Substrate Recognition by a Colistin Resistance Enzyme from Moraxella catarrhalis

PeterJ. Stogios, Georgina Cox, Haley L. Zubyk, Elena Evdokimova, Zdzislaw Wawrzak, Gerard D. Wright, Alexei Savchenko

Index: 10.1021/acschembio.8b00116

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Abstract

Lipid A phosphoethanolamine (PEtN) transferases render bacteria resistant to the last resort antibiotic colistin. The recent discoveries of pathogenic bacteria harboring plasmid-borne PEtN transferase (mcr) genes have illustrated the serious potential for wide dissemination of these resistance elements. The origin of mcr-1 is traced to Moraxella species co-occupying environmental niches with Enterobacteriaceae. Here, we describe the crystal structure of the catalytic domain of the chromosomally encoded colistin resistance PEtN transferase, ICRMc (for intrinsic colistin resistance) of Moraxella catarrhalis. The ICRMc structure in complex with PEtN reveals key molecular details including specific residues involved in catalysis and PEtN binding. It also demonstrates that ICRMc catalytic domain dimerization is required for substrate binding. Our structure-guided phylogenetic analysis provides sequence signatures defining potentially colistin-active representatives in this enzyme family. Combined, these results advance the molecular and mechanistic understanding of PEtN transferases and illuminate their origins.