López-Argüello S; Montaner M; Sayed AR; Oliver A; Bulitta JB; Moya B

Abstract: The β-lactam antibiotics have been successfully used for decades to combat susceptible Pseudomonas aeruginosa, which has a notoriously difficult to penetrate outer membrane (OM). However, there is a dearth of data on target site penetration and covalent binding of penicillin-binding proteins (PBP) for β-lactams and β-lactamase inhibitors in intact bacteria. We aimed to determine the time course of PBP binding in intact and lysed cells and estimate the target site penetration and PBP access for 15 compounds in P. aeruginosa PAO1. All β-lactams (at 2 × MIC) considerably bound PBPs 1 to 4 in lysed bacteria. However, PBP binding in intact bacteria was substantially attenuated for slow but not for rapid penetrating β-lactams. Imipenem yielded 1.5 ± 0.11 log10 killing at 1h compared to <0>2023 doi: 10.1128/aac.01603-22 https://pubmed.ncbi.nlm.nih.gov/37199612