Dissemination and Mechanism for the MCR-1 Colistin Resistance.

Rongsui Gao,Jian Sun,Zhencui Li,Jingxia Lin,Huiyan Ye,Youjun Feng,Ya-Hong Liu,Guo-Bao Tian,Defeng Li,Baoli Zhu,Yongfei Hu,Fei Liu,Swaminath Srinivas,Qingjing Wang,Gongyi Zhang

doi:10.1371/journal.ppat.1005957

Abstract

Polymyxins are the last line of defense against lethal infections caused by multidrug resistant Gram-negative pathogens. Very recently, the use of polymyxins has been greatly challenged by the emergence of the plasmid-borne mobile colistin resistance gene (mcr-1). However, the mechanistic aspects of the MCR-1 colistin resistance are still poorly understood. Here we report the comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota, highlighting the diversity in plasmid transfer of the mcr-1 gene. Further genetic dissection delineated that both the trans-membrane region and a substrate-binding motif are required for the MCR-1-mediated colistin resistance. The soluble form of the membrane protein MCR-1 was successfully prepared and verified. Phylogenetic analyses revealed that MCR-1 is highly homologous to its counterpart PEA lipid A transferase in Paenibacili, a known producer of polymyxins. The fact that the plasmid-borne MCR-1 is placed in a subclade neighboring the chromosome-encoded colistin-resistant Neisseria LptA (EptA) potentially implies parallel evolutionary paths for the two genes. In conclusion, our finding provids a first glimpse of mechanism for the MCR-1-mediated colistin resistance.

Highlights

The polymyxins (polymyxin E and polymyxin B) are a family of cationic polypeptide antibiotics with a lipophilic fatty acyl side chain [1,2]
We report comparative genomics of two new mcr-1-harbouring plasmids isolated from the human gut microbiota
They belong to an old generation of antibiotics, polymyxins represent the last line of defense against lethal infections by gram-negative pathogens with pan-drug resistance [3]

Summary

Introduction

The polymyxins (polymyxin E (colistin) and polymyxin B) are a family of cationic polypeptide antibiotics with a lipophilic fatty acyl side chain [1,2]. This type of chemical modification on the bacterial lipid A can be attributed to either the chromosome-encoded machinery in K. pneumoniae [6] or the plasmid-transferred mobilized colistin resistance (MCR-1) gene in certain species of Enterobacteriaceae like E. coli [7] For the former, two sets of bacterial two-component systems (pmrAB [8] plus phoPQ [6]) and the regulator mgrB [6] are implicated, in which the lipid A of LPS is chemically modified and thereafter exhibits reduced affinity to polymyxin [7]. Most of the studies in this field focused on epidemiological investigations, which is in part due to the relatively limited availability of the genomic information

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