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

Thomas A. Russo, Ulrike Carlino-MacDonald, Cassandra L. Alvarado, Connor J. Davies, Oscar Barnes, Grishma Trivedi, Parijat Mathur, Alan Hutson, Felise G. Adams, Maoge Zang, Alice Ascari, Bart A. Eijkelkamp

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article numbere0103322
Number of pages18
JournalAntimicrobial agents and chemotherapy
Issue number1
Early online date7 Dec 2022
Publication statusPublished - Jan 2023


  • Acinetobacter baumannii
  • drug development
  • drug target
  • pencillin binding protein 7/8


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