Fig. 8: Model for PCA pathway-mediated regulation of vacuolar detoxification and susceptibility to antifungal drugs in fungi.

We propose that the pathway for biosynthesis of CoA and AcCOA (the PCA pathway) from pantothenate has major regulatory function in the control of organellar biogenesis in fungi. a The upper panel illustrates the cellular events associated with the functioning PCA pathway. AcCoA and ergosterol are produced through the normal PCA pathway, with ergosterol supporting normal vacuole and mitochondrial function. b The lower panel illustrates the dysfunctional PCA pathway, resulting in severe downstream effects on vacuolar function. Vacuolar homeostasis and xenobiotic detoxification heavily rely on the functionality of the PCA pathway in fungal strains. A reduction in ergosterol synthesis inhibits the function of vacuole and results in defects in cysteine sequestration and impairments in drug/heavy metal detoxification. These vacuolar function defects also contribute to increased ROS levels and mitochondrial abnormalities. The pivotal role of the PCA pathway in these downstream cellular events creates a unique vulnerability in yeast strains that can be targeted through the use of potentiators (PAMS) like PZ-2891, in addition to other modulators of PanK, Acs, and V-ATPase enzyme activities. The figure was created using BioRender (BioRender.com) and PowerPoint (Microsoft.com). PA pantothenic acid, PTZ pyrimidone triazol, αPanAM alpha-methyl-N-phenethyl-pantothenamide, CoA Co-enzyme A, ROS reactive oxygen species, PAMS potentiators of antimicrobial susceptibility.