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

Publisher: Oxford University Press Country of Publication: England NLM ID: 0376600 Publication Model: Print Cited Medium: Internet ISSN: 1756-2651 (Electronic) Linking ISSN: 0021924X NLM ISO Abbreviation: J Biochem Subsets: MEDLINE

Publication: : Abingdon, UK : Oxford University Press
Original Publication: Tokyo : Japanese Biochemical Society

Colistin* ; Drug Resistance, Bacterial* ; Mutation*; Acinetobacter baumannii/*chemistry ; Bacterial Proteins/*chemistry ; DNA, Bacterial/*chemistry; Acinetobacter baumannii/genetics ; Acinetobacter baumannii/metabolism ; Amino Acid Motifs ; Bacterial Proteins/genetics ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; DNA, Bacterial/genetics ; DNA, Bacterial/metabolism ; Protein Domains

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 that 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 modelling. 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. Graphical Abstract.
(© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Erratum in: J Biochem. 2022 Mar 31;171(4):467. (PMID: 35137094)

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R01 AI136904 United States AI NIAID NIH HHS; R01 DE022350 United States DE NIDCR NIH HHS; R01 5R01AI136904-02, R01 AI136904 United States NH NIH HHS

Keywords: Acinetobacter baumannii; PmrA; colistin resistance; response regulator; two-component system

0 (Bacterial Proteins)
0 (DNA, Bacterial)
0 (pmrA protein, Bacteria)
Z67X93HJG1 (Colistin)

Date Created: 20210929 Date Completed: 20220207 Latest Revision: 20220929

20240628

PMC8753958

10.1093/jb/mvab102

34585233