@article{mbs:/content/journal/acmi/10.1099/acmi.cc2021.po0006, author = "Iyer, Kali and Camara, Kaddy and Daniel-Ivad, Martin and Revie, Nicole and Lou, Jennifer and Li, Sheena and Trilles, Richard and Elardo, Sheila and Yashiroda, Yoko and Fossen, Jen and Marchillo, Karen and Liu, Zhongle and Singh, Shakti and Muñoz, Jose and Hu Kim, Sang and Hirano, Hiroyuki and Yoshida, Minoru and Osada, Hiroyuki and Cuomo, Christina and Williams, Noelle and Ibrahim, Ashraf and Edwards, Jack and Andes, David and Nodwell, Justin and Porco, John and Boone, Charlie and Mazhab-Jafari, Mohammad and Brown, Lauren and Whitesell, Luke and Robbins, Nicole and Cowen, Leah", title = "Exploiting diverse chemical collections to uncover novel antifungals", journal= "Access Microbiology", year = "2021", volume = "3", number = "12", pages = "", doi = "https://doi.org/10.1099/acmi.cc2021.po0006", url = "https://www.microbiologyresearch.org/content/journal/acmi/10.1099/acmi.cc2021.po0006", publisher = "Microbiology Society", issn = "2516-8290", type = "Journal Article", eid = "po0006", abstract = "The rise in drug resistance amongst pathogenic fungi, paired with the limited arsenal of antifungals available is an imminent threat to our medical system. To address this, we screened two distinct compound libraries to identify novel strategies to expand the antifungal armamentarium. The first collection wasthe RIKEN Natural Product Depository (NPDepo), which was screened for antifungal activity against four major human fungal pathogens: Candida albicans, Candida glabrata, Candida auris, and Cryptococcus neoformans. Through a prioritization pipeline, one compound, NPD6433, emerged as having broad-spectrum antifungal activity and minimal mammalian cytotoxicity. Chemical-genetic and biochemical assays demonstrated that NPD6433 inhibits the essential fungal enzyme fatty acid synthase 1 (Fas1). Treatment with NPD6433 inhibited various virulence traits in C. neoformans and C. auris, and rescued mammalian cell growth in a co-culture model with C. auris. The second compound library screened was adiversity-oriented collectionfrom Boston University. This chemical screen was focused on identifying novel molecules that enhance the activity of the widely deployed antifungal, fluconazole, against C. auris. Through this endeavour, we discovered a potent compound that enhanced fluconazole efficacy against C. auris through increasing azole intracellular accumulation. This activity was dependent on expression of the multidrug transporter geneCDR1, suggesting that this compound targets efflux mechanisms. Furthermore, this molecule significantly reduced fungal burden alone and in combination with fluconazole in a murine model of C. auris disseminated infection. Overall, this work identifies novel compounds with bioactivity against fungal pathogens, revealing important biology, and paving the way for the critical development of therapeutic strategies.", }