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

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

JOURNAL=Frontiers in Microbiology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2020.588658

DOI=10.3389/fmicb.2020.588658

ISSN=1664-302X

ABSTRACT=<p>Rapid dissemination of the plasmid-born polymyxin resistance gene <italic>mcr-1</italic> 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 <italic>E. coli</italic> TOP10 at 8 and 24 h in response to different levels of expression of <italic>mcr-1</italic>. Induction of <italic>mcr-1</italic> 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 <italic>mcr-1</italic> dramatically declined with restored growth and membrane integrity, indicating regulation of <italic>mcr-1</italic> expression in bacteria to maintain membrane homeostasis. Intermediates of peptide and lipid biosynthesis were the most commonly affected metabolites when <italic>mcr-1</italic> was overexpressed in <italic>E. coli</italic>. 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 <italic>mcr-1</italic> resulted in a prolonged reduction in intermediates associated with pentose phosphate pathway and pantothenate and CoA biosynthesis. These findings indicate that over-expression of <italic>mcr-1</italic> results in global metabolic perturbations that mainly involve disruption to the bacterial membrane, pentose phosphate pathway as well as pantothenate and CoA biosynthesis.</p>