Amine Basicity of Quinoline ATP Synthase Inhibitors Drives Antibacterial Activity against Pseudomonas aeruginosa

Pseudomonas aeruginosa (PA), a Gram-negative pathogen, is a common cause of nosocomial infections, especially in immunocompromised and cystic fibrosis patients. PA is intrinsically resistant to many currently prescribed antibiotics due to its tightly packed, anionic lipopolysaccharide outer membrane, efflux pumps, and ability to form biofilms. PA can acquire additional resistance through mutation and horizontal gene transfer. PA ATP synthase is an attractive target for antibiotic development because it is essential for cell survival even under fermentation conditions. Previously, we developed two lead quinoline compounds that were capable of selectively inhibiting PA ATP synthase and acting as antibacterial agents against multidrug-resistant PA. Herein we conduct a structure-activity relationship analysis of the lead compounds through the synthesis and evaluation of 18 quinoline derivatives. These compounds function as new antibacterial agents while providing insight into the balance of physical properties needed to promote cellular entry while maintaining PA ATP synthase inhibition.