Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

ABSTRACT The 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 plasmid...

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Autores principales:	Susu He, Michael Chandler, Alessandro M. Varani, Alison B. Hickman, John P. Dekker, Fred Dyda
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2016
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/e69e1674fffe4b32ab4aab6f6115424c
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spelling	oai:doaj.org-article:e69e1674fffe4b32ab4aab6f6115424c2021-11-15T15:50:16ZMechanisms of Evolution in High-Consequence Drug Resistance Plasmids10.1128/mBio.01987-162150-7511https://doaj.org/article/e69e1674fffe4b32ab4aab6f6115424c2016-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01987-16https://doaj.org/toc/2150-7511ABSTRACT The 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.Susu HeMichael ChandlerAlessandro M. VaraniAlison B. HickmanJohn P. DekkerFred DydaAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 7, Iss 6 (2016)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Susu He Michael Chandler Alessandro M. Varani Alison B. Hickman John P. Dekker Fred Dyda Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
description	ABSTRACT The 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.
format	article
author	Susu He Michael Chandler Alessandro M. Varani Alison B. Hickman John P. Dekker Fred Dyda
author_facet	Susu He Michael Chandler Alessandro M. Varani Alison B. Hickman John P. Dekker Fred Dyda
author_sort	Susu He
title	Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
title_short	Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
title_full	Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
title_fullStr	Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
title_full_unstemmed	Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids
title_sort	mechanisms of evolution in high-consequence drug resistance plasmids
publisher	American Society for Microbiology
publishDate	2016
url	https://doaj.org/article/e69e1674fffe4b32ab4aab6f6115424c
work_keys_str_mv	AT susuhe mechanismsofevolutioninhighconsequencedrugresistanceplasmids AT michaelchandler mechanismsofevolutioninhighconsequencedrugresistanceplasmids AT alessandromvarani mechanismsofevolutioninhighconsequencedrugresistanceplasmids AT alisonbhickman mechanismsofevolutioninhighconsequencedrugresistanceplasmids AT johnpdekker mechanismsofevolutioninhighconsequencedrugresistanceplasmids AT freddyda mechanismsofevolutioninhighconsequencedrugresistanceplasmids
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Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids

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