Dissemination and Mechanism for the MCR-1 Colistin Resistance

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.

Genomic Insights into mcr-1 -Positive Plasmids Carried by Colistin-Resistant Escherichia coli Isolates from Inpatients

“…The pLS12 plasmid seems identical to the pE15004 plasmid isolated from a diarrhea inpatient's feces that we had analyzed earlier in 2016 ( Fig. 1B and 2B) (4,9). Sequence alignment suggested that the mcr-1-negative pSH146-32 plasmid might be an ancestor for the pLS12 and pmcr-1-IncX4 plasmids (Fig.…”

Antibiotic exposure elicits the emergence of colistin- and carbapenem-resistant Escherichia coli coharboring MCR-1 and NDM-5 in a patient

“…Unfortunately, it seems likely that the clinical use of carbapenems and colistin has been significantly challenged by the occurrence of mobilized colistin resistance determinant (MCR-1) in clinical carbapenem-resistant isolates producing New Delhi metallo- β -lactamase 1 (NDM-1) [6,7] or its variant NDM-5 [8,9]. In addition to the intrinsic determinants of colistin resistance (e.g., EptA [10,11] and ICR-Mo [12]), the transferable determinants (MCR-1 and MCR-2 [10,13,14]) consistently encode members of phosphoethanolamine (PEA)-lipid A transferases, which adopt a ‘ping-pong’ catalysis reaction in transferring of the PEA moiety to the 4ʹ-phosphate position of the lipopolysaccharide (LPS)-lipid A species anchored on bacterial surface [4,5]. …”

MCR-1.6, a New MCR Variant Carried by an IncP Plasmid in a Colistin-Resistant Salmonella enterica Serovar Typhimurium Isolate from a Healthy Individual

“…The MCR-1 enzyme modifies the chemical structure of lipid A moiety on bacterial lipopolysaccharide by the addition of phosphoethanolamine, which in turn reduces the binding affinity to colistin (i.e., producing the colistin resistance) (1,18,19). To date, only one functional variant of MCR-1, MCR-1.2, has been reported (17).…”