期刊
FUTURE MICROBIOLOGY
卷 15, 期 6, 页码 445-459出版社
FUTURE MEDICINE LTD
DOI: 10.2217/fmb-2019-0322
关键词
lipid A modification; PhoPQ; PmrAB; polymyxin resistance; two-component system
类别
资金
- National Institute of Allergy and Infectious Diseases of the NIH [R01 AI132154, AI132681]
- NHMRC CJ Martin Early Career Fellowship [1143366]
- National Health and Medical Research Council of Australia [1143366] Funding Source: NHMRC
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.
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