Emerging antimicrobial resistance urges the discovery of antibiotics with unexplored, resistance-breaking mechanisms. Armeniaspirols represent a novel class of antibiotics with a unique spiro[4.4]non-8-ene scaffold and potent activities against Gram-positive pathogens. We report a concise total synthesis of (±) armeniaspirol A in six steps with a yield of 20.3% that includes the formation of the spirocycle through a copper-catalyzed radical cross-coupling reaction. In mechanistic biological experiments, armeniaspirol A exerted potent membrane depolarization, accounting for the pH-dependent antibiotic activity. Armeniaspirol A also disrupted the membrane potential and decreased oxygen consumption in mitochondria. In planar lipid bilayers and in unilamellar vesicles, armeniaspirol A transported protons across membranes in a protein-independent manner, demonstrating that armeniaspirol A acted as a protonophore. We provide evidence that this mechanism might account for the antibiotic activity of multiple chloropyrrole-containing natural products isolated from various origins that share a 4-acylphenol moiety coupled to chloropyrrole as a joint pharmacophore. We additionally describe an efflux-mediated mechanism of resistance against armeniaspirols.

中文翻译：

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抗生素亚美尼亚螺A的全合成及作用机制

新出现的抗菌素耐药性促使人们发现具有未探索的耐药机制的抗生素。Armeniaspiols 是一类新型抗生素，具有独特的螺[4.4]非-8-烯支架和对革兰氏阳性病原体的有效活性。我们报告了一个简明的 (±) 亚美尼亚螺环素 A 的全合成，分六个步骤，产率为 20.3%，其中包括通过铜催化的自由基交叉偶联反应形成螺环。在机械生物学实验中，亚美尼亚螺 A 发挥了强大的膜去极化作用，解释了 pH 依赖性抗生素活性。Armeniaspirol A 还破坏了膜电位并降低了线粒体中的耗氧量。在平面脂质双层和单层囊泡中，armeniaspirol A 以不依赖于蛋白质的方式跨膜转运质子，表明 armeniaspirol A 充当质子载体。我们提供的证据表明，这种机制可能解释了多种来源的含有氯吡咯的天然产物的抗生素活性，这些天然产物具有与氯吡咯偶联作为联合药效团的 4-酰基苯酚部分。我们还描述了一种外排介导的抗亚美尼亚螺药机制。