Identification of a novel MCR-1 variant displaying low level of co-resistance to β-lactam antibiotics that uncovers a potential novel antimicrobial peptide
Liang, L.; Zhong, L.-L.; Wang, L.; Zhou, D.; Li, Y.; Li, J.; Chen, Y.; Liang, W.; Wei, W.; Zhang, C.; Zhao, H.; Lyu, L.; Stoesser, N.; Doi, Y.; Paterson, D. L.; Feng, S.; Tian, G.-B.
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The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. It is accepted that MCR-1 affects bacterial fitness, and this fitness cost correlates with bacterial membrane lipid A perturbation. However, the detailed molecular mechanism remains unclear. Here, we screened out a novel MCR-1 variant, named M6, with a two-point mutation that rendered a low level of co-resistance to {beta}-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe lipid A perturbation resulting in peptidoglycan layer remodelling and thus resulted in phenotypic co-resistance to {beta}-lactams. Moreover, we found that a lipid A loading cavity is localized at the linker domain of MCR-1 and governs colistin resistance and bacterial membrane permeability, and the mutated pocket of M6 facilitates the binding affinity of lipid A. More importantly, synthetic peptides derived from M6 achieved broad-spectrum antimicrobial activity. These findings provide insights into a potential vulnerability that could be exploited in future antimicrobial drug design.
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