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

## TL;DR

This study shows that inhibiting PBP7/8 in Acinetobacter baumannii increases the effectiveness of beta-lactam antibiotics against drug-resistant strains.

## Contribution

The study identifies PBP7/8 as a novel adjuvant target to enhance beta-lactam activity against carbapenem-resistant A. baumannii.

## Key findings

- Inhibition of PBP7/8 led to a 59.7% decrease in KC50 values across beta-lactams.
- Bacterial killing was greater in the PBP7/8 knockout isolate compared to the wild-type.
- The model accurately predicted bacterial population changes in a hollow-fiber infection model.

## 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.