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

The F-type ATP synthase/ATPase (FOF1) is important for cellular bioenergetics in eukaryotes and bacteria. We recently showed that venturicidins, a class of macrolides that inhibit the proton transporting complex (FO), can also induce time-dependent functional decoupling of F1-ATPase from FO 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 FO inhibitor, tributyltin, also can decouple FOF1-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 FO. Understanding such decoupling mechanisms could support development of novel antibacterial compounds that target dysregulation of FOF1 functions.