The fitness landscape of the mobilized colistin resistance gene mcr-1

Abstract

The emergence and global discovery of the mobilized colistin resistance gene, mcr-1, limits the clinical effectiveness of colistin as last-resort antibiotic against multiple-drug resistant bacteria. Although MCR-1 exhibits low levels of colistin resistance in E. coli, it is currently unknown whether mcr-1 may potentially evolve a high level of colistin resistance in the future. Here, we generated mcr-1 mutant library that included 27,965 variants, covering 94.44% of the single-nucleotide mutations. We quantified the relative growth of these variant strains under colistin exposure. Notably, most mutations in the catalytic domain, but not in the transmembrane domain, reduce colistin resistance. The structural basis for the mutational effects revealed that the transmembrane domain may contribute to MCR-1 evolution. Altogether, our data shed light on the prediction of MCR-1 evolution, which could be useful for designing novel treatment strategies.

Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide

“…Given that recent evidence indicates that MCR-1 causes defect in the permeability of outer membranes [30,34], we wondered if certain MCR-1 variants inducing significant OM defect may exhibit a co-resistance phenotype to other classes of antibiotics. We tested this hypothesis using our previous mcr-1 mutant library, which included 171,769 mutation genotypes [35]. Among these genotypes, 4858/4860 (99.9%) possible single point mutations were represented.…”

A new variant of the colistin resistance gene MCR-1 with co-resistance to β-lactam antibiotics reveals a potential novel antimicrobial peptide

“…Given that MCR-1 disrupts OM integrity [31,32] facilitating entry of various antibiotics, we hypothesized that specific mutations in mcr-1 could abolish this phenotype. We tested this hypothesis using our previously established mcr-1 mutant library, which encompassed 171,769 mutation genotypes [33], covering 99.96% (4858/4860) possible single-nucleotide mutations of mcr-1. Screening was performed at antibiotic concentrations below and above the minimal inhibitory concentration (MIC, 0.8-2× MIC) to distinguish mutants with low-and high-level resistance (S1A Fig and S1 Table ).…”