Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

dc.contributor.authorHe, Susu
dc.contributor.authorChandler, Michael
dc.contributor.authorVarani, Alessandro M. [UNESP]
dc.contributor.authorHickman, Alison B.
dc.contributor.authorDekker, John P.
dc.contributor.authorDyda, Fred
dc.contributor.institutionUniversidade Estadual Paulista (Unesp)
dc.description.abstractThe dissemination of resistance among bacteria has been facilitated by the fact that resistance genes are usually located on a diverse and evolving set of transmissible plasmids. However, the mechanisms generating diversity and enabling adaptation within highly successful resistance plasmids have remained obscure, despite their profound clinical significance. To understand these mechanisms, we have performed a detailed analysis of the mobilome (the entire mobile genetic element content) of a set of previously sequenced carbapenemase-producing Enterobacteriaceae (CPE) from the National Institutes of Health Clinical Center. This analysis revealed that plasmid reorganizations occurring in the natural context of colonization of human hosts were overwhelmingly driven by genetic rearrangements carried out by replicative transposons working in concert with the process of homologous recombination. A more complete understanding of the molecular mechanisms and evolutionary forces driving rearrangements in resistance plasmids may lead to fundamentally new strategies to address the problem of antibiotic resistance. IMPORTANCE The spread of antibiotic resistance among Gram-negative bacteria is a serious public health threat, as it can critically limit the types of drugs that can be used to treat infected patients. In particular, carbapenem-resistant members of the Enterobacteriaceae family are responsible for a significant and growing burden of morbidity and mortality. Here, we report on the mechanisms underlying the evolution of several plasmids carried by previously sequenced clinical Enterobacteriaceae isolates from the National Institutes of Health Clinical Center (NIH CC). Our ability to track genetic rearrangements that occurred within resistance plasmids was dependent on accurate annotation of the mobile genetic elements within the plasmids, which was greatly aided by access to long-read DNA sequencing data and knowledge of their mechanisms. Mobile genetic elements such as transposons and integrons have been strongly associated with the rapid spread of genes responsible for antibiotic resistance. Understanding the consequences of their actions allowed us to establish unambiguous evolutionary relationships between plasmids in the analysis set.en
dc.description.affiliationNIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA
dc.description.affiliationCNRS, Lab Microbiol & Genet Mol, Toulouse, France
dc.description.affiliationUniv Estadual Paulista, Dept Tecnol, Fac Ciencias Agr & Vet Jaboticabal, Sao Paulo, Brazil
dc.description.affiliationNIH, Dept Lab Med, Ctr Clin, Microbiol Serv, Bldg 10, Bethesda, MD 20892 USA
dc.description.affiliationUnespUniv Estadual Paulista, Dept Tecnol, Fac Ciencias Agr & Vet Jaboticabal, Sao Paulo, Brazil
dc.description.sponsorshipHHS | National Institutes of Health (NIH)
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
dc.description.sponsorshipHHS | NIH | NIH Clinical Center
dc.description.sponsorshipIntramural Program of the National Institute of Diabetes and Digestive and Kidney Diseases
dc.description.sponsorshipNIH Clinical Center
dc.identifier.citationMbio. Washington: Amer Soc Microbiology, v. 7, n. 6, 11 p., 2016.
dc.publisherAmer Soc Microbiology
dc.rights.accessRightsAcesso aberto
dc.sourceWeb of Science
dc.titleMechanisms of Evolution in High-Consequence Drug Resistance Plasmidsen
dcterms.rightsHolderAmer Soc Microbiology[3][3]


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