Adaptation of Enterococcus faecalis to Daptomycin Reveals an Ordered Progression to Resistance

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dc.citation.firstpage5373en_US
dc.citation.issueNumber11en_US
dc.citation.journalTitleAntimicrobial Agents and Chemotherapyen_US
dc.citation.lastpage5383en_US
dc.citation.volumeNumber57en_US
dc.contributor.authorMiller, Corwin A.en_US
dc.contributor.authorKong, Jiayien_US
dc.contributor.authorTran, Truc T.en_US
dc.contributor.authorArias, Cesar A.en_US
dc.contributor.authorSaxer, Gerdaen_US
dc.contributor.authorShamoo, Yousifen_US
dc.date.accessioned2014-10-06T17:18:03Zen_US
dc.date.available2014-10-06T17:18:03Zen_US
dc.date.issued2013en_US
dc.description.abstractWith increasing numbers of hospital-acquired antibiotic resistant infections each year and staggering health care costs, there is a clear need for new antimicrobial agents, as well as novel strategies to extend their clinical efficacy. While genomic studies have provided a wealth of information about the alleles associated with adaptation to antibiotics, they do not provide essential information about the relative importance of genomic changes, their order of appearance, or potential epistatic relationships between adaptive changes. Here we used quantitative experimental evolution of a single polymorphic population in continuous culture with whole-genome sequencing and allelic frequency measurements to study daptomycin (DAP) resistance in the vancomycin-resistant clinical pathogen Enterococcus faecalis S613. Importantly, we sustained both planktonic and nonplanktonic (i.e., biofilm) populations in coculture as the concentration of antibiotic was raised, facilitating the development of more ecological complexity than is typically observed in laboratory evolution. Quantitative experimental evolution revealed a clear order and hierarchy of genetic changes leading to resistance, the signaling and metabolic pathways responsible, and the relative importance of these mutations to the evolution of DAP resistance. Despite the relative simplicity of this ex vivo approach compared to the ecological complexity of the human body, we showed that experimental evolution allows for rapid identification of clinically relevant adaptive molecular pathways and new targets for drug design in pathogens.en_US
dc.identifier.citationMiller, Corwin A., Kong, Jiayi, Tran, Truc T., et al.. "Adaptation of Enterococcus faecalis to Daptomycin Reveals an Ordered Progression to Resistance." <i>Antimicrobial Agents and Chemotherapy,</i> 57, no. 11 (2013) American Society for Microbiology: 5373-5383. http://dx.doi.org/10.1128/AAC.01473-13.en_US
dc.identifier.doihttp://dx.doi.org/10.1128/AAC.01473-13en_US
dc.identifier.urihttps://hdl.handle.net/1911/77403en_US
dc.language.isoengen_US
dc.publisherAmerican Society for Microbiologyen_US
dc.rightsArticle is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use.en_US
dc.titleAdaptation of Enterococcus faecalis to Daptomycin Reveals an Ordered Progression to Resistanceen_US
dc.typeJournal articleen_US
dc.type.dcmiTexten_US
dc.type.publicationpublisher versionen_US
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