Synthesis and Evaluation of Pseudomonas aeruginosa ATP Synthase Inhibitors.

New antibiotics with unique biological targets are desperately needed to combat the growing number of resistant bacterial pathogens. ATP synthase, a critical protein found in all life, has recently become a target of interest for antibiotic development due to the success of the anti-tuberculosis drug bedaquiline, and while many groups have worked on developing drugs to target bacterial ATP synthase, few have been successful at inhibiting Pseudomonas aeruginosa (PA) ATP synthase specifically. PA is one of the leading causes of resistant nosocomial infections across the world and is extremely challenging to treat due to its various antibiotic resistance mechanisms for most commonly used antibiotics. Herein, we detail the synthesis and evaluation of a series of C1/C2 quinoline analogues for their ability to inhibit PA ATP synthase and act as antibiotics against wild-type PA. From this survey, we found six compounds capable of inhibiting PA ATP synthase in vitro showing that bulky/hydrophobic C1/C2 substitutions are preferred. The strongest inhibitor showed an IC50 of 10 µg/mL and decreased activity of PA ATP synthase to 24% relative to the control. While none of the compounds were able to inhibit wild-type PA in cell culture, two showed improved inhibition of PA growth when permeability of the outer membrane was increased or efflux was knocked out, thus demonstrating that these compounds could be further developed into efficacious antibiotics.

Advances in antibiotic drug discovery: reducing the barriers for antibiotic development.

Antibiotic drug discovery has been an essential field of research since the early 1900s, but the threat from infectious bacteria has only increased over the decades because of the emergence of widespread multidrug resistance. In this review, we discuss the recent advances in natural product, computational and medicinal chemistry that have reinvigorated the field of antibiotic drug discovery while giving perspective on how easily, both in cost and in expertise, these methods can be implemented by other researchers with the goal of increasing the number of scientists contributing to this public health crisis.