Regulating polymyxin resistance in Gram-negative bacteria: roles of two-component systems PhoPQ and PmrAB

Jiayuan Huang, Chen Li, Jiangning Song, Tony Velkov, Lushan Wang, Yan Zhu, Jian Li

Research output: Contribution to journalReview ArticleResearchpeer-review

50 Citations (Scopus)


Polymyxins (polymyxin B and colistin) are last-line antibiotics against multidrug-resistant Gram-negative pathogens. Polymyxin resistance is increasing worldwide, with resistance most commonly regulated by two-component systems such as PmrAB and PhoPQ. This review discusses the regulatory mechanisms of PhoPQ and PmrAB in mediating polymyxin resistance, from receiving an external stimulus through to activation of genes responsible for lipid A modifications. By analyzing the reported nonsynonymous substitutions in each two-component system, we identified the domains that are critical for polymyxin resistance. Notably, for PmrB 71% of resistance-conferring nonsynonymous mutations occurred in the HAMP (present in histidine kinases, adenylate cyclases, methyl accepting proteins and phosphatase) linker and DHp (dimerization and histidine phosphotransfer) domains. These results enhance our understanding of the regulatory mechanisms underpinning polymyxin resistance and may assist with the development of new strategies to minimize resistance emergence.

Original languageEnglish
Pages (from-to)445-459
Number of pages15
JournalFuture Microbiology
Issue number6
Publication statusPublished - 6 Apr 2020


  • Lipid A modification
  • PhoPQ
  • PmrAB
  • Polymyxin resistance
  • Two-component system

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