Poacic acid, a β‐1,3‐glucan–binding antifungal agent, inhibits cell‐wall remodeling and activates transcriptional responses regulated by the cell‐wall integrity and high‐osmolarity glycerol pathways in yeast

As a result of the relatively few available antifungals and the increasing frequency of resistance to them, the development of novel antifungals is increasingly important. The plant natural product poacic acid (PA) inhibits β-1,3-glucan synthesis in Saccharomyces cerevisiae and has antifungal activity against a wide range of plant pathogens. However, the mode of action of PA is unclear. Here, we reveal that PA specifically binds to β-1,3-glucan, its affinity for which is ~30-fold that for chitin. Besides its effect on β-1,3-glucan synthase activity, PA inhibited the yeast glucan-elongating activity of Gas1 and Gas2 and the chitin–glucan transglycosylase activity of Crh1. Regarding the cellular response to PA, transcriptional co-regulation was mediated by parallel activation of the cell-wall integrity (CWI) and high-osmolarity glycerol signaling pathways. Despite targeting β-1,3-glucan remodeling, the transcriptional profiles and regulatory circuits activated by caspofungin, zymolyase, and PA differed, indicating that their effects on CWI have different mechanisms. The effects of PA on the growth of yeast strains indicated that it has a mode of action distinct from that of echinocandins, suggesting it is a unique antifungal agent

Rational selection of morphological phenotypic traits to extract essential similarities in chemical perturbation in the ergosterol pathway

Abstract Terbinafine, fluconazole, and amorolfine inhibit fungal ergosterol synthesis by acting on their target enzymes at different steps in the synthetic pathway, causing the accumulation of various intermediates. We found that the effects of these three in- hibitors on yeast morphology were different. The number of morphological parameters commonly altered by these drugs was only approximately 6% of the total. Using a rational strategy to find commonly changed parameters,we focused on hidden essential similarities in the phenotypes possibly due to decreased ergosterol levels. This resulted in higher apparent morphological similarity. Improvements in morphological similarity were observed even when canonical correlation analysis was used to select biologically meaningful morphological parameters related to gene function. In addition to changes in cell morphology, we also observed differences in the synergistic effects among the three inhibitors and in their fungicidal effects against pathogenic fungi possibly due to the accumulation of different intermediates. This study provided a comprehensive understanding of the properties of inhibitors acting in the same biosynthetic pathway