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

Summary The identification of novel molecular targets for antifungal drugs is critical due to limited treatment options and drug-resistance threats. We screened inhibitors of small GTPases, molecular switches in signal transduction, in Trichophyton rubrum , the primary cause of dermatophytosis. Our study found that chemical and genetic inhibition of Cdc42 and Rac GTPases, which are involved in cellular morphological changes, significantly impair hyphal formation, and are crucial for pathogenic fungal growth and virulence. Genetic repression of Cdc24, a guanine nucleotide exchange factor of Cdc42 and Rac, led to hyphal growth defects, abnormal cell morphology, and cell death. Chemical screening identified EHop-016 as an inhibitor of Cdc24 activity, which improved outcomes in in vitro nail infection and invertible infection models of T. rubrum . Our results suggest the Cdc24-Cdc42/Rac pathway as a promising therapeutic target for antifungal agent development, with EHop-016 as a potential lead compound.