PDF(Pubmed)
Abstract：
The development of antifungal drugs requires novel molecular targets due to limited treatment options and drug resistance. Through chemical screening and establishment of a novel genetic technique to repress gene expression in Trichophyton rubrum, the primary causal fungus of dermatophytosis, we demonstrated that fungal Cdc42 and Rac GTPases are promising antifungal drug targets. Chemical inhibitors of these GTPases impair hyphal formation, which is crucial for growth and virulence in T. rubrum. Conditional repression of Cdc24, a guanine nucleotide exchange factor for Cdc42 and Rac, led to hyphal growth defects, abnormal cell morphology, and cell death. EHop-016 inhibited the promotion of the guanine nucleotide exchange reaction in Cdc42 and Rac by Cdc24 as well as germination and growth on the nail fragments of T. rubrum and improved animal survival in an invertebrate infection model of T. rubrum. Our results provide a novel antifungal therapeutic target and a potential lead compound.
摘要：
由于有限的治疗选择和耐药性，抗真菌药物的开发需要新的分子靶标。通过化学筛选和建立一种新的遗传技术来抑制红色毛癣菌的基因表达，皮肤癣菌病的主要致病真菌，我们证明了真菌Cdc42和RacGTP酶是有希望的抗真菌药物靶标。这些GTP酶的化学抑制剂损害菌丝形成，这对红豆杉的生长和毒力至关重要。Cdc42和Rac的鸟嘌呤核苷酸交换因子Cdc24的条件抑制，导致菌丝生长缺陷，细胞形态异常,细胞死亡。EHop-016抑制Cdc24对Cdc42和Rac中鸟嘌呤核苷酸交换反应的促进，以及在红毛虫的指甲片段上的萌发和生长，并在红毛虫的无脊椎动物感染模型中提高了动物的存活率。我们的结果提供了一种新的抗真菌治疗靶标和潜在的先导化合物。
