Millions of people per year suffer from antibiotic resistance bacterial infections and of those tens of thousands lose their lives. This is due to the fact that strains of pathogenic bacteria are becoming resistant to currently prescribed antibiotics at a rate faster than new antibiotics with novel mechanisms of action have been developed over the past 50 years. One promising new target for antibiotic development is ATP synthase. The first FDA approved ATP synthase inhibiting antibiotic was Bedaquiline (BDQ), which was approved to treat multidrug resistant Mycobacterium tuberculosis in 2013. BDQ inhibits ATP synthase by binding to the c subunit of the Fo domain and stopping proton pumping, which results in cell death. Interactions between BDQ and the Asp32 and Glu65 residues of M. tuberculosis are crucial for inhibition. This work builds off of the success of BDQ and evaluates ATP synthase as a potential target for antibiotic development against Pseudomonas aeruginosa, a highly infectious Gram-negative pathogen. To this end, a series of amino acid substituted diarylquinoline analogs were designed and synthesized based off of computational docking models with P. aeruginosa ATP synthase. These analogs selectively target the corresponding, but less polar, residues within the BDQ binding site of ATP synthase in P. aeruginosa. Each analog was evaluated for the ability to inhibit P. aeruginosa growth in liquid culture and ATP synthesis in vitro.

Synthesis of diarylquinoline compounds for use as selective Pseudomonas aeruginosa ATP synthase inhibitors

ACS Spring 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.