Critical role of the RpoE stress response pathway in polymyxin resistance of Escherichia coli

文献类型： 外文期刊

第一作者： Zeng, Ximin

作者： Zeng, Ximin;Hinenoya, Atsushi;Xu, Fuzhou;Lin, Jun;Hinenoya, Atsushi;Hinenoya, Atsushi;Hinenoya, Atsushi;Guan, Ziqiang;Xu, Fuzhou

作者机构：

期刊名称：JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY （ 影响因子：5.2； 五年影响因子：5.4 ）

ISSN： 0305-7453

年卷期： 2023 年 78 卷 3 期

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收录情况： SCI

摘要： Objectives Polymyxins, including colistin, are the drugs of last resort to treat MDR bacterial infections in humans. In-depth understanding of the molecular basis and regulation of polymyxin resistance would provide new therapeutic opportunities to combat increasing polymyxin resistance. Here we aimed to identify novel targets that are crucial for polymyxin resistance using Escherichia coli BL21(DE3), a unique colistin-resistant model strain. Methods BL21(DE3) was subjected to random transposon mutagenesis for screening colistin-susceptible mutants. The insertion sites of desired mutants were mapped; the key genes of interest were also inactivated in different strains to examine functional conservation. Specific genes in the known PmrAB and PhoPQ regulatory network were inactivated to examine crosstalk among different pathways. Lipid A species and membrane phospholipids were analysed by normal phase LC/MS. Results Among eight mutants with increased susceptibility to colistin, five mutants contained different mutations in three genes (rseP, degS and surA) that belong to the RpoE stress response pathway. Inactivation of rpoE, pmrB, eptA or pmrD led to significantly increased susceptibility to colistin; however, inactivation of phoQ or eptB did not change colistin MIC. RpoE mutation in different E. coli and Salmonella resistant strains all led to significant reduction in colistin MIC (16-32-fold). Inactivation of rpoE did not change the lipid A profile but significantly altered the phospholipid profile. Conclusions Inactivation of the important members of the RpoE regulon in polymyxin-resistant strains led to a drastic reduction in polymyxin MIC and an increase of lysophospholipids with no change in lipid A modifications.

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