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dc.contributor.authorLee, Henry Hung-Yien_US
dc.date.accessioned2018-10-25T12:51:26Z
dc.date.issued2012
dc.date.submitted2012
dc.identifier.otherb38910391
dc.identifier.urihttps://hdl.handle.net/2144/31582
dc.descriptionThesis (Ph.D.)--Boston Universityen_US
dc.descriptionPLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.en_US
dc.description.abstractAntibiotic-resistant bacterial strains continually arise and their increasing prevalence poses significant clinical and societal challenges. Functional analyses of resistant mutants and the study of general stress responses perturbed by antibiotic treatment have yielded valuable insights into how resistance arises through mutations. However, less is known about the population dynamics and communal interactions that underlie the development of resistance through mutations. In this work, we utilize systems approaches to study the functional dynamics of bacterial populations evolving antibiotic resistance. We follow a continuous culture of Escherichia coli facing increasing levels of antibiotic and show that the vast majority of isolates are less resistant than the population as a whole. We find that the few highly resistant mutants improve the survival of the populations less resistant constituents, in part, by producing indole, a signaling molecule generated by actively growing and unstressed cells. We show, through transcriptional profiling, that indole serves to turn on drug efflux pumps and oxidative stress protective mechanisms. The indole production comes at a fitness cost to the highly resistant isolates, and wholegenome sequencing reveals that this bacterial altruism is enabled by drug-resistance mutations unrelated to indole production. This work establishes a population-based resistance mechanism constituting a form of kin selection whereby a small number of resistant mutants can, at some cost to themselves, provide protection to other more vulnerable cells, enhancing the survival capacity of the overall population in stressful environments. Deeper studies into cooperative strategies bacteria use to evade antibiotics may prove critical for the rational design of more effective antimicrobial interventions.en_US
dc.language.isoen_US
dc.publisherBoston Universityen_US
dc.subjectAntibioticsen_US
dc.subjectAntibiotic resistanceen_US
dc.titleA systems approach to the evolution of antibiotic resistanceen_US
dc.typeThesis/Dissertationen_US
dc.description.embargo2031-01-01
etd.degree.nameDoctor of Philosophyen_US
etd.degree.leveldoctoralen_US
etd.degree.disciplineBiomedical Engineeringen_US
etd.degree.grantorBoston Universityen_US
dc.identifier.barcode11719032086987
dc.identifier.mmsid99196003500001161


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