The Response Regulator BfmR Is a Potential Drug Target for Acinetobacter baumannii
- Veterans Administration Western New York Healthcare System, Buffalo, New York, USA, Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA, Department of Microbiology and Immunology, University at Buffalo, State University of New York, Buffalo, New York, USA, The Witebsky Center for Microbial Pathogenesis, University at Buffalo, State University of New York, Buffalo, New York, USA
- Veterans Administration Western New York Healthcare System, Buffalo, New York, USA, Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA
- Hauptman Woodward Medical Research Institute, Buffalo, New York, USA
- Department of Structural Biology, University at Buffalo, State University of New York, Buffalo, New York, USA, Hauptman Woodward Medical Research Institute, Buffalo, New York, USA
Identification and validation is the first phase of target-based antimicrobial development. BfmR (RstA), a response regulator in a two-component signal transduction system (TCS) in Acinetobacter baumannii, is an intriguing potential antimicrobial target. A unique characteristic of BfmR is that its inhibition would have the dual benefit of significantly decreasing in vivo survival and increasing sensitivity to selected antimicrobials. Studies on the clinically relevant strain AB307-0294 have shown BfmR to be essential in vivo. Here, we demonstrate that this phenotype in strains AB307-0294 and AB908 is mediated, in part, by enabling growth in human ascites fluid and serum. Further, BfmR conferred resistance to complement-mediated bactericidal activity that was independent of capsular polysaccharide. Importantly, BfmR also increased resistance to the clinically important antimicrobials meropenem and colistin. BfmR was highly conserved among A. baumannii strains. The crystal structure of the receiver domain of BfmR was determined, lending insight into putative ligand binding sites. This enabled an in silico ligand binding analysis and a blind docking strategy to assess use as a potential druggable target. Predicted binding hot spots exist at the homodimer interface and the phosphorylation site. These data support pursuing the next step in the development process, which includes determining the degree of inhibition needed to impact growth/survival and the development a BfmR activity assay amenable to high-throughput screening for the identification of inhibitors. Such agents would represent a new class of antimicrobials active against A. baumannii which could be active against other Gram-negative bacilli that possess a TCS with shared homology.
- Research Organization:
- SLAC National Accelerator Laboratory (SLAC), Menlo Park, CA (United States). Stanford Synchrotron Radiation Lightsource (SSRL)
- Sponsoring Organization:
- USDOE Office of Science (SC), Basic Energy Sciences (BES); USDOE Office of Science (SC), Biological and Environmental Research (BER)
- Grant/Contract Number:
- AC02-76SF00515
- OSTI ID:
- 1618369
- Alternate ID(s):
- OSTI ID: 1626154
- Journal Information:
- mSphere, Journal Name: mSphere Vol. 1 Journal Issue: 3; ISSN 2379-5042
- Publisher:
- American Society for MicrobiologyCopyright Statement
- Country of Publication:
- United States
- Language:
- English
Web of Science
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