Macrolides have been effective clinical antibiotics for over 70 years. They inhibit protein biosynthesis in bacterial pathogens by narrowing the nascent protein exit tunnel in the ribosome. The macrolide class of natural products consist of a macrolactone ring linked to one or more sugar molecules. Most of the macrolides used currently are semi-synthetic erythromycin derivatives, composed of a 14- or 15-membered macrolactone ring. Rapidly emerging resistance in bacterial pathogens is among the most urgent global health challenges, which render many antibiotics ineffective, including next-generation macrolides. To address this threat and advance a longer-term plan for developing new antibiotics, we demonstrate how 16-membered macrolides overcome erythromycin resistance in clinically isolated Staphylococcus aureus strains. By determining the structures of complexes of the large ribosomal subunit of Deinococcus radiodurans (D50S) with these 16-membered selected macrolides, and performing anti-microbial studies, we identified resistance mechanisms they may overcome. This new information provides important insights toward the rational design of therapeutics that are effective against drug resistant human pathogens.

中文翻译：

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来自灰红小单孢菌的霉素、16 元大环内酯类抗生素的核糖体结合和抗微生物研究

70 多年来，大环内酯类药物一直是有效的临床抗生素。它们通过缩小核糖体中新生蛋白质的出口通道来抑制细菌病原体中的蛋白质生物合成。大环内酯类天然产物由与一个或多个糖分子连接的大环内酯环组成。目前使用的大环内酯类药物大多是半合成的红霉素衍生物，由14或15元大环内酯环组成。细菌病原体迅速出现的耐药性是全球最紧迫的健康挑战之一，这使得许多抗生素失效，包括下一代大环内酯类药物。为了应对这一威胁并推进开发新抗生素的长期计划，我们展示了 16 元大环内酯类药物如何克服临床分离的金黄色葡萄球菌菌株对红霉素的耐药性。通过确定耐辐射奇球菌 (D50S) 的大核糖体亚基与这些 16 元选定大环内酯类的复合物的结构，并进行抗微生物研究，我们确定了它们可以克服的耐药机制。这一新信息为合理设计有效对抗耐药人类病原体的疗法提供了重要见解。