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A Genomic, Evolutionary, and Mechanistic Study of MCR-5 Action Suggests Functional Unification across the MCR Family of Colistin Resistance.


ABSTRACT: A growing number of mobile colistin resistance (MCR) proteins is threatening the renewed interest of colistin as a "last-resort" defense against carbapenem-resistant pathogens. Here, the comparative genomics of a large plasmid harboring mcr-5 from Aeromonas hydrophila and the structural/functional perspectives of MCR-5 action are reported. Whole genome sequencing has identified the loss of certain parts of the Tn3-type transposon typically associated with mcr-5, providing a clue toward its mobilization. Phylogeny of MCR-5 suggests that it is distinct from the MCR-1/2 sub-lineage, but might share a common ancestor of MCR-3/4. Domain-swapping analysis of MCR-5 elucidates that its two structural motifs (transmembrane domain and catalytic domain) are incompatible with its counterparts in MCR-1/2. Like the rest of the MCR family, MCR-5 exhibits a series of conservative features, including zinc-dependent active sites, phosphatidylethanolamine-binding cavity, and the mechanism of enzymatic action. In vitro and in vivo evidence that MCR-5 catalyzes the addition of phosphoethanolamine to the suggestive 4'-phosphate of lipid A moieties is integrated, and results in the consequent polymyxin resistance. In addition, MCR-5 alleviates the colistin-induced formation of reactive oxygen species in E. coli. Taken together, the finding suggests that a growing body of MCR family resistance enzymes are functionally unified.

SUBMITTER: Zhang H 

PROVIDER: S-EPMC6548960 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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A Genomic, Evolutionary, and Mechanistic Study of MCR-5 Action Suggests Functional Unification across the MCR Family of Colistin Resistance.

Zhang Huimin H   Zong Zhiyong Z   Lei Sheng S   Srinivas Swaminath S   Sun Jian J   Feng Yu Y   Huang Man M   Feng Youjun Y  

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20190403 11


A growing number of mobile colistin resistance (MCR) proteins is threatening the renewed interest of colistin as a "last-resort" defense against carbapenem-resistant pathogens. Here, the comparative genomics of a large plasmid harboring <i>mcr-5</i> from <i>Aeromonas hydrophila</i> and the structural/functional perspectives of MCR-5 action are reported. Whole genome sequencing has identified the loss of certain parts of the Tn<i>3</i>-type transposon typically associated with <i>mcr-5</i>, provi  ...[more]

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