Metabolic Perturbations Caused by the Over-Expression of mcr-1 in Escherichia coli

Yi-Yun Liu, Yan Zhu, Hasini Wickremasinghe, Phillip J. Bergen, Jing Lu, Xiao Qing Zhu, Qiao Li Zhou, Mohammad Azad, Sue C. Nang, Mei-Ling Han, Tao Lei, Jian Li, Jian Hua Liu

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Abstract

Rapid dissemination of the plasmid-born polymyxin resistance gene mcr-1 poses a critical medical challenge. MCR-1 expression is tightly controlled and imposes a fitness cost on the bacteria. We used growth studies and metabolomics to examine growth and metabolic changes within E. coli TOP10 at 8 and 24 h in response to different levels of expression of mcr-1. Induction of mcr-1 greatly increased expression at 8 h and markedly reduced bacterial growth; membrane disruption and cell lysis were evident at this time. At 24 h, the expression of mcr-1 dramatically declined with restored growth and membrane integrity, indicating regulation of mcr-1 expression in bacteria to maintain membrane homeostasis. Intermediates of peptide and lipid biosynthesis were the most commonly affected metabolites when mcr-1 was overexpressed in E. coli. Cell wall biosynthesis was dramatically affected with the accumulation of lipids including fatty acids, glycerophospholipids and lysophosphatidylethanolamines, especially at 8 h. In contrast, levels of intermediate metabolites of peptides, amino sugars, carbohydrates and nucleotide metabolism and secondary metabolites significantly decreased. Moreover, the over-expression of mcr-1 resulted in a prolonged reduction in intermediates associated with pentose phosphate pathway and pantothenate and CoA biosynthesis. These findings indicate that over-expression of mcr-1 results in global metabolic perturbations that mainly involve disruption to the bacterial membrane, pentose phosphate pathway as well as pantothenate and CoA biosynthesis.

Original languageEnglish
Article number588658
Number of pages13
JournalFrontiers in Microbiology
Volume11
DOIs
Publication statusPublished - 9 Oct 2020

Keywords

  • colistin
  • fitness cost
  • glycerophospholipids
  • mcr-1
  • metabolomics
  • pantothenate and CoA biosynthesis
  • pentose phosphate pathway

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