Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics 1 . Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins 2 , potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome 3 . Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed 2 . Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus , exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. Modular synthesis and structural biology are used to design and characterize group A streptogramin antibiotics, one of which has activity against streptogramin-resistant strains and demonstrates efficacy in a mouse model of bacterial infection.

中文翻译：

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克服增值税抗性的合成 A 组链霉素抗生素

天然产物可作为临床使用的大多数抗生素的化学蓝图。这些分子产生的进化过程本质上伴随着抗性机制的共同进化，这些机制会缩短任何给定类别的抗生素 1 的临床寿命。维吉尼亚霉素乙酰转移酶 (Vat) 酶是抗性蛋白，可提供抗链菌素 2 的保护作用，这是一种针对革兰氏阳性菌的强效抗生素，可抑制细菌核糖体 3 。由于选择性地修饰 A 组链菌素的化学复杂的 23 元大环支架的挑战，克服 Vat 酶赋予的抗性的类似物以前尚未开发 2。在这里，我们报告设计，合成，和具有广泛结构变异性的 A 组链霉素抗生素的抗菌评价。使用低温电子显微镜和基于力场的细化，我们以高分辨率表征了八种类似物与细菌核糖体的结合，揭示了延伸到肽基 tRNA 结合位点和占据新生肽出口通道的协同粘合剂的结合相互作用。其中一种类似物对几种金黄色葡萄球菌抗链阳菌素菌株具有优异的活性，在体外表现出降低的乙酰化率，并且在降低感染小鼠模型中的细菌负荷方面有效。我们的研究结果表明，合理设计和模块化化学合成的结合可以振兴受自然产生的耐药机制限制的抗生素类别。