High efficiency drug repurposing design for new antifungal agents

Authors: Kim, Jong Heon; Chan, Kathleen - Kathy; Cheng, Luisa; TELL, LISA - University Of California, Davis; BYRNE, BARBARA - University Of California, Davis; CLOTHIER, KRISTIN - University Of California, Davis; LAND, KIRKWOOD - University Of The Pacific

Submitted to: Methods and Protocols
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/12/2019
Publication Date: 4/17/2019
Citation: Kim, J., Chan, K.L., Cheng, L.W., Tell, L.A., Byrne, B.A., Clothier, K., Land, K.M. 2019. High efficiency drug repurposing design for new antifungal agents. Methods and Protocols. 2(2):31. https://doi.org/10.3390/mps2020031.
DOI: https://doi.org/10.3390/mps2020031

Interpretive Summary: There have been continuous efforts to improve efficacy of conventional antimycotic drugs. However, current antimycotic interventions have often limited efficiency in treating fungal pathogens, especially those resistant to drugs. Considering development of entirely new antimycotic drugs is a capital-intensive and time-consuming process, we investigated an alternative approach termed drug repurposing whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antimycotic agents. As a proof of concept, we applied a method termed chemosensitization as a new screening strategy, where combined application of a second compound, viz., chemosensitizer, with a conventional drug could greatly enhance antifungal efficacy of the drug co-applied. Unlike the conventional combination therapy, a chemosensitizer itself does not necessarily have to possess an antifungal activity, but the chemosensitizer significantly debilitates defense systems of pathogens to drugs, enabling improved identification of antifungal activity of off-patent drugs. Of note, inclusion of fungal mutants, such as antioxidant mutants, could facilitate drug repurposing process by enhancing the sensitivity of antifungal screening. Altogether, our strategy led to the development of high efficiency drug repurposing design, which enhances the drug susceptibility of targeted fungal pathogens.

Technical Abstract: Current antifungal interventions have often limited efficiency in treating fungal pathogens, particularly those resistant to commercial drugs or fungicides. Antifungal drug repurposing is an alternative intervention strategy, whereby new utility of various marketed, non-antifungal drugs could be repositioned as novel antifungal agents. In this study, we investigated “chemosensitization” as a method to improve the efficiency of antifungal drug repurposing, where combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance antifungal activity of the drug co-applied. Redox-active natural compounds or structural derivatives, such as thymol (2-isopropyl-5-methylphenol), 4-isopropyl-3-methylphenol, or 3,5-dimethoxybenzaldehyde, could serve as potent chemosensitizers to enhance antifungal activity of the repurposed drug bithionol. Of note, inclusion of fungal mutants, such as antioxidant mutants, could also facilitate drug repurposing efficiency, which is reflected by the enhancement of antifungal efficacy of bithionol. Bithionol also overcame antifungal (viz., fludioxonil) tolerance of the antioxidant mutants of the human/animal pathogen Aspergillus fumigatus. Altogether, our strategy can lead to the development of high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abate drug or fungicide resistance.