Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/11374
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dc.contributor.authorHowden, Benjamin P-
dc.contributor.authorMcEvoy, Christopher R E-
dc.contributor.authorAllen, David L-
dc.contributor.authorChua, Kyra Y L-
dc.contributor.authorGao, Wei-
dc.contributor.authorHarrison, Paul F-
dc.contributor.authorBell, Jan-
dc.contributor.authorCoombs, Geoffrey W-
dc.contributor.authorBennett-Wood, Vicki-
dc.contributor.authorPorter, Jessica L-
dc.contributor.authorRobins-Browne, Roy-
dc.contributor.authorDavies, John K-
dc.contributor.authorSeemann, Torsten-
dc.contributor.authorStinear, Timothy P-
dc.date.accessioned2015-05-16T00:57:52Z-
dc.date.available2015-05-16T00:57:52Z-
dc.date.issued2011-11-10-
dc.identifier.citationPlos Pathogens 2011; 7(11): e1002359en_US
dc.identifier.otherPUBMEDen
dc.identifier.urihttps://ahro.austin.org.au/austinjspui/handle/1/11374en
dc.description.abstractAntimicrobial resistance in Staphylococcus aureus is a major public health threat, compounded by emergence of strains with resistance to vancomycin and daptomycin, both last line antimicrobials. Here we have performed high throughput DNA sequencing and comparative genomics for five clinical pairs of vancomycin-susceptible (VSSA) and vancomycin-intermediate ST239 S. aureus (VISA); each pair isolated before and after vancomycin treatment failure. These comparisons revealed a frequent pattern of mutation among the VISA strains within the essential walKR two-component regulatory locus involved in control of cell wall metabolism. We then conducted bi-directional allelic exchange experiments in our clinical VSSA and VISA strains and showed that single nucleotide substitutions within either walK or walR lead to co-resistance to vancomycin and daptomycin, and caused the typical cell wall thickening observed in resistant clinical isolates. Ion Torrent genome sequencing confirmed no additional regulatory mutations had been introduced into either the walR or walK VISA mutants during the allelic exchange process. However, two potential compensatory mutations were detected within putative transport genes for the walK mutant. The minimal genetic changes in either walK or walR also attenuated virulence, reduced biofilm formation, and led to consistent transcriptional changes that suggest an important role for this regulator in control of central metabolism. This study highlights the dramatic impacts of single mutations that arise during persistent S. aureus infections and demonstrates the role played by walKR to increase drug resistance, control metabolism and alter the virulence potential of this pathogen.en_US
dc.language.isoenen
dc.subject.otherAnimalsen
dc.subject.otherAnti-Bacterial Agents.pharmacology.therapeutic useen
dc.subject.otherBacterial Proteins.genetics.metabolismen
dc.subject.otherBiofilmsen
dc.subject.otherCell Wall.genetics.metabolismen
dc.subject.otherDaptomycin.pharmacology.therapeutic useen
dc.subject.otherDrug Resistance, Multiple, Bacterial.geneticsen
dc.subject.otherHigh-Throughput Nucleotide Sequencingen
dc.subject.otherHumansen
dc.subject.otherMicrobial Sensitivity Testsen
dc.subject.otherMolecular Typingen
dc.subject.otherMutationen
dc.subject.otherPolymorphism, Single Nucleotideen
dc.subject.otherStaphylococcal Infections.drug therapy.microbiologyen
dc.subject.otherStaphylococcus aureus.drug effects.genetics.metabolism.pathogenicityen
dc.subject.otherVancomycin.pharmacology.therapeutic useen
dc.subject.otherVancomycin Resistance.geneticsen
dc.subject.otherVirulence Factorsen
dc.titleEvolution of multidrug resistance during Staphylococcus aureus infection involves mutation of the essential two component regulator WalKR.en_US
dc.typeJournal Articleen_US
dc.identifier.journaltitlePlos Pathogensen_US
dc.identifier.affiliationDepartment of Microbiology and Immunology, University of Melbourne, Victoria, Australiaen_US
dc.identifier.affiliationInfectious Diseasesen_US
dc.identifier.doi10.1371/journal.ppat.1002359en_US
dc.description.pagese1002359en
dc.relation.urlhttps://pubmed.ncbi.nlm.nih.gov/22102812en
dc.type.contentTexten_US
dc.type.austinJournal Articleen
local.name.researcherChua, Kyra Y L
item.openairetypeJournal Article-
item.cerifentitytypePublications-
item.grantfulltextnone-
item.fulltextNo Fulltext-
item.openairecristypehttp://purl.org/coar/resource_type/c_18cf-
item.languageiso639-1en-
crisitem.author.deptInfectious Diseases-
crisitem.author.deptMicrobiology-
crisitem.author.deptMicrobiology-
crisitem.author.deptInfectious Diseases-
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