MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria. Issue 1 (31st December 2022)

• Record Type: Journal Article
• Authors: Feng, Siyuan; Liang, Wanfei; Li, Jiachen; Chen, Yong; Zhou, Dianrong; Liang, Lujie; Lin, Daixi; Li, Yaxin; Zhao, Hui; Du, Huihui; Dai, Min; Qin, Li-Na; Bai, Fan; Doi, Yohei; Zhong, Lan-Lan; Tian, Guo-bao
• Is Part Of: Emerging microbes & infections. Volume 11:Issue 1(2022)
• Page Start: 1236
• Page End: 1249
• Publication Date: 2022-12-31
• Subjects: MCR-1 -- outer membrane (OM) permeability -- viability -- lipid homeostasis -- colistin; Medical microbiology -- Periodicals; Communicable diseases -- Periodicals; Infection -- Periodicals; 616.9041
• DOI: 10.1080/22221751.2022.2065934
• Languages: English
• ISSNs: 2222-1751

Abstract

ABSTRACT: The global dissemination of the mobilized colistin resistance gene, mcr-1, threatens human health. Recent studies by our group and others have shown that the withdrawal of colistin as a feed additive dramatically reduced the prevalence of mcr-1 . Although it is accepted that the rapid reduction in mcr-1 prevalence may have resulted, to some extent, from the toxic effects of MCR-1, the detailed mechanism remains unclear. Here, we found that MCR-1 damaged the outer membrane (OM) permeability in Escherichia coli and Klebsiella pneumonia and that this event was associated with MCR-1-mediated cell shrinkage and death during the stationary phase. Notably, the capacity of MCR-1-expressing cells for recovery from the stationary phase under improved conditions was reduced in a time-dependent manner. We also showed that mutations in the potential lipid-A-binding pocket of MCR-1, but not in the catalytic domain, restored OM permeability and cell viability. During the stationary phase, PbgA, a sensor of periplasmic lipid-A and LpxC production that performed the first step in lipid-A synthesis, was reduced after MCR-1 expression, suggesting that MCR-1 disrupted lipid homeostasis. Consistent with this, the overexpression of LpxC completely reversed the MCR-1-induced OM permeability defect. We propose that MCR-1 causes lipid remodelling that results in an OM permeability defect, thus compromising the viability of Gram-negative bacteria. These findings extended our understanding of the effect of MCR-1 on bacterial physiology and provided a potential strategy for eliminating drug-resistant bacteria.