Synthesis and Evaluation of Pyridine-Based Antibacterial Agents that Inhibit ATP Synthase in <i>Acinetobacter baumannii</i>

Multidrug resistant <i>Acinetobacter baumannii</i> (MDR AB) is a growing global health threat due to rising infection rates and lack of treatment options. Specifically, like other Gram-negative pathogens, MDR AB employs a suite of robust cellular resistance mechanisms, including reduced penetration of the outer membrane, increased efflux, target modification, and others, that greatly impede antibiotic activity even for antibiotics of last resort like colistin and tigecycline. Bacterial bioenergetics are an under-explored antibiotic target and can be selectively exploited, as demonstrated by the success of the antitubercular drug bedaquiline, which inhibits ATP synthase in <i>Mycobacterium tuberculosis</i>. While work has been done to expand the success of bedaquiline to Gram-negative pathogens like AB through quinoline derivation, modifications to the quinoline core have been minimal. Herein, we report the synthesis and evaluation of a library of trisubstituted pyridines for their ability to inhibit AB ATP synthase and act as antibacterial agents against both susceptible and MDR AB clinical isolates. From this work, four lead compounds were developed that are highly potent and selective AB ATP synthase inhibitors and act as antibiotics against MDR AB. Additionally, each of the lead compounds were found to act synergistically with colistin against AB in bacterial culture, which demonstrates the further potential of this class to be developed into potent antibiotics.