Structure of the Acinetobacter baumannii PmrA receiver domain and insights into clinical mutants affecting DNA binding and promoting colistin resistance.
Acinetobacter baumannii
PmrA
colistin resistance
response regulator
two-component system
Journal
Journal of biochemistry
ISSN: 1756-2651
Titre abrégé: J Biochem
Pays: England
ID NLM: 0376600
Informations de publication
Date de publication:
07 Jan 2022
07 Jan 2022
Historique:
received:
09
08
2021
accepted:
22
09
2021
pubmed:
30
9
2021
medline:
8
2
2022
entrez:
29
9
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34585233
pii: 6377494
doi: 10.1093/jb/mvab102
pmc: PMC8753958
doi:
Substances chimiques
Bacterial Proteins
0
DNA, Bacterial
0
pmrA protein, Bacteria
0
Colistin
Z67X93HJG1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
787-800Subventions
Organisme : NIAID NIH HHS
ID : R01 AI136904
Pays : United States
Organisme : NIDCR NIH HHS
ID : R01 DE022350
Pays : United States
Organisme : NIH HHS
ID : R01 5R01AI136904-02, R01 AI136904
Pays : United States
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.
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