Multi-drug-resistant bacteria present an urgent threat to modern medicine, creating a desperate need for antibiotics with new modes of action. As natural products remain an unsurpassed source for clinically viable antibiotic compounds, we investigate the mechanism of action of armeniaspirol. The armeniaspirols are a structurally unique class of Gram-positive antibiotic discovered from Streptomyces armeniacus for which resistance cannot be readily obtained. We show that armeniaspirol inhibits the ATP-dependent proteases ClpXP and ClpYQ in vitro and in the model Gram-positive Bacillus subtilis. This inhibition dysregulates the divisome and elongasome supported by an upregulation of key proteins FtsZ, DivIVA, and MreB inducing cell division arrest. The inhibition of ClpXP and ClpYQ to dysregulate cell division represents a unique antibiotic mechanism of action and armeniaspirol is the only known natural product inhibitor of the coveted anti-virulence target ClpP. Thus, armeniaspirol possesses a promising lead scaffold for antibiotic development with unique pharmacology.

多重耐药细菌对现代医学构成了紧迫的威胁，迫切需要具有新作用方式的抗生素。由于天然产物仍然是临床上可行的抗生素化合物的无与伦比的来源，我们研究了亚美尼亚螺的作用机制。亚美尼亚螺菌素是从亚美尼亚链霉菌中发现的一类结构独特的革兰氏阳性抗生素，其耐药性不易获得。我们表明，亚美尼亚螺在体外和革兰氏阳性枯草芽孢杆菌模型中抑制 ATP 依赖性蛋白酶 ClpXP 和 ClpYQ. 这种抑制失调了由关键蛋白 FtsZ、DivIVA 和 MreB 上调诱导细胞分裂停滞所支持的分裂体和细长体。ClpXP 和 ClpYQ 抑制细胞分裂失调代表了一种独特的抗生素作用机制，亚美尼亚螺环醇是唯一已知的令人垂涎的抗毒靶点 ClpP 的天然产物抑制剂。因此，亚美尼亚螺环醇具有用于抗生素开发的有前景的先导支架，具有独特的药理学。