Comprehensive proteomic and metabolomic profiling of mcr-1 mediated colistin resistance in Escherichia coli

Abstract The spread of mcr-1 in human and veterinary medicine has jeopardized the use of polymyxins, the last-resort antibiotics against life-threatening multidrug-resistant Gram-negative bacteria. As a lipid-modified gene, whether mcr-1 brings proteomic and metabolomic changes in the bacteria and affects the corresponding metabolic pathway is largely unknown. Herein, we used label-free quantitative proteomics and untargeted metabolomics to profile comprehensive proteome and metabolome characteristics of mcr-1 -mediated colistin-resistant and -sensitive Escherichia coli and further insight the resistant mechanism of colistin. We identified large sets of differential expression proteins and metabolites that contributed to mcr-1 -mediated antibiotic resistance predominantly in the different growth conditions with and without colistin. mcr-1 could cause the down-regulated expression of most proteins to adapt drug pressure. Pathway analysis showed that metabolic process was significantly affected, mainly related to glycerophospholipid metabolism, thiamine metabolism, and lipopolysaccharide biosynthesis. The substrate phosphatidylethanolamine for mcr-1 to mediate colistin resistance is accumulated in colistin-resistant E. coli . Notably, mcr-1 can not only cause the phosphoethanolamine modification of bacterial cell membrane lipid A, but also affect the biosynthesis and transport of lipoprotein in colistin resistance through disturbing the expression of efflux pump proteins involved in cationic antibacterial peptide resistance pathway. Overall, the disturbed glycerophospholipid metabolism, lipopolysaccharide biosynthesis and the accumulation of the substrate phosphatidylethanolamine is closely related with mcr-1 -mediated colistin resistance and these findings can further provide valuable information to inhibit colistin resistance by blocking this metabolic process.