Pharmacodynamic Evaluation of Adjuvant Targets: Low Molecular Weight PBP7/8 Effects on β-Lactam Activity Against Carbapenem-Resistant Acinetobacter Baumannii

Brian M Ho; Jingxiu Jin; Jacob T Sanborn; Thomas D Nguyen; Navaldeep Singh; Christina Cheng; Nader N Nasief; Ulrike Carlino-MacDonald; Brian T Tsuji; Yanan Zhao; Liang Chen; Bartolome Moya; Thomas A Russo; Nicholas M Smith

doi:10.3390/ph18060918

Pharmacodynamic Evaluation of Adjuvant Targets: Low Molecular Weight PBP7/8 Effects on β-Lactam Activity Against Carbapenem-Resistant Acinetobacter Baumannii

Pharmaceuticals (Basel). 2025 Jun 18;18(6):918. doi: 10.3390/ph18060918.

Authors

Brian M Ho¹, Jingxiu Jin¹, Jacob T Sanborn¹, Thomas D Nguyen¹, Navaldeep Singh¹, Christina Cheng¹, Nader N Nasief¹, Ulrike Carlino-MacDonald^{2

3}, Brian T Tsuji¹, Yanan Zhao¹, Liang Chen¹, Bartolome Moya^{4

5}, Thomas A Russo^{2

3

6}, Nicholas M Smith¹

Affiliations

¹ Department of Pharmacy Practice, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA.
² Department of Medicine, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA.
³ Veterans Administration Western New York Healthcare System, Buffalo, NY 14215, USA.
⁴ Servicio de Microbiología and Unidad de Investigación, Hospital Universitario Son Espases, Instituto de Investigación Sanitaria Illes Balears (IdISBa), 07120 Palma, Balearic Islands, Spain.
⁵ Centro de Investigación Biomédica en Red en Enfermedades Infecciosas (CIBERINFEC), 07120 Palma, Balearic Islands, Spain.
⁶ The Witebsky Center for Microbial Pathogenesis, University at Buffalo, The State University of New York, Buffalo, NY 14203, USA.

Abstract

Background/Objectives: The increasing occurrence of carbapenem resistance A. baumannii (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7/8 has been shown to result in an increased outer membrane permeability and could serve as a potential new adjuvant target. Methods: Two isogenic clinical isolates of A. baumannii HUMC1 were utilized (WT and HUMC1 ΔPBP7/8). Static concentration time-kill assays were performed against both isolates with escalating exposures to antibiotics. The resulting data were modeled using the Monolix software suite to capture parameters related to bacterial killing and PBP7/8 synergism. The model results were used to prospectively simulate clinically relevant antibiotic dosing of three antibiotics under physiological conditions and were validated using a hollow-fiber infection model (HFIM). Results: Treatment with monotherapy or combination therapy resulted in concentration-dependent killing for both isolates. Bacterial killing was greater with HUMC1 ΔPBP7/8 for all tested antibiotic concentrations. The mean bacterial population reduction was 4.38 log₁₀ CFU/mL for HUMC1 and 5.38 log₁₀ CFU/mL for HUMC1ΔPBP7/8 knockout isolate. The final mechanism-based model demonstrated improved antibacterial activity with PBP7/8 inhibition through a decline in KC₅₀ values of 59.7% across the beta-lactams in the PBP7/8 knockout. HFIM observations that were retrospectively compared to the simulated model-predicted bacterial concentration time course showed our final model was able to appropriately capture changes in bacterial population within a dynamic HFIM scenario. Conclusions: The quantification of KC₅₀ decline and increase in effectiveness of previously sidelined antimicrobial therapies with PBP7/8 inhibition suggests PBP7/8 is a promising potential target for an antibacterial adjuvant. This lends further support to advance to next-stage studies for identifying compounds that specifically inhibit PBP7/8 activity.

Keywords: acinetobacter baumannii; antibiotic resistance; low molecular weight penicillin binding proteins.

Abstract

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