New generation modified azole antifungals against multidrug-resistant Candida auris

The increasing prevalence of antifungal resistance and the limited numbers of antifungal agents available to treat patients with invasive fungal disease underscores the urgent need for novel drug classes. Candida auris has emerged as a major public pathogen of global concern with reduced effective treatment options. A targeted modification of azole core-scaffold with a cyclic heteroaliphatic linker linked aromatic and heteroaromatic rings resulted in compounds with exceptional activity, with MICs ranging from 0.016 to 4 µg/mL against a panel of Candida auris, including azole-resistant isolates. The research employed a systematic approach, varying substitutions of the linkers and the terminal aromatic rings to develop a structure activity relationship (SAR). The compounds also showed excellent activity against public health Candida species including C. albicans, N. glabrata, C. tropicalis and C. parasliosis, with MICs less than 1 µg/mL for most compounds. The study identified compounds 7, 18 and 21 as promising lead candidates with superior potency than both fluconazole and voriconazole against both C. auris and diverse Candida strains. The compounds were found to be non-toxic up to 50 mg/Kg in a Galleria mellonella model while showing efficacy against C. auris at a dose of 5 mg/Kg. This study offers a new chemical scaffold that can be taken forward to develop new generation azole antifungal agents against C. auris.