Discovery of a Pseudomonas aeruginosa-specific small molecule targeting outer membrane protein OprH-LPS interaction by a multiplexed screen.

ABSTRACT: The surge of antimicrobial resistance threatens efficacy of current antibiotics, particularly against Pseudomonas aeruginosa, a highly resistant gram-negative pathogen. The asymmetric outer membrane (OM) of P. aeruginosa combined with its array of efflux pumps provide a barrier to xenobiotic accumulation, thus making antibiotic discovery challenging. We adapted PROSPECT, a target-based, whole-cell screening strategy, to discover small molecule probes that kill P. aeruginosa mutants depleted for essential proteins localized at the OM. We identified BRD1401, a small molecule that has specific activity against a P. aeruginosa mutant depleted for the essential lipoprotein, OprL. Genetic and chemical biological studies identified that BRD1401 acts by targeting the OM β-barrel protein OprH to di

SUBMITTER: Poulsen BE 

PROVIDER: S-EPMC12117999 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature