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Defining ICR-Mo, an intrinsic colistin resistance determinant from Moraxella osloensis.
- Source :
-
PLoS genetics [PLoS Genet] 2018 May 14; Vol. 14 (5), pp. e1007389. Date of Electronic Publication: 2018 May 14 (Print Publication: 2018). - Publication Year :
- 2018
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Abstract
- 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.<br />Competing Interests: The authors have declared that no competing interests exist.
- Subjects :
- 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
Bacterial Proteins genetics
Colistin pharmacology
Drug Resistance, Bacterial genetics
Membrane Proteins genetics
Moraxella drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1553-7404
- Volume :
- 14
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- PLoS genetics
- Publication Type :
- Academic Journal
- Accession number :
- 29758020
- Full Text :
- https://doi.org/10.1371/journal.pgen.1007389