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dc.creatorChampion, MD
dc.creatorGray, V
dc.creatorEberhard, C
dc.creatorKumar, S
dc.date.accessioned2021-01-31T19:21:34Z
dc.date.available2021-01-31T19:21:34Z
dc.date.issued2013-02-12
dc.identifier.issn1932-6203
dc.identifier.issn1932-6203
dc.identifier.doihttp://dx.doi.org/10.34944/dspace/5393
dc.identifier.other23424663 (pubmed)
dc.identifier.urihttp://hdl.handle.net/20.500.12613/5411
dc.description.abstractThe evolution of resistance in Staphylococcus aureus occurs rapidly, and in response to all known antimicrobial treatments. Numerous studies of model species describe compensatory roles of mutations in mediating competitive fitness, and there is growing evidence that these mutation types also drive adaptation of S. aureus strains. However, few studies have tracked amino acid changes during the complete evolutionary trajectory of antibiotic adaptation or been able to predict their functional relevance. Here, we have assessed the efficacy of computational methods to predict biological resistance of a collection of clinically known Resistance Associated Mutations (RAMs). We have found that >90% of known RAMs are incorrectly predicted to be functionally neutral by at least one of the prediction methods used. By tracing the evolutionary histories of all of the false negative RAMs, we have discovered that a significant number are reversion mutations to ancestral alleles also carried in the MSSA476 methicillin-sensitive isolate. These genetic reversions are most prevalent in strains following daptomycin treatment and show a tendency to accumulate in biological pathway reactions that are distinct from those accumulating non-reversion mutations. Our studies therefore show that in addition to non-reversion mutations, reversion mutations arise in isolates exposed to new antibiotic treatments. It is possible that acquisition of reversion mutations in the genome may prevent substantial fitness costs during the progression of resistance. Our findings pose an interesting question to be addressed by further clinical studies regarding whether or not these reversion mutations lead to a renewed vulnerability of a vancomycin or daptomycin resistant strain to antibiotics administered at an earlier stage of infection. © 2013 Champion et al.
dc.format.extente56466-e56466
dc.language.isoen
dc.relation.haspartPLoS ONE
dc.relation.isreferencedbyPublic Library of Science (PLoS)
dc.rightsCC BY
dc.subjectAlleles
dc.subjectBacterial Proteins
dc.subjectComputational Biology
dc.subjectDrug Resistance, Bacterial
dc.subjectEvolution, Molecular
dc.subjectFalse Negative Reactions
dc.subjectHumans
dc.subjectMethicillin
dc.subjectMutation
dc.subjectPhenotype
dc.subjectStaphylococcus aureus
dc.titleThe Evolutionary History of Amino Acid Variations Mediating Increased Resistance of S. aureus Identifies Reversion Mutations in Metabolic Regulators
dc.typeArticle
dc.type.genreJournal Article
dc.relation.doi10.1371/journal.pone.0056466
dc.ada.noteFor Americans with Disabilities Act (ADA) accommodation, including help with reading this content, please contact scholarshare@temple.edu
dc.creator.orcidKumar, Sudhir|0000-0002-9918-8212
dc.date.updated2021-01-31T19:21:31Z
refterms.dateFOA2021-01-31T19:21:34Z


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