|KIM, JONG - Former ARS Employee|
|Chan, Kathleen - Kathy|
Submitted to: Open Access Journal of Multidisciplinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/18/2018
Publication Date: 5/23/2018
Citation: Kim, J.H., Chan, K.L., Cheng, L.W. 2018. Octyl gallate as an intervention catalyst to augment antifungal efficacy of caspofungin. Open Access Journal of Multidisciplinary Science. 1(1):19-28. https://doi.org/10.3390/j1010004.
Interpretive Summary: Fungal diseases, such as infection of crops by Penicillium or human invasive aspergillosis caused by Aspergillus, etc., are problematic since effective antimycotic agents, especially those for control of drug/fungicide-resistant pathogens, are often scant. Studies have shown that the cell wall integrity system of fungal pathogens could serve as an effective target of many antimycotic drugs, such as caspofungin. Antifungal chemosensitization is an intervention strategy for control of fungal pathogens, where co-administration of a certain natural or synthetic compound with a commercial antimycotic drug can increase the efficacy of the conventional drug co-applied. Antifungal chemosensitization renders the pathogens highly susceptible to the drug co-applied, where the chemosensitizing agent (e.g., octylgallate used in this study), significantly incapacitates fungal defense system to the conventional drug (e.g., caspofungin). The key advantage of antifungal chemosensitization is that a chemosensitizer itself does not have to possess a high degree of antifungal potency. However, implementation of chemosensitization not only enhances the antifungal efficacy of the conventional drug co-applied, but also mitigates pathogen resistance to conventional antimycotic agents. Accordingly, chemosensitization-based fungal intervention could complement the combination therapy currently in use.
Technical Abstract: The fungal cell wall integrity system is a target of the antimycotic drug caspofungin (CAS). To intensify CAS drug efficacy, octylgallate (OG) was investigated as a chemosensitizer to CAS against Aspergillus, Penicillium, and the model fungus Saccharomyces cerevisiae. Co-administration of OG with CAS (chemosensitization) augmented antimycotic activity of either compound, compared to independent application of each agent, alone. For instance, wild type (WT) and ten out of eleven cell wall integrity mutants of S. cerevisiae exhibited increased susceptibility to CAS or OG during chemosensitization. Augmentation of drug efficacy via chemosensitization was also achieved in filamentous fungal pathogens (Aspergillus, Penicillium). The A. fumigatus sakA' and mpkC', signaling mutants in the antioxidant system, were more susceptible to chemosensitization compared to WT, suggesting that the redox-active OG further debilitated vulnerability (viz., defects in ameliorating oxidative stress) of the antioxidant mutants. Above all, Penicillium exhibited higher susceptibility to CAS during chemosensitization compared to Aspergillus, indicating “chemosensitization-strain specificity” exists. In summary, OG possesses chemosensitizing capability to augment the efficacy of CAS and thereby lowers antifungal dosages of the drug. OG-mediated chemosensitization can also lead to targeted intervention of pathogens, such as Penicillium, considering that Penicillium strains are more susceptible to CAS during OG-based chemosensitization than Aspergillus.