Targeting dermatophyte Cdc42 and Rac GTPase signaling to hinder hyphal elongation and virulence

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. [Display omitted] •A screen of small GTPase inhibitors identifies Cdc42/Rac as a novel antifungal target•We identified compounds that inhibit T. rubrum Cdc24-mediated Cdc42/Rac activation•Genetic repression of Cdc42/Rac pathway in T. rubrum markedly impairs hyphal formation•Fungal Cdc42/Rac inhibitor alleviates infection in an animal model and growth on nails Molecular biology; Microbiology; Mycology; Cell biology