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

Advanced Science - Tập 6 Số 11 - 2019
Huimin Zhang1,2, Zhiyong Zong3, Shenglei Che2, Swaminath Srinivas1, Jian Sun4, Yu Feng3, Man Huang2, Youjun Feng5,2,4
1Carl R. Woese Institute for Genomic Biology and Department of Biochemistry University of Illinois at Urbana-Champaign Urbana IL 61801 USA
2Department of Pathogen Biology & Microbiology and Department of General Intensive Care Unit of the Second Affiliated Hospital Zhejiang University School of Medicine Hangzhou Zhejiang 310058 China
3Center of Infectious Diseases, West China Hospital, Sichuan University, Chengdu 610041, China
4National Risk Assessment Laboratory for Antimicrobial Resistance of Animal Original Bacteria, South China Agricultural University, Guangzhou, 510642, China
5College of Animal Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China

Tóm tắt

AbstractA 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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Advanced Science

Tập 6 Số 11

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