E. coli aminoglycoside treatment

Aminoglycosides are broad-spectrum antibiotics whose mechanism of action is under debate. It is widely accepted that membrane voltage potentiates aminoglycoside activity, which is ascribed to voltage-dependent drug uptake. In this paper, we measured the response of Escherichia coli treated with aminoglycosides and discovered that the bactericidal action arises not from the downstream effects of voltage dependent drug uptake, but rather directly from dysregulated membrane potential. In the absence of voltage, aminoglycosides are taken into cells and exert bacteriostatic effects by inhibiting translation. However, cell killing was immediate upon re-polarization. The hyperpolarization arose from altered ATP flux, which induced a reversal of the F1Fo-ATPase to hydrolyze ATP and generated the deleterious voltage. Heterologous expression of an ATPase inhibitor completely eliminated bactericidal activity, while loss of the F-ATPase reduced the electrophysiological response to aminoglycosides. ...

氨基糖苷类抗生素（Aminoglycosides）是一类广谱抗生素，其作用机制仍存在争议。学界普遍认为细胞膜电位可增强氨基糖苷类抗生素的抗菌活性，这一现象被归因于电压依赖性的药物摄取过程。本研究中，我们检测了经氨基糖苷类抗生素处理后的大肠杆菌（Escherichia coli）的响应，发现其杀菌作用并非源自电压依赖性药物摄取的下游效应，而是直接源于失调的细胞膜电位。当不存在电位时，氨基糖苷类抗生素可进入细胞，并通过抑制翻译过程发挥抑菌作用。但当细胞膜复极化后，细胞会立即被杀死。这种超极化现象源于改变的ATP通量，该通量诱导F1Fo-ATP合酶（F1Fo-ATPase）发生逆转以水解ATP，并由此产生了有害的膜电位。异源表达ATP合酶抑制剂可完全消除其杀菌活性，而F-ATP合酶的缺失则会减弱氨基糖苷类抗生素引发的电生理响应。……