Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY, 13210, USA.
Department of Biochemistry & Molecular Biology, SUNY Upstate Medical University, 750 E Adams St, Syracuse, NY, 13210, USA.
Biochem Biophys Res Commun. 2024 Nov 12;733:150705. doi: 10.1016/j.bbrc.2024.150705. Epub 2024 Sep 15.
The F-type ATP synthase/ATPase (FF) 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), can also induce time-dependent functional decoupling of F-ATPase from F 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 inhibitor, tributyltin, also can decouple FF-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 F but does not induce dissociation of the F-ATPase complex from membrane-embedded F. Understanding such decoupling mechanisms could support development of novel antibacterial compounds that target dysregulation of FF functions.
F 型 ATP 合酶/ATP 酶（FF）对真核生物和细菌的细胞生物能量学很重要。我们最近表明，venturicidins 是一类大环内酯类抗生素，可抑制质子转运复合物（F），还可以诱导来自大肠杆菌和铜绿假单胞菌的膜上 F-ATP 酶与 F 的时间依赖性功能解偶联。这种失调的 ATP 酶活性会耗尽细菌的 ATP 水平，并有助于 venturicidins 增强氨基糖苷类抗生素的杀菌作用。我们现在表明，一种不同类型的 F 抑制剂，三丁基锡，也可以使大肠杆菌膜的 FF-ATP 酶活性解偶联。与 venturicidins 的作用相反，三丁基锡的解偶联作用不依赖于 ATP，表明存在机制上的差异。三丁基锡破坏了 F 的 ε 亚基的偶联作用，但不会诱导 F-ATP 酶复合物从膜嵌入的 F 中解离。了解这种解偶联机制可以支持开发针对 FF 功能失调的新型抗菌化合物。
