Augmenting the efficacy of antifungal intervention via chemo-biological approaches

Mycotic infection is becoming a serious health problem since effective antifungal agents for control of pathogenic fungi, especially drug-resistant pathogens, is often very limited. Fungal resistance to antimycotic agents frequently involves mutations caused by environmental stressors. In fungal pathogens, stress signals resulting from oxidative, cell wall stress, etc., are integrated into the upstream mitogen-activated protein kinase (MAPK) pathways that regulate genes countering the stress. Noteworthy is that mutations in MAPK signaling system result in fungal tolerance to cell wall disrupting agents or phenylpyrrole. In a chemo-biological platform to achieve targeted antifungal intervention, the model yeast Saccharomyces cerevisiae served as a tool for identifying mechanisms of actions of redox-active or cell wall disrupting agents. This also enabled the identification of new utility of known compounds or the utilization of natural products/derivatives as chemosensitizing agents to intensify the efficacy of conventional antimycotic agents. Compounds targeting cellular antioxidant, mitochondrial or cell wall integrity systems effectively inhibited the growth of pathogens and/or overcame fungal tolerance to antimycotic agents. Therefore, chemo-biological approaches lead to the development of novel intervention strategies, such as antifungal chemosensitization, which enhance the drug susceptibility of targeted fungi, and ensure the maintenance of healthy microbiome dynamics.