GaMF1.39's antibiotic efficacy and its enhanced antitubercular activity in combination with clofazimine, Telacebec, ND-011992, or TBAJ-876

The Mycobacterium tuberculosis (Mtb) F-ATP synthase generates most of the biological energy currency ATP. Previously, we identified the mycobacterium-specific loop of the F-ATP synthase subunit gamma as a new anti-tuberculosis target and discovered the novel diaminopyrimidine GaMF1, whose potency was improved by structure-activity relationship studies leading to the analog GaMF1.39. Here, we report that GaMF1.39 depletes cellular ATP formation by targeting the mycobacterial F-ATP synthase without affecting proton coupling or oxygen consumption. The antimycobacterial compound is bactericidal and potent against Mtb in macrophages without inducing phenotypic changes in biofilm formation, planktonic bacteria, or being toxic to zebrafish larvae. Combining GaMF1.39 with the NADH dehydrogenase inhibitor clofazimine, the cyt-bcc:aa3 inhibitor Telacebec, or the F-ATP synthase inhibitor TBAJ-876 showed enhanced whole ATP synthesis inhibition and anti-tuberculosis activity. These results suggest that GaMF1.39 may add value to a compound combination targeting oxidative phosphorylation for tuberculosis treatment.