Quinoline ATP Synthase Inhibitors with Activity Against Multidrug Resistant Acinetobacter baumannii and Pseudomonas aeruginosa

Abstract 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.