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Author (up) Blair, J.M.A.; Webber, M.A.; Baylay, A.J.; Ogbolu, D.O.; Piddock, L.J.V. file  url
doi  openurl
  Title Molecular mechanisms of antibiotic resistance Type Journal Article
  Year 2015 Publication Nature Reviews. Microbiology Abbreviated Journal Nat Rev Microbiol  
  Volume 13 Issue 1 Pages 42-51  
  Keywords *Anti-Bacterial Agents/metabolism/pharmacology; *Bacteria/drug effects/metabolism/pathogenicity; *Drug Resistance, Bacterial; Signal Transduction  
  Abstract Antibiotic-resistant bacteria that are difficult or impossible to treat are becoming increasingly common and are causing a global health crisis. Antibiotic resistance is encoded by several genes, many of which can transfer between bacteria. New resistance mechanisms are constantly being described, and new genes and vectors of transmission are identified on a regular basis. This article reviews recent advances in our understanding of the mechanisms by which bacteria are either intrinsically resistant or acquire resistance to antibiotics, including the prevention of access to drug targets, changes in the structure and protection of antibiotic targets and the direct modification or inactivation of antibiotics.  
  Call Number Serial 1136  
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Author (up) Cohen, M.L. file  doi
  Title Epidemiology of drug resistance: implications for a post-antimicrobial era Type Journal Article
  Year 1992 Publication Science (New York, N.Y.) Abbreviated Journal Science  
  Volume 257 Issue 5073 Pages 1050-1055  
  Keywords Bacterial Infections/*drug therapy/epidemiology/prevention & control/transmission; Cross Infection; *Drug Resistance, Microbial; Humans; Risk Factors  
  Abstract In the last several years, the frequency and spectrum of antimicrobial-resistant infections have increased in both the hospital and the community. Certain infections that are essentially untreatable have begun to occur as epidemics both in the developing world and in institutional settings in the United States. The increasing frequency of drug resistance has been attributed to combinations of microbial characteristics, selective pressures of antimicrobial use, and societal and technologic changes that enhance the transmission of drug-resistant organisms. Antimicrobial resistance is resulting in increased morbidity, mortality, and health-care costs. Prevention and control of these infections will require new antimicrobial agents, prudent use of existing agents, new vaccines, and enhanced public health efforts to reduce transmission.  
  Call Number Serial 1129  
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Author (up) Firsov, A.A.; Strukova, E.N.; Portnoy, Y.A.; Shlykova, D.S.; Zinner, S.H. file  url
  Title Bacterial antibiotic resistance studies using in vitro dynamic models: Population analysis vs. susceptibility testing as endpoints of mutant enrichment Type Journal Article
  Year 2015 Publication International Journal of Antimicrobial Agents Abbreviated Journal Int J Antimicrob Agents  
  Volume 46 Issue 3 Pages 313-318  
  Keywords Anti-Bacterial Agents/*pharmacology; Ciprofloxacin/*pharmacology; *Drug Resistance, Bacterial; Humans; Microbial Sensitivity Tests; Models, Theoretical; Mutation; Pseudomonas Infections/microbiology; Pseudomonas aeruginosa/*drug effects/*growth & development/isolation & purification; *Selection, Genetic; Time Factors; Bacterial resistance studies; Fluoroquinolones; Population analysis; Pseudomonas aeruginosa; Susceptibility testing  
  Abstract Emergence of bacterial antibiotic resistance is usually characterised either by population analysis or susceptibility testing. To compare these endpoints in their ability to demonstrate clear relationships with the ratio of 24-h area under the concentration-time curve (AUC24) to the minimum inhibitory concentration (MIC), enrichment of ciprofloxacin-resistant mutants of four clinical isolates of Pseudomonas aeruginosa was studied in an in vitro dynamic model that simulates mono-exponential pharmacokinetics of ciprofloxacin over a wide range of the AUC24/MIC ratios. Each organism was exposed to twice-daily ciprofloxacin for 3 days. Amplification of resistant mutants was monitored by plating on media with 2x, 4x, 8x and 16x MIC of ciprofloxacin. Population analysis data were expressed by the area under the bacterial mutant concentration-time curve (AUBCM). Changes in P. aeruginosa susceptibility were examined by daily MIC determinations. To account for the different susceptibilities of P. aeruginosa strains, post-exposure MICs (MICfinal) were related to the MICs determined with the starting inoculum (MICinitial). For each organism, AUC24/MIC relationships both with AUBCM and MICfinal/MICinitial were bell-shaped, but the latter were more strain-specific than the former. Using combined data on all four isolates, AUBCM showed a better correlation than MICfinal/MICinitial (r(2)=0.75 vs. r(2)=0.53). The shift of MICfinal/MICinitial relative to AUBCM vs. AUC24/MIC curves resulted in a weak correlation between AUBCM and MICfinal/MICinitial (r(2)=0.41). These data suggest that population analysis is preferable to susceptibility testing in bacterial resistance studies and that these endpoints should not be considered interchangeable.  
