Yeast species-specific, differential inhibition of β-1,3-glucan synthesis by poacic acid and caspofungin

The rise of widespread antifungal resistance fuels the need to explore new classes of inhibitory molecules as potential novel inhibitors. Recently a plant natural product poacic acid (PA) was shown to inhibit β-1,3-glucan synthesis, and to have antifungal activity against a range of plant pathogens and against Saccharomyces cerevisiae. As with the echinocandins, such as caspofungin, PA targets the synthesis of cell wall β-1,3-glucan and has potential utility in the treatment of medically important fungi. However, the antifungal activity of PA against human pathogenic Candida species has not been explored and the precise mode of action of this compound is not understood. Here, we show that PA sensitivity is regulated by the calcineurin pathway and that susceptibility to PA varied significantly between Candida species, but did not correlate with in vitro β-glucan synthase activity, cell wall β-glucan content or the sensitivity of the species to caspofungin. Strains with point mutations (S645Y or S645P) in the hotspot1 region of the β-1,3-glucan synthase subunit Fks1, had decreased sensitivity to caspofungin but increased sensitivity to PA. C. guilliermondii, C. orthopsilosis, and C. parapsilosis were more sensitive to PA than C. albicans, C. dubliniensis, C. tropicalis, and C. glabrata. These observations suggest that there are significant differences in the mode of action of PA and caspofungin and that PA or PA analogues are not likely to have broad spectrum activity in the treatment of Candida infections.