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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 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.

SUBMITTER: He S

PROVIDER: S-EPMC5142620 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature

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Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

He Susu S Chandler Michael M Varani Alessandro M AM Hickman Alison B AB Dekker John P JP Dyda Fred F

mBio 20161206 6

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 ...[more]

PMID: 27923922

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Project description:We examined 185 complete, publicly available FII-33 plasmid sequences, characterizing their backbone and various insertions. The variable characteristic insertions facilitated evolutionary reconstruction for this plasmid group, beginning with the acquisition of a primary resistance region (PRR) over 10 years ago. FII-33 plasmids have evolved by acquiring additional resistance genes in the PRR via translocatable elements and by forming cointegrates with plasmids of other types. In all cases, IS26 is suspected to have mediated cointegration. Plasmid cointegration has contributed to the accumulation of resistance genes and may have increased the transmissibility, stability, and host range of the original FII-33 lineage. A particularly important sublineage was formed by a replicative IS26 cointegration event that fused an FII-33 plasmid with a blaKPC-2-containing R-type plasmid, interrupting the FII-33 traI gene encoding the conjugative relaxase. The FII-33:R cointegrate arose in the Klebsiella pneumoniae ST11 clone and remains largely confined there due to the abolition of transfer ability by the FII-33:R cointegration event. However, in some cases FII-33:R cointegrates have fused with additional plasmids and acquired complete transfer regions or oriT sequences that might restore their ability to transfer horizontally. Cointegration events across FII-33 plasmid sublineages have involved plasmids of at least 15 different types. This suggests that plasmid cointegration occurs readily and is more common than previously appreciated, raising questions about the effects of cointegrate formation on plasmid host range, stability, and capacity for horizontal transfer. Resources are provided for detecting and characterizing FII-33 plasmid sublineages from complete or draft genome sequences. IMPORTANCE Effective genomic surveillance of antibiotic-resistant bacterial pathogens must consider plasmids, which are frequently implicated in the accumulation and transfer of resistance genes between bacterial strains or species. However, the evolution of plasmids is complex, and simple typing or comparison tools cannot accurately determine whether plasmids belong to the same sublineages. This precludes precise tracking of plasmid movement in bacterial populations. We have examined the FII-33 group, which has been associated with multidrug resistance and particularly carbapenem resistance in clinically significant members of the Enterobacterales in China. Our analysis has provided insight into the evolution of this important plasmid group, allowing us to develop resources for rapidly typing them to the sublineage level in complete or draft genome sequences. Our approach will improve detection and characterization of FII-33 plasmids and facilitate surveillance within and outside China. The approach can serve as a model for similar studies of other plasmid types.

Dataset Information

Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

Publications

Mechanisms of Evolution in High-Consequence Drug Resistance Plasmids.

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