Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis

Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of <i>Candida</i>, <i>Cryptococcus</i>, and <i>Aspergillus</i>. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (<b>4b</b>) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of <i>Candida</i> (chiefly <i>C. albicans</i>), <i>Cryptococcus</i>, and <i>Aspergillus</i> at a concentration of as low as 0.5 μg/mL. Furthermore, <b>4b</b>, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in <i>C. albicans</i> pathogenesis. Three yeast deletion strains (<i>cox17</i>Δ, <i>ssa1</i>Δ, and <i>aft2</i>Δ) related to metal ion homeostasis were found to be highly sensitive to <b>4b</b> in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to <b>4b</b>, further corroborating that the compound targets metal ion homeostasis. <b>4b</b>’s potent antifungal activity was validated in vivo, as the compound enhanced the survival of <i>Caenorhabditis elegans</i> infected with fluconazole-resistant <i>C. albicans</i>. The present study indicates that <b>4b</b> warrants further investigation as a novel antifungal agent