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.
Highlights
Prevalent antibiotic resistance is posing a threat to providing safe and effective health care worldwide
This work represents the first functional definition of ICR-Mo, a member of a family of MCR-1/2 like genes from Moraxella. This is the closest family of chromosomally encoded determinants of colistin resistance
Structure-guided functional studies reveal that ICR-Mo possesses a PE lipid substrate recognizing cavity having a role in enzymatic catalysis and the resulting bestowal of antibiotic resistance against colistin
Summary
Prevalent antibiotic resistance is posing a threat to providing safe and effective health care worldwide. Antimicrobial resistance (AMR) is associated with 700,000 deaths each year [1, 2]. It is estimated by O’Neill and his team that AMR would claim as many as 10,000,000 deaths per year globally by 2050 [3]. Despite this prediction being exaggerated and unreliable [4], we acknowledge that AMR has been posing an ever-growing burden on clinical therapies and public health, thereby highlighting the urgent need for a nationwide response to alleviate this burden [4, 5]. To the best of our knowledge, mcr-1-harboring Enterobacteriaceae have been detected in no less than 40 countries worldwide, spanning 5 of 7 continents [11], including the United States of America [12, 13]
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