  Call Number Serial 1214  
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Author (up) Heuer, H.; Schmitt, H.; Smalla, K. file  url
  Title Antibiotic resistance gene spread due to manure application on agricultural fields Type Journal Article
  Year 2011 Publication Current Opinion in Microbiology Abbreviated Journal Curr Opin Microbiol  
  Volume 14 Issue 3 Pages 236-243  
  Keywords Agriculture/*methods; Animals; Anti-Bacterial Agents/*pharmacology; Bacteria/*drug effects/*genetics; *Drug Resistance, Bacterial; Gene Transfer, Horizontal; Humans; Interspersed Repetitive Sequences; Manure/*microbiology; Selection, Genetic  
  Abstract The usage of antibiotics in animal husbandry has promoted the development and abundance of antibiotic resistance in farm environments. Manure has become a reservoir of resistant bacteria and antibiotic compounds, and its application to agricultural soils is assumed to significantly increase antibiotic resistance genes and selection of resistant bacterial populations in soil. The genome location of resistance genes is likely to shift towards mobile genetic elements such as broad-host-range plasmids, integrons, and transposable elements. Horizontal transfer of these elements to bacteria adapted to soil or other habitats supports their environmental transmission independent of the original host. The human exposure to soil-borne resistance has yet to be determined, but is likely to be severely underestimated.  
  Call Number Serial 1955  
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Author (up) Ling, L.L.; Schneider, T.; Peoples, A.J.; Spoering, A.L.; Engels, I.; Conlon, B.P.; Mueller, A.; Schaberle, T.F.; Hughes, D.E.; Epstein, S.; Jones, M.; Lazarides, L.; Steadman, V.A.; Cohen, D.R.; Felix, C.R.; Fetterman, K.A.; Millett, W.P.; Nitti, A.G.; Zullo, A.M.; Chen, C.; Lewis, K. file  url
  Title A new antibiotic kills pathogens without detectable resistance Type Journal Article
  Year 2015 Publication Nature Abbreviated Journal Nature  
  Volume 517 Issue 7535 Pages 455-459  
  Keywords Animals; Anti-Bacterial Agents/biosynthesis/chemistry/isolation & purification/*pharmacology; Betaproteobacteria/chemistry/genetics; Biological Products/chemistry/isolation & purification/pharmacology; Cell Wall/chemistry/drug effects/metabolism; Depsipeptides/biosynthesis/chemistry/isolation & purification/*pharmacology; Disease Models, Animal; *Drug Resistance, Microbial/genetics; Female; Mice; Microbial Sensitivity Tests; Microbial Viability/*drug effects; Molecular Sequence Data; Multigene Family/genetics; Mycobacterium tuberculosis/cytology/*drug effects/genetics; Peptidoglycan/biosynthesis; Staphylococcal Infections/drug therapy/microbiology; Staphylococcus aureus/chemistry/cytology/*drug effects/genetics; Teichoic Acids/biosynthesis; Time Factors  
  Abstract Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance.  
