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

The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identifie...

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Veröffentlicht in:PLoS biology 2023-12, Vol.21 (12), p.e3002433-e3002433
Hauptverfasser: Liang, Lujie, Zhong, Lan-Lan, Wang, Lin, Zhou, Dianrong, Li, Yaxin, Li, Jiachen, Chen, Yong, Liang, Wanfei, Wei, Wenjing, Zhang, Chenchen, Zhao, Hui, Lyu, Lingxuan, Stoesser, Nicole, Doi, Yohei, Bai, Fang, Feng, Siyuan, Tian, Guo-Bao
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Sprache:eng
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Zusammenfassung:The emerging and global spread of a novel plasmid-mediated colistin resistance gene, mcr-1, threatens human health. Expression of the MCR-1 protein affects bacterial fitness and this cost correlates with lipid A perturbation. However, the exact molecular mechanism remains unclear. Here, we identified the MCR-1 M6 variant carrying two-point mutations that conferred co-resistance to β-lactam antibiotics. Compared to wild-type (WT) MCR-1, this variant caused severe disturbance in lipid A, resulting in up-regulation of L, D-transpeptidases (LDTs) pathway, which explains co-resistance to β-lactams. Moreover, we show that a lipid A loading pocket is localized at the linker domain of MCR-1 where these 2 mutations are located. This pocket governs colistin resistance and bacterial membrane permeability, and the mutated pocket in M6 enhances the binding affinity towards lipid A. Based on this new information, we also designed synthetic peptides derived from M6 that exhibit broad-spectrum antimicrobial activity, exposing a potential vulnerability that could be exploited for future antimicrobial drug design.
ISSN:1545-7885
1544-9173
1545-7885
DOI:10.1371/journal.pbio.3002433