A genetic screen in combination with biochemical analysis in Saccharomyces cerevisiae indicates that phenazine-1-carboxylic acid is harmful to vesicular trafficking and autophagy

Abstract

The environmentally friendly antibiotic phenazine-1-carboxylic acid (PCA) protects plants, mammals and humans effectively against various fungal pathogens. However, the mechanism by which PCA inhibits or kills fungal pathogens is not fully understood. We analyzed the effects of PCA on the growth of two fungal model organisms, Saccharomyces cerevisiae and Candida albicans, and found that PCA inhibited yeast growth in a dose-dependent manner which was inversely dependent on pH. In contrast, the commonly used antibiotic hygromycin B acted in a dose-dependent manner as pH increased. We then screened a yeast mutant library to identify genes whose mutation or deletion conferred resistance or sensitivity to PCA. We isolated 193 PCA-resistant or PCA-sensitive mutants in clusters, including vesicle-trafficking- and autophagy-defective mutants. Further analysis showed that unlike hygromycin B, PCA significantly altered intracellular vesicular trafficking under growth conditions and blocked autophagy under starvation conditions. These results suggest that PCA inhibits or kills pathogenic fungi in a complex way, in part by disrupting vesicular trafficking and autophagy.

Inhibition Molecular Mechanism of the Novel Fungicidal N-(Naphthalen-1-yl) phenazine-1-carboxamide against Rhizoctonia solani

“…However, it was reported that the antifungal mechanism of a similar compound, phenazine-1-carboxylic acid, involved destruction of the vesicle trafficking and autophagy of host cells, which may be due to different pharmacodynamic groups. However, this difference requires further study with respect to the structure-activity relationship [56].…”

Activity of bacteria isolated from bats against Pseudogymnoascus destructans in China

“…Additionally, PCA is used as a biocontrol agent against various plant pathogens in China (Zhou et al ., 2010 ). The inhibitory effect of PCA on fungi may be a complicated process, which involves multiple complex physiological processes such as cell wall structure and synthesis, cell membrane integrity, intracellular redox system, protein sorting and vesicle transport, and chromatin remodelling (Xu et al ., 2015 ; Zhu et al ., 2017 ). Moreover, PCA is an ideal compound for the development of microbial metabolites because of its stable chemical structure, low toxicity and compatibility with the environment (Yuan et al ., 2008 ), and represents a new type of microorganism‐derived pesticide (Huasong et al ., 2020 ).…”

Soil bacteria protect fungi from phenazines by acting as toxin sponges

“…species and destabilizing the electron transport chain of the target cell dependent upon the ability of the phenazine to cycle its redox state in the presence of oxygen. 13,[34][35][36][37][38][39] It may therefore seem paradoxical that the Aspergillus species achieves protection against PCA by promoting concentration of PCA within its co-culture. Given that P. edwinii colonies show a trend toward reduced PCA enrichment relative to the phenazine producer, P. fluorescens (Figure 3D), we hypothesized that a solution to this paradox might come from limiting oxygen by maintaining a reducing environment within the bacterial aggregates.…”