Bacterial F₀F₁-adenosine triphosphate synthase (F₀F₁-ATPase) (F₀F₁-ATPase)

Bacterial F₀F₁-ATPase, also known as the F-type ATP synthase, is a multi-subunit enzyme complex located in the cytoplasmic membrane of bacteria [1]. It plays a fundamental role in energy metabolism by coupling the movement of protons across the membrane to the synthesis of adenosine triphosphate (ATP) from adenosine diphosphate (ADP) and inorganic phosphate [1, 2]. The enzyme consists of two main domains: the membrane-embedded F₀ sector, which facilitates proton translocation, and the peripheral F₁ sector, which contains the catalytic sites for ATP synthesis and hydrolysis [1]. In many bacteria, this enzyme is essential for survival, particularly under conditions where oxidative phosphorylation is the primary source of energy [2]. The bacterial F₀F₁-ATPase has emerged as a significant therapeutic target, most notably in the treatment of Mycobacterium tuberculosis [3, 4]. Drugs like bedaquiline selectively bind to the c-subunit of the bacterial F₀ sector, inhibiting the rotation of the enzyme and effectively shutting down ATP production [3, 4]. This mechanism is bactericidal against both active and dormant bacterial populations, making it a critical component of regimens for multidrug-resistant tuberculosis [4, 5]. While the enzyme is highly conserved across life, structural differences between bacterial and human mitochondrial ATP synthases allow for the development of selective inhibitors that minimize toxicity to the host [4, 6].

Other names

Bacterial ATP synthaseComplex VF-type ATPaseProton-translocating ATPaseF1F0-ATPaseF-type ATP synthase

Bedaquiline and related diarylquinolines bind to the c-subunit of the F₀ sector of the bacterial ATP synthase, physically blocking the rotation of the c-ring [3, 4]. This inhibition prevents the translocation of protons across the membrane and halts the mechanical energy required for the F₁ sector to synthesize ATP from ADP and inorganic phosphate [4, 7]. The resulting depletion of cellular ATP levels leads to the death of both replicating and non-replicating bacteria [3, 5].