Cytotoxic necrotizing factor 1 (CNF1) is a toxin produced by pathogenic strains of Escherichia coli responsible for extra‐intestinal infections. CNF1 deamidates Rac1, thereby triggering its permanent activation and worsening inflammatory reactions. Activated Rac1 is prone to proteasomal degradation. There is no targeted therapy against CNF1, despite its clinical relevance. In this work we developed a fluorescent cell‐based immunoassay to screen for inhibitors of CNF1‐induced Rac1 degradation among 1120 mostly approved drugs. Eleven compounds were found to prevent CNF1‐induced Rac1 degradation, and five also showed a protective effect against CNF1‐induced multinucleation. Finally, lasalocid, monensin, bepridil, and amodiaquine protected cells from both diphtheria toxin and CNF1 challenges. These data highlight the potential for drug repurposing to fight several bacterial infections and Rac1‐based diseases.

中文翻译：

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药物库的筛选确定了CNF1对细胞中毒的抑制剂

细胞毒性坏死因子1（CNF1）是由大肠杆菌的致病性菌株产生的毒素负责肠外感染。CNF1使Rac1脱氨基，从而触发其永久激活并加剧炎症反应。激活的Rac1容易发生蛋白酶体降解。尽管CNF1具有临床相关性，但尚无针对性的治疗方法。在这项工作中，我们开发了一种基于荧光细胞的免疫测定法，以在1120种获准批准的药物中筛选CNF1诱导的Rac1降解抑制剂。发现有11种化合物可防止CNF1诱导的Rac1降解，还有5种还显示出对CNF1诱导的多核化的保护作用。最后，拉索洛西德，莫能菌素，贝普地尔和阿莫地喹保护细胞免受白喉毒素和CNF1攻击。这些数据突显了针对多种细菌感染和基于Rac1的疾病进行药物再利用的潜力。