posted on 2023-12-26, 16:37authored byKatie
T. Ward, Alexander P. L. Williams, Courtney A. Blair, Ananya M. Chatterjee, Abirami Karthikeyan, Addison S. Roper, Casey N. Kellogg, P. Ryan Steed, Amanda L. Wolfe
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.