  Call Number Serial 1893  
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Author (up) Mah, T.F.; O'Toole, G.A. file  url
  Title Mechanisms of biofilm resistance to antimicrobial agents Type Journal Article
  Year 2001 Publication Trends in Microbiology Abbreviated Journal Trends Microbiol  
  Volume 9 Issue 1 Pages 34-39  
  Keywords Anti-Bacterial Agents/*pharmacology; Bacterial Proteins/metabolism; Biofilms/*drug effects/growth & development; *Drug Resistance, Microbial; Drug Resistance, Multiple; Klebsiella pneumoniae/drug effects/growth & development/metabolism; Phenotype; Polysaccharides, Bacterial/chemistry/metabolism; Pseudomonas aeruginosa/drug effects/growth & development/metabolism; Sigma Factor/metabolism; Staphylococcus epidermidis/drug effects/growth & development/metabolism  
  Abstract Biofilms are communities of microorganisms attached to a surface. It has become clear that biofilm-grown cells express properties distinct from planktonic cells, one of which is an increased resistance to antimicrobial agents. Recent work has indicated that slow growth and/or induction of an rpoS-mediated stress response could contribute to biocide resistance. The physical and/or chemical structure of exopolysaccharides or other aspects of biofilm architecture could also confer resistance by exclusion of biocides from the bacterial community. Finally, biofilm-grown bacteria might develop a biofilm-specific biocide-resistant phenotype. Owing to the heterogeneous nature of the biofilm, it is likely that there are multiple resistance mechanisms at work within a single community. Recent research has begun to shed light on how and why surface-attached microbial communities develop resistance to antimicrobial agents.  
  Call Number Serial 1538  
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Author (up) Parsons, A.B.; Brost, R.L.; Ding, H.; Li, Z.; Zhang, C.; Sheikh, B.; Brown, G.W.; Kane, P.M.; Hughes, T.R.; Boone, C. file  url
doi  openurl
  Title Integration of chemical-genetic and genetic interaction data links bioactive compounds to cellular target pathways Type Journal Article
  Year 2004 Publication Nature Biotechnology Abbreviated Journal Nat Biotechnol  
  Volume 22 Issue 1 Pages 62-69  
  Keywords Biotechnology/*methods; Cluster Analysis; Drug Industry/*methods; *Drug Resistance; Fungal Proteins/metabolism; Gene Deletion; *Gene Expression Regulation; Mutation; Pharmacogenetics; Proton-Translocating ATPases/metabolism; Saccharomyces cerevisiae/*genetics; Software  
  Abstract Bioactive compounds can be valuable research tools and drug leads, but it is often difficult to identify their mechanism of action or cellular target. Here we investigate the potential for integration of chemical-genetic and genetic interaction data to reveal information about the pathways and targets of inhibitory compounds. Taking advantage of the existing complete set of yeast haploid deletion mutants, we generated drug-hypersensitivity (chemical-genetic) profiles for 12 compounds. In addition to a set of compound-specific interactions, the chemical-genetic profiles identified a large group of genes required for multidrug resistance. In particular, yeast mutants lacking a functional vacuolar H(+)-ATPase show multidrug sensitivity, a phenomenon that may be conserved in mammalian cells. By filtering chemical-genetic profiles for the multidrug-resistant genes and then clustering the compound-specific profiles with a compendium of large-scale genetic interaction profiles, we were able to identify target pathways or proteins. This method thus provides a powerful means for inferring mechanism of action.  
