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Defining ICR-Mo, an intrinsic colistin resistance determinant from Moraxella osloensis.
- Source :
-
PLoS Genetics . 5/14/2018, Vol. 14 Issue 5, p1-30. 30p. - Publication Year :
- 2018
-
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 hosphothanolmine (PEA) moiety from its donor hosphatidylthanolamine (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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *POLYMYXIN
*CARBAPENEMS
*MORAXELLA
*COLISTIN
*REACTIVE oxygen species
Subjects
Details
- Language :
- English
- ISSN :
- 15537390
- Volume :
- 14
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 129596456
- Full Text :
- https://doi.org/10.1371/journal.pgen.1007389