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A small molecule inhibitor prevents gut bacterial genotoxin production
Nature Chemical Biology ( IF 12.9 ) Pub Date : 2022-10-17 , DOI: 10.1038/s41589-022-01147-8
Matthew R Volpe 1 , José A Velilla 2 , Martin Daniel-Ivad 1 , Jenny J Yao 1 , Alessia Stornetta 3 , Peter W Villalta 3, 4 , Hsin-Che Huang 5 , Daniel A Bachovchin 5 , Silvia Balbo 3, 6 , Rachelle Gaudet 2 , Emily P Balskus 1, 7
Affiliation  

The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin’s biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.



中文翻译:

一种小分子抑制剂可防止肠道细菌基因毒素的产生

人类肠道细菌基因毒素大肠菌素可能是结直肠癌 (CRC) 发展的关键驱动因素。由于拟议的活性物种的不稳定性和肠道微生物群的复杂性,理解大肠菌素的生物学效应仍然很困难。在这里,我们报告了大肠菌素生物合成的小分子硼酸抑制剂。这些化合物旨在模拟生物合成前体前大肠杆菌素,可有效抑制大肠杆菌素激活肽酶 ClbP。使用生化分析和晶体学,我们表明它们与 ClbP 结合口袋结合,与催化丝氨酸形成共价键。这些抑制剂重现了在clbP中观察到的表型缺失突变体并阻断大肠杆菌素对真核细胞的遗传毒性作用。ClbP 抑制剂的可用性将允许对大肠杆菌素的产生进行精确的时间控制,从而能够进一步研究其对 CRC 的贡献。最后,我们的抑制剂在相关肽酶编码途径中的应用突出了化学工具探测天然产物生物合成的能力。

更新日期:2022-10-17
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