2025/03/10 by Katie T. Ward, Alexander P. L. Williams, A. Dennison +7 · 1 voice
Biochemistry, Genetics and Molecular Biology · Chemistry · #ATP Synthase and ATPases Research #Chemical Reaction Mechanisms #Organic Chemistry Cycloaddition Reactions
paper · pdf · doi:10.1002/cmdc.202400952
openalex publication_date 2025/03/10 · openalex created_date 2025/10/10 · openalex updated_date 2026/06/30
The Gram-negative, pathogenic bacteria Acinetobacter baumannii (AB) and Pseudomonas aeruginosa (PA) have been identified as a particular threat due to rising multidrug resistance, and antibiotics with novel mechanisms of action are needed. Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230 ng/mL in vitro, expands the quinoline structure-activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.