Defining ICR-Mo, an intrinsic colistin resistance determinant from Moraxella osloensis.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101239074 Publication Model: eCollection Cited Medium: Internet ISSN: 1553-7404 (Electronic) Linking ISSN: 15537390 NLM ISO Abbreviation: PLoS Genet Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science, c2005-

Bacterial Proteins/*genetics ; Colistin/*pharmacology ; Drug Resistance, Bacterial/*genetics ; Membrane Proteins/*genetics ; Moraxella/*drug effects; Anti-Bacterial Agents/pharmacology ; Bacterial Proteins/classification ; Bacterial Proteins/metabolism ; Ethanolamines/metabolism ; Membrane Proteins/classification ; Membrane Proteins/metabolism ; Molecular Docking Simulation ; Moraxella/enzymology ; Moraxella/genetics ; Phosphatidylethanolamines/metabolism ; Phylogeny ; Protein Binding ; Substrate Specificity

Polymyxin is the last line of defense against severe infections caused by carbapenem-resistant gram-negative pathogens. The emergence of transferable MCR-1/2 polymyxin resistance greatly challenges the renewed interest in colistin (polymyxin E) for clinical treatments. Recent studies have suggested that Moraxella species are a putative reservoir for MCR-1/2 genetic determinants. Here, we report the functional definition of ICR-Mo from M. osloensis, a chromosomally encoded determinant of colistin resistance, in close relation to current MCR-1/2 family. ICR-Mo transmembrane protein was prepared and purified to homogeneity. Taken along with an in vitro enzymatic detection, MALDI-TOF mass spectrometry of bacterial lipid A pools determined that the ICR-Mo enzyme might exploit a possible "ping-pong" mechanism to accept the phosphoethanolamine (PEA) moiety from its donor phosphatidylethanolamine (PE) and then transfer it to the 1(or 4')-phosphate position of lipid A via an ICR-Mo-bound PEA adduct. Structural decoration of LPS-lipid A by ICR-Mo renders the recipient strain of E. coli resistant to polymyxin. Domain swapping assays indicate that the two domains of ICR-Mo cannot be functionally-exchanged with its counterparts in MCR-1/2 and EptA, validating its phylogenetic position in a distinct set of MCR-like genes. Structure-guided functional mapping of ICR-Mo reveals a PE lipid substrate recognizing cavity having a role in enzymatic catalysis and the resultant conference of antibiotic resistance. Expression of icr-Mo in E. coli significantly prevents the formation of reactive oxygen species (ROS) induced by colistin. Taken together, our results define a member of a group of intrinsic colistin resistance genes phylogenetically close to the MCR-1/2 family, highlighting the evolution of transferable colistin resistance.
Competing Interests: The authors have declared that no competing interests exist.

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0 (Anti-Bacterial Agents)
0 (Bacterial Proteins)
0 (Ethanolamines)
0 (Membrane Proteins)
0 (Phosphatidylethanolamines)
39382-08-6 (phosphatidylethanolamine)
78A2BX7AEU (phosphorylethanolamine)
Z67X93HJG1 (Colistin)

Date Created: 20180515 Date Completed: 20180626 Latest Revision: 20231105

20231215

PMC5983563

10.1371/journal.pgen.1007389

29758020