episodic diversifying selection, MEDS provides a superior fit to most sites known to be involved in drug resistance, and neither one test for episodic diversifying selection nor another for constant directional selection are able to detect as many true positives as MEDS and EDEPS while maintaining acceptable levels of false positives. This suggests that episodic directional selection is a better description of the process driving the evolution of drug resistance. PMID:22589711

  4. Optimizing drug exposure to minimize selection of antibiotic resistance.

    PubMed

    Olofsson, Sara K; Cars, Otto

    2007-09-01

    The worldwide increase in antibiotic resistance is a concern for public health. The fact that the choice of dose and treatment duration can affect the selection of antibiotic-resistant mutants is becoming more evident, and an increased number of studies have used pharmacodynamic models to describe the drug exposure and pharmacodynamic breakpoints needed to minimize and predict the development of resistance. However, there remains a lack of sufficient data, and future work is needed to fully characterize these target drug concentrations. More knowledge is also needed of drug pharmacodynamics versus bacteria with different resistance mutations and susceptibility levels. The dosing regimens should exhibit high efficacy not only against susceptible wild-type bacteria but, preferably, also against mutated bacteria that may exist in low numbers in "susceptible" populations. Thus, to prolong the life span of existing and new antibiotics, it is important that dosing regimens be carefully selected on the basis of pharmacokinetic and pharmacodynamic properties that prevent emergence of preexisting and newly formed mutants.

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

    SciTech Connect

    Hopwood, L.E.; Davies, B.M.; Moulder, J.E. )

    1990-09-01

    RIF-1 tumors contain a small number of cells (1 to 100 per 10(6) cells) that are resistant to 5-fluorouracil, methotrexate, or adriamycin. The frequency of drug-resistant cells among individual untreated tumors is highly variable. Radiation, delivered in vivo at doses of 3 to 12 Gy, increases the frequency of methotrexate- and 5-fluorouracil-resistant cells, but not the frequency of adriamycin-resistant cells. The magnitude of induction of 5-fluorouracil and methotrexate resistance shows a complex dependence on the radiation dose and on the interval between irradiation and assessment of drug resistance. For a dose of 3 Gy, induced 5-fluorouracil and methotrexate resistance is seen only after an interval of 5 to 7 days, whereas for a dose of 12 Gy, high levels of induced resistance are observed 1 to 3 days after irradiation. The maximum absolute risk for induction of resistance is 4 per 10(4) cells per Gy for methotrexate, and 3 per 10(6) cells per Gy for 5-fluorouracil. These results indicate that tumor hypoxia may play a role in the increased levels of drug resistance seen after irradiation, and that both genetic and environmental factors may influence radiation-induction of drug resistance. These studies provide essential data for models of the development of tumor drug resistance, and imply that some of the drug resistance seen when chemotherapy follows radiotherapy may be caused by radiation-induced drug resistance.

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

    PubMed

    Shobrak, Mohammed Y; Abo-Amer, Aly E

    2014-01-01

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

  7. Gene expression and evolution of antifungal drug resistance.

    PubMed

    Anderson, James B; Sirjusingh, Caroline; Syed, Nazia; Lafayette, Shantelle

    2009-05-01

    Permanent changes in gene expression result from certain forms of antifungal resistance. In this study, we asked whether any changes in gene expression are required for the evolution of a drug-resistant phenotype in populations. We examined the changes in gene expression resulting from the evolution of resistance in experimental populations of the yeast Saccharomyces cerevisiae with two antifungal drugs, fluconazole (FLC) in a previous study and amphotericin B (AmB) in this study, in which five populations were subjected to increasing concentrations of AmB, from 0.25 to 128 microg/ml in twofold increments. Six genes, YGR035C, YOR1, ICT1, GRE2, PDR16, and YPLO88W, were consistently overexpressed with resistance to AmB reported here and with resistance to FLC involving a mechanism of increased efflux reported previously. We then asked if the deletion of these genes impaired the ability of populations to evolve resistance to FLC over 108 generations of asexual reproduction in 32 and 128 microg/ml FLC, the same conditions under which FLC-resistant types evolved originally. For each of three deletion strains, YOR1, ICT1, and PDR16 strains, extinctions occurred in one of two replicate populations growing in 128 microg/ml FLC. Each of these three deletion strains was mixed 1:1 with a marked version of the wild type to measure the relative ability of the deletion strain to adapt over 108 generations. In these assays, only the PDR16 deletion strain consistently became extinct both at 32 and at 128 microg/ml FLC. The deletion of PDR16 reduces the capacity of a population to evolve to resistance to FLC.

  8. Engineering serendipity: High-throughput discovery of materials that resist bacterial attachment☆

    PubMed Central

    Magennis, E.P.; Hook, A.L.; Davies, M.C.; Alexander, C.; Williams, P.; Alexander, M.R.

    2016-01-01

    Controlling the colonisation of materials by microorganisms is important in a wide range of industries and clinical settings. To date, the underlying mechanisms that govern the interactions of bacteria with material surfaces remain poorly understood, limiting the ab initio design and engineering of biomaterials to control bacterial attachment. Combinatorial approaches involving high-throughput screening have emerged as key tools for identifying materials to control bacterial attachment. The hundreds of different materials assessed using these methods can be carried out with the aid of computational modelling. This approach can develop an understanding of the rules used to predict bacterial attachment to surfaces of non-toxic synthetic materials. Here we outline our view on the state of this field and the challenges and opportunities in this area for the coming years. Statement of significance This opinion article on high throughput screening methods reflects one aspect of how the field of biomaterials research has developed and progressed. The piece takes the reader through key developments in biomaterials discovery, particularly focusing on need to reduce bacterial colonisation of surfaces. Such bacterial resistant surfaces are increasingly required in this age of antibiotic resistance. The influence and origin of high-throughput methods are discussed with insights into the future of biomaterials development where computational methods may drive materials development into new fertile areas of discovery. New biomaterials will exhibit responsiveness to adapt to the biological environment and promote better integration and reduced rejection or infection. PMID:26577984

  9. Insights into the mechanism of drug resistance. X-ray structure analysis of multi-drug resistant HIV-1 protease ritonavir complex

    SciTech Connect

    Liu, Zhigang; Yedidi, Ravikiran S.; Wang, Yong; Dewdney, Tamaria G.; Reiter, Samuel J.; Brunzelle, Joseph S.; Kovari, Iulia A.; Kovari, Ladislau C.

    2013-01-08

    Ritonavir (RTV) is a first generation HIV-1 protease inhibitor with rapidly emerging drug resistance. Mutations at residues 46, 54, 82 and 84 render the HIV-1 protease drug resistant against RTV. We report