Open AccessExploiting diverse chemical collections to uncover novel antifungals
Author(s) -
Kali R. Iyer,
Kaddy Camara,
Martin Daniel-Ivad,
Nicole M. Revie,
Jennifer W. Lou,
Sheena Li,
Richard Trilles,
Sheila Elardo,
Yoko Yashiroda,
Jen Fossen,
Karen Marchillo,
Zhongle Liu,
Shakti Singh,
José F. Muñoz,
Sang Hu Kim,
Hiroyuki Hirano,
Minoru Yoshida,
Hiroyuki Osada,
Christina A. Cuomo,
Noelle S. Williams,
Ashraf Ibrahim,
Jack Edwards,
David R. Andes,
Justin R. Nodwell,
John A. Porco,
Charlie Boone,
Mohammad T. Mazhab-Jafari,
Lauren E. Brown,
Luke Whitesell,
Nicole Robbins,
Leah E. Cowen
Publication year - 2021
Publication title -
access microbiology
Language(s) - English
Resource type - Journals
ISSN - 2516-8290
DOI - 10.1099/acmi.cc2021.po0006
Subject(s) - candida auris , fluconazole , cryptococcus neoformans , efflux , microbiology and biotechnology , biology , candida albicans , chemical library , candida glabrata , antifungal , biochemistry , small molecule
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.