Small molecule inhibitors of fungal Δ(9) fatty acid desaturase as antifungal agents against Candida auris

<i>Candida auris</i> has emerged as a significant healthcare-associated pathogen due to its multidrug-resistant nature. Ongoing constraints in the discovery and provision of new antifungals create an urgent imperative to design effective remedies to this pressing global blight. Herein, we screened a chemical library and identified aryl-carbohydrazide analogs with potent activity against both <i>C. auris</i> and the most prevalent human fungal pathogen, <i>C. albicans</i>. SPB00525 [<i>N</i>'-(2,6-dichlorophenyl)-5-nitro-furan-2-carbohydrazide] exhibited potent activity against different strains that were resistant to standard antifungals. Using drug-induced haploinsufficient profiling, transcriptomics and metabolomic analysis, we uncovered that Ole1, a Δ(9) fatty acid desaturase, is the likely target of SPB00525. An analog of the latter, HTS06170 [<i>N</i>'-(2,6-dichlorophenyl)-4-methyl-1,2,3-thiadiazole-5-carbohydrazide], had a superior antifungal activity against both <i>C. auris</i> and <i>C. albicans</i>. Both SPB00525 and HTS06170 act as antivirulence agents and inhibited the invasive hyphal growth and biofilm formation of <i>C. albicans</i>. SPB00525 and HTS06170 attenuated fungal damage to human enterocytes and ameliorate the survival of <i>Galleria mellonella</i> larvae used as systemic candidiasis model. These data suggest that inhibiting fungal Δ(9) fatty acid desaturase activity represents a potential therapeutic approach for treating fungal infection caused by the superbug <i>C. auris</i> and the most prevalent human fungal pathogen, <i>C. albicans</i>.