Despite the remarkable advances due to the discovery and development of antimicrobials agents, infectious diseases remain the second leading cause of death worldwide. This fact underlines the importance of developing new therapeutic strategies to address the widespread antibiotic resistance, which is the major contributing factor for clinical failures of the current therapeutics. In a screen for antibiotic adjuvants, we identified a natural product from actinomycetes, venturicidin A (VentA), that potentiates the aminoglycoside antibiotic gentamicin against multidrug-resistant clinical isolates of Staphylococcus, Enterococcus, and Pseudomonas aeruginosa. Furthermore, the combination of gentamicin and VentA was bactericidal and rapidly eradicated methicillin-resistant S. aureus (MRSA). The molecular mechanism of gentamicin potentiation activity is attributed to uncoupling of ATP synthesis by VentA from electron transport presumably by blocking the proton flow through ATP synthase, which results in an elevated concentration of extracellular protons and subsequent anticipated raise in gentamicin uptake. The disruption of the proton flux was characterized by perturbed membrane potential in MRSA. These results demonstrate that inhibition of ATP synthase along with the subsequent membrane dysregulation, as shown here with VentA, complements aminoglycoside antibiotics against MDR bacteria, and that this approach may be employed to combat bacterial resistance.

中文翻译：

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Venturicidin A是ATP合酶的膜活性天然产物抑制剂，可增强氨基糖苷类抗生素。

尽管由于发现和开发了抗菌剂而取得了令人瞩目的进步，但传染病仍然是全世界第二大死亡原因。这一事实强调了开发新的治疗策略以应对广泛的抗生素耐药性的重要性，这是造成当前治疗方法临床失败的主要因素。在筛选抗生素佐剂时，我们从放线菌，文丘里汀A（VentA）中鉴定出一种天然产物，该产物可增强氨基糖苷类抗生素庆大霉素对金黄色葡萄球菌，肠球菌和铜绿假单胞菌的多药耐药临床分离株的耐受性。此外，庆大霉素和VentA的结合具有杀菌作用，并能迅速根除耐甲氧西林的金黄色葡萄球菌（MRSA）。庆大霉素增强活性的分子机制归因于VentA与电子传递的ATP合成解偶联，大概是通过阻止质子流过ATP合酶，从而导致细胞外质子浓度升高，以及随后预期的庆大霉素吸收增加。质子通量的破坏以MRSA中膜电位的扰动为特征。这些结果表明，如此处用VentA所示，对ATP合酶的抑制以及随后的膜失调可补充抗MDR细菌的氨基糖苷类抗生素，并且该方法可用于抵抗细菌耐药性。导致细胞外质子浓度升高，随后庆大霉素的摄取预计会增加。质子通量的破坏以MRSA中膜电位的扰动为特征。这些结果表明，如此处用VentA所示，对ATP合酶的抑制以及随后的膜失调可补充抗MDR细菌的氨基糖苷类抗生素，并且该方法可用于抵抗细菌耐药性。导致细胞外质子浓度升高，随后庆大霉素的摄取预计会增加。质子通量的破坏以MRSA中膜电位的扰动为特征。这些结果表明，如此处用VentA所示，对ATP合酶的抑制以及随后的膜失调可补充针对MDR细菌的氨基糖苷类抗生素，并且该方法可用于对抗细菌耐药性。