Mycobacterial F-ATP Synthase: From Structures to Target Sites to Inhibitors

Mycobacteria cause difficult-to-cure lung diseases. Tuberculosis (TB), which is caused by the pathogen Mycobacterium tuberculosis (Mtb), is one of the most important bacterial diseases in our days. The prevalence of lung disease caused by the cousins of Mtb, the non-tuberculous mycobacteria (NTM), is significantly arising. The diseases caused by the NTM Mycobacterium abscessus (Mab) is not reliably curable. New pan anti-mycobacterial drugs are needed to keep drug resistance at bay and enable more efficacious therapies. In the past decade, the oxidative phosphorylation pathway in which ATP is formed by the essential catalyst F₁F_O-ATP synthase has become an important drug target. Evolutionary modifications of structural, mechanistic, and regulatory elements within the enzyme complex equipped mycobacterial pathogens with tools to prevent wastage of ATP, maintain their membrane potential, and regulate ATP formation. Understanding these mycobacterial-specific elements within the mycobacterial F₁F_O-ATP synthase opened the door for new structure-based target findings and compound design. Here we describe such insights, targets, and inhibitors together with anti-TB and anti- Mab compounds derived from high-throughput and lead repurposing campaigns.