ABSTRACT 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 γ 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. IMPORTANCE New drugs are needed to combat multidrug-resistant tuberculosis. The electron transport chain (ETC) maintains the electrochemical potential across the cytoplasmic membrane and allows the production of ATP, the energy currency of any living cell. The mycobacterial engine F-ATP synthase catalyzes the formation of ATP and has come into focus as an attractive and rich drug target. Recent deep insights into these mycobacterial F1FO-ATP synthase elements opened the door for a renaissance of structure-based target identification and inhibitor design. In this study, we present the GaMF1.39 antimycobacterial compound, targeting the rotary subunit γ of the biological engine. The compound is bactericidal, inhibits infection ex vivo, and displays enhanced anti-tuberculosis activity in combination with ETC inhibitors, which promises new strategies to shorten tuberculosis chemotherapy.
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