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- Title
Vitamin B5 metabolism is essential for vacuolar and mitochondrial functions and drug detoxification in fungi.
- Authors
Choi, Jae-Yeon; Gihaz, Shalev; Munshi, Muhammad; Singh, Pallavi; Vydyam, Pratap; Hamel, Patrice; Adams, Emily M.; Sun, Xinghui; Khalimonchuk, Oleh; Fuller, Kevin; Ben Mamoun, Choukri
- Abstract
Summary: Fungal infections, a leading cause of mortality among eukaryotic pathogens, pose a growing global health threat due to the rise of drug-resistant strains. New therapeutic strategies are urgently needed to combat this challenge. The PCA pathway for biosynthesis of Co-enzyme A (CoA) and Acetyl-CoA (AcCoA) from vitamin B5 (pantothenic acid) has been validated as an excellent target for the development of new antimicrobials against fungi and protozoa. The pathway regulates key cellular processes including metabolism of fatty acids, amino acids, sterols, and heme. In this study, we provide genetic evidence that disruption of the PCA pathway in Saccharomyces cerevisiae results in a significant alteration in the susceptibility of fungi to a wide range of xenobiotics, including clinically approved antifungal drugs through alteration of vacuolar morphology and drug detoxification. The drug potentiation mediated by genetic regulation of genes in the PCA pathway could be recapitulated using the pantazine analog PZ-2891 as well as the celecoxib derivative, AR-12 through inhibition of fungal AcCoA synthase activity. Collectively, the data validate the PCA pathway as a suitable target for enhancing the efficacy and safety of current antifungal therapies. The PCA pathway, essential for synthesizing CoA and AcCoA from vitamin B5, plays a crucial role in fungal cellular processes. Targeting this pathway could enhance antifungal drug efficacy by affecting vacuolar morphology and drug detoxification.
- Subjects
PANTOTHENIC acid; DRUG synergism; GENETIC regulation; METABOLISM; XENOBIOTICS; ANTIFUNGAL agents; FUNGAL cell walls
- Publication
Communications Biology, 2024, Vol 7, Issue 1, p1
- ISSN
2399-3642
- Publication type
Article
- DOI
10.1038/s42003-024-06595-7