Penicillin Binding Protein 7/8 Is a Potential Drug Target in Carbapenem-Resistant Acinetobacter baumannii.

Autor: Russo TA; 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., Carlino-MacDonald U; 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., Alvarado CL; 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., Davies CJ; Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA., Barnes O; Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA., Trivedi G; Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA., Mathur P; Department of Medicine, University at Buffalo, State University of New York, Buffalo, New York, USA., Hutson A; Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA., Adams FG; Molecular Sciences and Technology, College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia., Zang M; Molecular Sciences and Technology, College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia., Ascari A; Molecular Sciences and Technology, College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia.; School of Biological Sciences, Department of Molecular and Biomedical Science, Research Centre for Infectious Diseases, University of Adelaide, Adelaide, South Australia, Australia., Eijkelkamp BA; Molecular Sciences and Technology, College of Science and Engineering, Flinders University, Bedford Park, South Australia, Australia.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2023 Jan 24; Vol. 67 (1), pp. e0103322. Date of Electronic Publication: 2022 Dec 07.
DOI: 10.1128/aac.01033-22
Abstrakt: Limited therapeutic options dictate the need for new classes of antimicrobials active against carbapenem-resistant Acinetobacter baumannii. Presented data confirm and extend penicillin binding protein 7/8 (PBP 7/8) as a high-value target in the CR A. baumannii strain HUMC1. PBP 7/8 was essential for optimal growth/survival of HUMC1 in ex vivo human ascites and in a rat subcutaneous abscess model; in a mouse pneumonia model, the absence of PBP 7/8 decreased lethality 11-fold. The loss of PBP 7/8 resulted in increased permeability, sensitivity to complement, and lysozyme-mediated bactericidal activity. These changes did not appear to be due to alterations in the cellular fatty acid composition or capsule production. However, a decrease in lipid A and an increase in coccoidal cells and cell aggregation were noted. The compromise of the stringent permeability barrier in the PBP 7/8 mutant was reflected by an increased susceptibility to several antimicrobials. Importantly, expression of ampC was not significantly affected by the loss of PBP 7/8 and serial passage of the mutant strain in human ascites over 7 days did not yield revertants possessing a wild-type phenotype. In summary, these data and other features support PBP 7/8 as a high-value drug target for extensively drug-resistant and CR A. baumannii. Our results guide next-stage studies; the determination that the inactivation of PBP 7/8 results in an increased sensitivity to lysozyme enables the design of a high-throughput screening assay to identify small molecule compounds that can specifically inhibit PBP 7/8 activity.
Databáze: MEDLINE