Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON K1N 6N5, Canada.
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Cell Chem Biol. 2021 Dec 16;28(12):1703-1715.e11. doi: 10.1016/j.chembiol.2021.07.001. Epub 2021 Jul 21.
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.
多药耐药菌对现代医学构成了紧迫威胁，因此迫切需要具有新作用模式的抗生素。由于天然产物仍然是具有临床可行性的抗生素化合物的无与伦比的来源，我们研究了 armeniaspirol 的作用机制。armeniaspirol 是一类结构独特的革兰氏阳性抗生素，从链霉菌属中发现，不易产生耐药性。我们表明，armeniaspirol 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。这种抑制作用通过上调关键蛋白 FtsZ、DivIVA 和 MreB 来扰乱由 Divisome 和 Elongasome 支持的细胞分裂，导致细胞分裂停滞。ClpXP 和 ClpYQ 的抑制作用扰乱细胞分裂代表了一种独特的抗生素作用机制，并且 armeniaspirol 是唯一已知的天然产物抑制剂，靶向抗毒力目标 ClpP。因此，armeniaspirol 具有独特的药理学，是一种有前途的抗生素开发先导骨架。
