Evolutionary Trajectories to Daptomycin Resistance in Enterococcus faecalis

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dc.contributor.advisorOlson, John S.en_US
dc.contributor.committeeMemberShamoo, Yousifen_US
dc.contributor.committeeMemberBennett, Matthew R.en_US
dc.contributor.committeeMemberRudolf, Volker H. W.en_US
dc.contributor.committeeMemberTao, Yizhi Janeen_US
dc.creatorMiller, Corwinen_US
dc.date.accessioned2014-09-23T16:33:35Zen_US
dc.date.available2014-09-23T16:33:35Zen_US
dc.date.created2013-12en_US
dc.date.issued2013-11-18en_US
dc.date.submittedDecember 2013en_US
dc.date.updated2014-09-23T16:33:36Zen_US
dc.description.abstractWith increasing amounts of hospital-acquired antibiotic resistant infections each year and staggering healthcare 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 relative importance of genomic changes, their order of appearance, or potential epistatic relationships between adaptive changes. In this thesis, I have combined experimental evolution, comparative whole genome sequencing, and allelic frequency measurements to study daptomycin (DAP) resistance in the vancomycin resistant clinical pathogen Enterococcus faecalis strain S613. Maintaining cells inside a turbidostat, a single polymorphic culture was grown sustaining both planktonic and non-planktonic (e.g. biofilm) populations in co-culture as the concentration of antibiotic was raised, facilitating the development of more ecological complexity than is typically observed in laboratory evolution. This approach 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. Genetic and phenotypic comparisons between resistant isolates also identified convergent evolutionary trajectories, suggesting a common biochemical mechanism of resistance. Despite the relative ecological simplicity of this approach compared to the complexity of the human body, I show that experimental evolution can be used to rapidly identify clinically relevant adaptive molecular pathways and new targets for drug design in pathogens.en_US
dc.format.mimetypeapplication/pdfen_US
dc.identifier.citationMiller, Corwin. "Evolutionary Trajectories to Daptomycin Resistance in Enterococcus faecalis." (2013) Diss., Rice University. <a href="https://hdl.handle.net/1911/77228">https://hdl.handle.net/1911/77228</a>.en_US
dc.identifier.urihttps://hdl.handle.net/1911/77228en_US
dc.language.isoengen_US
dc.rightsCopyright is held by the author, unless otherwise indicated. Permission to reuse, publish, or reproduce the work beyond the bounds of fair use or other exemptions to copyright law must be obtained from the copyright holder.en_US
dc.subjectDaptomycinen_US
dc.subjectAntibiotic resistanceen_US
dc.subjectVREen_US
dc.subjectEnterococcien_US
dc.subjectEnterococcus faecalisen_US
dc.subjectExperimental evolutionen_US
dc.titleEvolutionary Trajectories to Daptomycin Resistance in Enterococcus faecalisen_US
dc.typeThesisen_US
dc.type.materialTexten_US
thesis.degree.departmentBiochemistry and Cell Biologyen_US
thesis.degree.disciplineNatural Sciencesen_US
thesis.degree.grantorRice Universityen_US
thesis.degree.levelDoctoralen_US
thesis.degree.nameDoctor of Philosophyen_US
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