荷兰莱顿大学van der Stelt, Mario团队报道了异喹啉磺胺类药物作为对氟喹诺酮耐药菌具有活性的变构回转酶抑制剂的发现。相关研究成果于2024年6月19日发表于国际顶尖学术期刊《自然—化学》。

细菌对几乎所有已知的抗菌药物都具有耐药性，说明了识别通过新机制发挥作用的抗生素的必要性。

该文报道了一类对临床分离的耐氟喹诺酮类大肠杆菌具有抗菌活性的DNA回旋酶变构抑制剂。对小分子文库的筛选揭示了一种初始的异喹啉磺酰胺命中率，该命中率通过药物化学研究进行了优化，以提供更强效的抗菌LEI-800。靶点鉴定研究，包括对体外筛选的对异喹啉磺酰胺具有耐药性的突变体进行全基因组测序，一致指出DNA旋转酶复合物是一种重要的细菌拓扑异构酶，也是一种已确定的抗菌靶点。

使用单粒子冷冻电子显微镜，研究人员确定了回旋酶-LEI-800-DNA复合物的结构。该化合物在GyrA亚基中占据一个变构的疏水口袋，其作用模式与迄今为止报道的临床使用的氟喹诺酮类或任何其他旋转酶抑制剂不同。

LEI-800提供了一种适合开发的化学型，以对抗日益广泛的细菌对氟喹诺酮类药物的耐药性。

附：英文原文

Title: Discovery of isoquinoline sulfonamides as allosteric gyrase inhibitors with activity against fluoroquinolone-resistant bacteria

Author: Bakker, Alexander T., Kotsogianni, Ioli, Avalos, Mariana, Punt, Jeroen M., Liu, Bing, Piermarini, Diana, Gagestein, Berend, Slingerland, Cornelis J., Zhang, Le, Willemse, Joost J., Ghimire, Leela B., van den Berg, Richard J. H. B. N., Janssen, Antonius P. A., Ottenhoff, Tom H. M., van Boeckel, Constant A. A., van Wezel, Gilles P., Ghilarov, Dmitry, Martin, Nathaniel I., van der Stelt, Mario

Issue&Volume: 2024-06-19

Abstract: Bacteria have evolved resistance to nearly all known antibacterials, emphasizing the need to identify antibiotics that operate via novel mechanisms. Here we report a class of allosteric inhibitors of DNA gyrase with antibacterial activity against fluoroquinolone-resistant clinical isolates of Escherichia coli. Screening of a small-molecule library revealed an initial isoquinoline sulfonamide hit, which was optimized via medicinal chemistry efforts to afford the more potent antibacterial LEI-800. Target identification studies, including whole-genome sequencing of in vitro selected mutants with resistance to isoquinoline sulfonamides, unanimously pointed to the DNA gyrase complex, an essential bacterial topoisomerase and an established antibacterial target. Using single-particle cryogenic electron microscopy, we determined the structure of the gyrase–LEI-800–DNA complex. The compound occupies an allosteric, hydrophobic pocket in the GyrA subunit and has a mode of action that is distinct from the clinically used fluoroquinolones or any other gyrase inhibitor reported to date. LEI-800 provides a chemotype suitable for development to counter the increasingly widespread bacterial resistance to fluoroquinolones.

DOI: 10.1038/s41557-024-01516-x

Source: https://www.nature.com/articles/s41557-024-01516-x