ATP synthase of E. coli: F₁-ATPase activity is functionally decoupled from the proton-transporting complex (F_O) by...

The F-type ATP synthase/ATPase (F_OF₁) is important for cellular bioenergetics in eukaryotes and bacteria. We recently showed that venturicidins, a class of macrolides that inhibit the proton transporting complex (F_O), can also induce time-dependent functional decoupling of F₁-ATPase from F_O on membranes from Escherichia coli and Pseudomonas aeruginosa. This dysregulated ATPase activity could deplete bacterial ATP levels and contribute to venturicidin's capacity to enhance the bactericidal action of aminoglycosides antibiotics. We now show that a distinct type of F_O inhibitor, tributyltin, also can decouple F_OF₁-ATPase activity of E. coli membranes. In contrast to the action of venturicidins, decoupling by tributyltin is not dependent on ATP, indicating mechanistic differences. Tributyltin disrupts the coupling role of the ε subunit of F₁ but does not induce dissociation of the F₁-ATPase complex from membrane-embedded F_O. Understanding such decoupling mechanisms could support development of novel antibacterial compounds that target dysregulation of F_OF₁ functions.