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Identification of triazenyl indoles as inhibitors of fungal fatty acid biosynthesis with broad-spectrum activity

2023; Elsevier BV; Volume: 30; Issue: 7 Linguagem: Inglês

10.1016/j.chembiol.2023.06.005

2451-9456

Kali R. Iyer, Sheena C. Li, Nicole M. Revie, Jennifer W. Lou, Dustin Duncan, Sara Fallah, Hiram Sánchez, Iwona Skulska, Mojca Mattiazzi Ušaj, Hamid Safizadeh, Brett Larsen, Cassandra J. Wong, Ahmed Aman, Taira Kiyota, Mami Yoshimura, Hiromi Kimura, Hiroyuki Hirano, Minoru Yoshida, Hiroyuki Osada, Anne‐Claude Gingras, David R. Andes, Rebecca S. Shapiro, Nicole Robbins, Mohammad T. Mazhab‐Jafari, Luke Whitesell, Yoko Yashiroda, Charles Boone, Leah E. Cowen,

Antimicrobial Resistance in Staphylococcus

Rising drug resistance among pathogenic fungi, paired with a limited antifungal arsenal, poses an increasing threat to human health. To identify antifungal compounds, we screened the RIKEN natural product depository against representative isolates of four major human fungal pathogens. This screen identified NPD6433, a triazenyl indole with broad-spectrum activity against all screening strains, as well as the filamentous mold Aspergillus fumigatus. Mechanistic studies indicated that NPD6433 targets the enoyl reductase domain of fatty acid synthase 1 (Fas1), covalently inhibiting its flavin mononucleotide-dependent NADPH-oxidation activity and arresting essential fatty acid biosynthesis. Robust Fas1 inhibition kills Candida albicans, while sublethal inhibition impairs diverse virulence traits. At well-tolerated exposures, NPD6433 extended the lifespan of nematodes infected with azole-resistant C. albicans. Overall, identification of NPD6433 provides a tool with which to explore lipid homeostasis as a therapeutic target in pathogenic fungi and reveals a mechanism by which Fas1 function can be inhibited.