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Structure of the Acinetobacter baumannii PmrA receiver domain and insights into clinical mutants affecting DNA-binding and promoting colistin resistance

Palethorpe, S; Milton, ME; Pesci, EC; Cavanagh, J; (2021) Structure of the Acinetobacter baumannii PmrA receiver domain and insights into clinical mutants affecting DNA-binding and promoting colistin resistance. The Journal of Biochemistry 10.1093/jb/mvab102. (In press).

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Abstract

Acinetobacter baumannii is an insidious emerging nosocomial pathogen that has developed resistance to all available antimicrobials, including the last resort antibiotic, colistin. Colistin resistance often occurs due to mutations in the PmrAB two component regulatory system. To better understand the regulatory mechanisms contributing to colistin resistance, we have biochemically characterized the A. baumannii PmrA response regulator. Initial DNA-binding analysis shows that A. baumannii PmrA bound to the Klebsiella pneumoniae PmrA box motif. This prompted analysis of the putative A. baumannii PmrAB regulon which indicated that the A. baumannii PmrA consensus box is 5′- HTTAAD N5 HTTAAD. Additionally, we provide the first structural information for the A. baumannii PmrA N-terminal domain through X-ray crystallography, and we present a full-length model using molecular modeling. From these studies, we were able to infer the effects of two critical PmrA mutations, PmrA::I13M and PmrA::P102R, both of which confer increased colistin resistance. Based on these data, we suggest structural and dynamic reasons for how these mutations can affect PmrA function and hence encourage resistive traits. Understanding these mechanisms will aid in the development of new targeted antimicrobial therapies.

Type: Article
Title: Structure of the Acinetobacter baumannii PmrA receiver domain and insights into clinical mutants affecting DNA-binding and promoting colistin resistance
DOI: 10.1093/jb/mvab102
Publisher version: https://doi.org/10.1093/jb/mvab102
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Acinetobacter baumannii, colistin resistance, PmrA, response regulator, two-component system
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Respiratory Medicine
URI: https://discovery.ucl.ac.uk/id/eprint/10135658
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