MCR-1-dependent lipid remodelling compromises the viability of Gram-negative bacteria

Siyuan Feng, Wanfei Liang, Jiachen Li, Yong Chen, Dianrong Zhou, Lujie Liang, Daixi Lin, Yaxin Li, Hui Zhao, Huihui Du, Min Dai, Li Na Qin, Fan Bai, Yohei Doi, Lan Lan Zhong, Guo bao Tian

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1236-1249
Number of pages14
JournalEmerging Microbes and Infections
Volume11
Issue number1
DOIs
Publication statusPublished - 2022

All Science Journal Classification (ASJC) codes

  • Epidemiology
  • Parasitology
  • Microbiology
  • Immunology
  • Drug Discovery
  • Infectious Diseases
  • Virology

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