小柯机器人

美国洛克菲勒大学Elizabeth A. Campbell、威斯康辛大学麦迪逊分校Robert Landick等研究人员合作揭示非达霉素对艰难梭菌的窄谱活性基础。这一研究成果于2022年4月6日在线发表在国际学术期刊《自然》上。

研究人员表示，非达霉素（Fdx）被广泛用于治疗艰难梭菌（Cdiff）感染，但其在人类肠道微生物组中窄谱活性的分子基础仍然未知。Cdiff感染是造成医院内死亡的一个主要原因。抑制RNA聚合酶的Fdx以Cdiff为靶标，对肠道共生动物的影响最小，可减少Cdiff感染的复发。

研究人员展示了Cdiff RNA聚合酶与Fdx复合物的冷冻电镜结构，并确定了Cdiff RNA聚合酶的一个关键的Fdx结合决定因素，该因素在大多数肠道微生物群（如变形菌和拟杆菌）中都不存在。通过结合结构、生化、遗传和生物信息学分析，研究人员确定Cdiff RNA聚合酶中的一个残基是Fdx窄谱活性的敏感元素。这些结果为一个重要人类病原体的靶向药物设计提供了一个蓝图。

附：英文原文

Title: Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Author: Cao, Xinyun, Boyaci, Hande, Chen, James, Bao, Yu, Landick, Robert, Campbell, Elizabeth A.

Issue&Volume: 2022-04-06

Abstract: Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths1. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection2,3. Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen. Structural analysis of Clostridioides difficile RNA polymerase in complex with fidaxomicin combined with biochemical, genetic and bioinformatic analyses identifies a key residue that determines fidaxomicin sensitivity.

DOI: 10.1038/s41586-022-04545-z

Source: https://www.nature.com/articles/s41586-022-04545-z

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