Substrate analog interaction with MCR-1 offers insight into the rising threat of the plasmid-mediated transferable colistin resistance

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Pengcheng WeiLei Yin

Abstract

Colistin is considered a last-resort antibiotic against most gram-negative bacteria. Recent discoveries of a plasmid-mediated, transferable mobilized colistin-resistance gene ( mcr-1) on all continents have heralded the imminent emergence of pan-drug-resistant superbacteria. The inner-membrane protein MCR-1 can catalyze the transfer of phosphoethanolamine (PEA) to lipid A, resulting in colistin resistance. However, little is known about the mechanism, and few drugs exist to address this issue. We present crystal structures revealing the MCR-1 catalytic domain (cMCR-1) as a monozinc metalloprotein with ethanolamine (ETA) and d-glucose, respectively, thus highlighting 2 possible substrate-binding pockets in the MCR-1-catalyzed PEA transfer reaction. Mutation of the residues involved in ETA and d-glucose binding impairs colistin resistance in recombinant Escherichia coli containing full-length MCR-1. Partial analogs of the substrate are used for cocrystallization with cMCR-1, providing valuable information about the family of PEA transferases. One of the analogs, ETA, causes clear inhibition of polymyxin B resistance, highlighting its potential for drug development. These data demonstrate the crucial role of the PEA- and lipid A-b...Continue Reading

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Citations

Feb 21, 2018·The Journal of Biological Chemistry·Yongchang XuYoujun Feng
Dec 22, 2019·Applied and Environmental Microbiology·Yan GuoJianfeng Wang
Jul 31, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xiu-Juan LanSong Li
Dec 25, 2019·International Microbiology : the Official Journal of the Spanish Society for Microbiology·Jindan Kai, Sheng Wang
Oct 22, 2020·Scientific Reports·Uma GabaleSusanne Ressl
May 20, 2021·Cell Reports·Yongchang XuYoujun Feng
Sep 4, 2021·Frontiers in Medicine·Firdoos Ahmad GogryQazi Mohd Rizwanul Haq

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