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

Kali R Iyer; Sheena C Li; Nicole M Revie; Jennifer W Lou; Dustin Duncan; Sara Fallah; Hiram Sanchez; Iwona Skulska; Mojca Mattiazzi Ušaj; Hamid Safizadeh; Brett Larsen; Cassandra 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

doi:10.1016/j.chembiol.2023.06.005

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

Cell Chem Biol. 2023 Jul 20;30(7):795-810.e8. doi: 10.1016/j.chembiol.2023.06.005. Epub 2023 Jun 26.

Authors

Kali R Iyer¹, Sheena C Li², Nicole M Revie¹, Jennifer W Lou³, Dustin Duncan¹, Sara Fallah¹, Hiram Sanchez⁴, Iwona Skulska⁵, Mojca Mattiazzi Ušaj⁶, Hamid Safizadeh⁷, Brett Larsen⁸, Cassandra Wong⁸, Ahmed Aman⁹, Taira Kiyota¹⁰, Mami Yoshimura¹¹, Hiromi Kimura¹¹, Hiroyuki Hirano¹¹, Minoru Yoshida¹¹, Hiroyuki Osada¹¹, Anne-Claude Gingras⁸, David R Andes⁴, Rebecca S Shapiro⁵, Nicole Robbins¹, Mohammad T Mazhab-Jafari¹², Luke Whitesell¹, Yoko Yashiroda¹³, Charles Boone¹⁴, Leah E Cowen¹⁵

Affiliations

¹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
² Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ON, Canada; RIKEN Center for Sustainable Resource Science, Wako, Japan.
³ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
⁴ Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; Department of Medical Microbiology and Immunology, University of Wisconsin, Madison, WI, USA.
⁵ Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada.
⁶ Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON, Canada.
⁷ Department of Computer Science and Engineering and Department of Electrical and Computer Engineering, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
⁸ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.
⁹ Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, Canada.
¹⁰ Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
¹¹ RIKEN Center for Sustainable Resource Science, Wako, Japan.
¹² Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
¹³ RIKEN Center for Sustainable Resource Science, Wako, Japan. Electronic address: ytyy@riken.jp.
¹⁴ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada; Donnelly Centre for Cellular & Biomolecular Research, University of Toronto, Toronto, ON, Canada; RIKEN Center for Sustainable Resource Science, Wako, Japan. Electronic address: charlie.boone@utoronto.ca.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada. Electronic address: leah.cowen@utoronto.ca.

Abstract

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.

Keywords: Candida; Cryptococcus; FMN; Fas1; antifungal; chemogenomic; enoyl reductase; pathogen.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Antifungal Agents* / pharmacology
Aspergillus fumigatus
Candida albicans*
Humans
Microbial Sensitivity Tests
Virulence

Substances

Antifungal Agents

Grants and funding

R01 AI127375/AI/NIAID NIH HHS/United States