Beyond ATP Synthase Inhibition: Chemical Diversification, Bioactivities, and Therapeutic Potential of Oligomycin A

Oligomycin A, initially identified as a macrolide antibiotic and a mitochondrial ATP synthase inhibitor, has recently transitioned from a laboratory tool to a multifaceted agent with promising therapeutic and industrial applications. Its irreversible inhibition of the F₀ subunit interrupts ATP synthesis and informs about metabolic susceptibilities in neoplastic cells, such as the Warburg effect and reversal of multidrug resistance by P-glycoprotein inhibition. Guided by structural studies of its interaction with the c10-ring of ATP synthase, analogs like bedaquiline were rationally designed as antibacterial candidates, and the analog spiropiperidine derivatives were inspired by improving ischemia–reperfusion injury. Although this derivative has great potential, clinical translation is limited by systemic toxicity, poor solubility, and environmental persistence. Emerging approaches like PEGylation and combination therapies (e.g., with docetaxel) have started to address selectivity and off-target effects. There are still challenges in balancing efficacy, safety, and environmental impact. This review summarizes the current knowledge and mechanisms of action of oligomycin A and its derivatives that should be of interest in the design of bioactive agents with potential therapeutic applications. This is intended to serve as a motivator for moving forward with future research avenues toward optimizing Oligomycin A-based therapeutics to derive as much of the potential benefit as possible while mitigating the harms associated.