|KIM, JONG - Former ARS Employee|
|Chan, Kathleen - Kathy|
Submitted to: Meeting Abstract
Publication Type: Proceedings
Publication Acceptance Date: 10/25/2015
Publication Date: 11/2/2015
Citation: Kim, J.H., Chan, K.L., Cheng, L.W. 2015. Augmenting the efficacy of antifungal intervention via chemo-biological approaches. Meeting Abstract. Vol 1, A011 doi:10.3390/ecmc-1-A011.
Interpretive Summary: Chemical biology is powerful approach for the discovery of novel antifungal agents and/or their mechanisms of action. With recent advances in biological and chemical tools, rapid identification of antifungal agents or novel targets is possible. Natural compounds that pose no significant medical or environmental side effects are potential sources of antimicrobial agents, either in their nascent structure or as leads for more effective derivatives. For example, natural benzo analogs not only inhibited the growth of fungal pathogens (Aspergillus sp., Fusarium sp., Penicillium sp.), but also disrupted the synthesis of toxic secondary metabolites. The redox-active natural compounds, such as phenolic agents, can effectively disrupt the integrity of cellular components. Chemosensitization, a combined application of a certain natural or synthetic compound with a conventional antimycotic agent, significantly enhances the effectiveness of the antimycotic agent co-applied, and mitigates pathogen resistance to the conventional antimycotic drug. The key value of antimycotic chemosensitization is that, in contrast to combination therapy (administration of two or more antimycotic drugs), a chemosensitizer, itself, does not necessarily possess a high level of antifungal potency. However, chemosensitization in pathogen control renders the target microorganism more susceptible to the conventional drug/agent in use, since the chemosensitizer mainly debilitates a defense response of a target pathogen to the conventional drug/agent. Accordingly, chemosensitization strategy further helps the maintenance of healthy mycobiome dynamics.
Technical Abstract: 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 action 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.