期刊
ADVANCED SCIENCE
卷 6, 期 11, 页码 -出版社
WILEY
DOI: 10.1002/advs.201900034
关键词
Aeromonas hydrophila; colistin resistance; functional unification; lipid A; MCR-5; phosphatidylethanolamine (PE) cavity; ping-pong reaction mechanism; transferable resistance
资金
- National Natural Science Foundation of China [31830001, 31570027, 81772142, 81772233]
- National Key R&D Program of China [2017YFD0500202]
- National Young 1000 Talents Award of China
- Newton Advanced Fellowship, Royal Society, UK [NA150363]
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.
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