Characterization of a selective, iron-chelating antifungal compound that disrupts fungal metabolism and synergizes with fluconazole

Fungal infections are a growing global health concern due to the limited number of available antifungal therapies as well as the emergence of fungi that are resistant to first-line antimicrobials, particularly azoles and echinocandins. Development of novel, selective antifungal therapies is challenging due to similarities between fungal and mammalian cells. An attractive source of potential antifungal treatments is provided by ecological niches co-inhabited by bacteria, fungi and multicellular organisms, where complex relationships between multiple organisms has resulted in evolvement of a wide variety of selective antimicrobials. Here, we characterized several analogs of the one such natural compound, Collismycin A. We show that NR-6226C has antifungal activity against several pathogenicCandidaspecies, includingC. albicansandC. glabrata, whereas it only has little toxicity against mammalian cells. Mechanistically, NR-6226C selectively chelates iron, which is a limiting factor for pathogenic fungi during infection. As a result, NR-6226C treatment causes severe mitochondrial dysfunction, leading to formation of reactive oxygen species, metabolic reprogramming and a severe reduction in ATP levels. Using anin vivomodel for fungal infections, we show that NR-6226C significantly increases survival ofCandida-infectedGalleria mellonellalarvae. Finally, our data indicate that NR-6226C synergizes strongly with fluconazole in inhibition ofC. albicans. Taken together, NR-6226C is a promising antifungal compound that acts by chelating iron and disrupting mitochondrial functions.