Bacterial F1Fo-ATP synthase (F1Fo-ATPase)

Bacterial F1Fo-ATP synthase is a complex, membrane-bound enzyme that plays a central role in bacterial bioenergetics by synthesizing adenosine triphosphate (ATP). It operates as a rotary motor, utilizing the energy from a transmembrane proton or sodium gradient to drive the phosphorylation of ADP. The enzyme consists of two distinct sectors: the F0 domain, which is embedded in the plasma membrane and functions as an ion-conducting rotor, and the F1 domain, which extends into the cytoplasm and contains the catalytic sites. This target has gained significant clinical importance with the approval of bedaquiline, the first drug in its class to treat multi-drug-resistant tuberculosis by specifically inhibiting the mycobacterial ATP synthase. By binding to the c-subunit of the F0 rotor, bedaquiline prevents the mechanical rotation necessary for ATP production, leading to energy depletion and death of the pathogen. The high degree of structural divergence between bacterial and human mitochondrial ATP synthases allows for the development of highly selective inhibitors with minimal impact on host energy metabolism.

Other names

Bacterial ATP synthaseF-type ATPaseH+-transporting ATPaseProton-translocating ATPaseF1Fo complexATP phosphohydrolase

Bedaquiline and other diarylquinolines bind to the c-subunit of the F0 domain of the bacterial F1Fo-ATP synthase, inhibiting the rotation of the c-ring and blocking proton translocation, which prevents ATP synthesis and leads to energy depletion and bacterial cell death.