  Call Number Serial 339  
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Author (up) Poole, K. file  url
doi  openurl
  Title Stress responses as determinants of antimicrobial resistance in Gram-negative bacteria Type Journal Article
  Year 2012 Publication Trends in Microbiology Abbreviated Journal Trends Microbiol  
  Volume 20 Issue 5 Pages 227-234  
  Keywords Animals; Anti-Bacterial Agents/*pharmacology; Biofilms/drug effects; *Drug Resistance, Bacterial; Gram-Negative Bacteria/*drug effects/genetics/*physiology; Gram-Negative Bacterial Infections/*microbiology; Humans  
  Abstract Bacteria encounter a myriad of potentially growth-compromising conditions in nature and in hosts of pathogenic bacteria. These 'stresses' typically elicit protective and/or adaptive responses that serve to enhance bacterial survivability. Because they impact upon many of the same cellular components and processes that are targeted by antimicrobials, adaptive stress responses can influence antimicrobial susceptibility. In targeting and interfering with key cellular processes, antimicrobials themselves are 'stressors' to which protective stress responses have also evolved. Cellular responses to nutrient limitation (nutrient stress), oxidative and nitrosative stress, cell envelope damage (envelope stress), antimicrobial exposure and other growth-compromising stresses, have all been linked to the development of antimicrobial resistance in Gram-negative bacteria – resulting from the stimulation of protective changes to cell physiology, activation of resistance mechanisms, promotion of resistant lifestyles (biofilms), and induction of resistance mutations.  
  Call Number Serial 1144  
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Author (up) Rahube, T.O.; Yost, C.K. file  url
  Title Characterization of a mobile and multiple resistance plasmid isolated from swine manure and its detection in soil after manure application Type Journal Article
  Year 2012 Publication Journal of Applied Microbiology Abbreviated Journal J Appl Microbiol  
  Volume 112 Issue 6 Pages 1123-1133  
  Keywords Animals; Bacteria/genetics/metabolism; Culture Media/chemistry; *Drug Resistance, Multiple; Erythromycin/metabolism; Manure/*microbiology; Plasmids/analysis/*genetics; *Soil Microbiology; *Sus scrofa; Tetracycline Resistance  
  Abstract AIMS: To isolate and characterize multiple antibiotic resistance plasmids found in swine manure and test for plasmid-associated genetic markers in soil following manure application to an agricultural field. METHODS AND RESULTS: Plasmids were isolated from an erythromycin enrichment culture that used liquid swine manure as an inoculant. Plasmids were transformed into Escherichia coli DH10beta for subsequent characterization. We isolated and DNA sequenced a 22 102-bp plasmid (pMC2) that confers macrolide, and tetracycline resistances, and carries genes predicted to code for mercury and chromium resistance. Conjugation experiments using an pRP4 derivative as a helper plasmid confirm that pMC2 has a functional mobilization unit. PCR was used to detect genetic elements found on pMC2 in DNA extracted from manure amended soil. CONCLUSIONS: The pMC2 plasmid has a tetracycline-resistant core and has acquired additional resistance genes by insertion of an accessory region (12 762 bp) containing macrolide, mercury and chromium resistance genes, which was inserted between the truncated DDE motifs within the Tn903/IS102 mobile element. SIGNIFICANCE AND IMPACT OF THE STUDY: Liquid swine manure used for manure spreading contains multiple antibiotic resistance plasmids that can be detected in soil following manure application.  
  Call Number Serial 1958  
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Author (up) Teuber, M. file  url
  Title Veterinary use and antibiotic resistance Type Journal Article
  Year 2001 Publication Current Opinion in Microbiology Abbreviated Journal Curr Opin Microbiol  
  Volume 4 Issue 5 Pages 493-499  
  Keywords Agriculture; Animals; *Animals, Domestic; Anti-Bacterial Agents/administration & dosage/*pharmacology/therapeutic use; Bacteria/*drug effects; *Drug Resistance, Bacterial; Drug Utilization; Humans; *Veterinary Drugs; *Veterinary Medicine  
  Abstract Globally, an estimated 50% of all antimicrobials serve veterinary purposes. Bacteria that inevitably develop antibiotic resistance in animals comprise food-borne pathogens, opportunistic pathogens and commensal bacteria. The same antibiotic resistance genes and gene transfer mechanisms can be found in the microfloras of animals and humans. Direct contact, food and water link animal and human habitats. The accumulation of resistant bacteria by the use of antibiotics in agriculture and veterinary medicine and the spread of such bacteria via agriculture and direct contamination are documented.  
  Call Number Serial 1671  
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