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High Efficiency Drug Repurposing Design for New Antifungal Agents

1
Foodborne Toxin Detection and Prevention Research Unit, Western Regional Research Center, USDA-ARS, 800 Buchanan St., Albany, CA 94710, USA
2
Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
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Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
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California Animal Health and Food Safety Laboratory, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
5
Department of Biological Sciences, University of the Pacific, 3601 Pacific Avenue, Stockton, CA 95211, USA
*
Author to whom correspondence should be addressed.
This paper is an extended version of our paper published in Kim, J.H.; Chan, K.L.; Cheng, L.W.; Tell, L.A.; Byrne, B.A.; Clothier, K.; Land, K.M. High Efficiency Drug Repurposing for New Antifungal Agents, In Proceedings of 4th International Electronic Conference on Medicinal Chemistry, Basel, Switzerland, 1–30 November 2018.
Methods Protoc. 2019, 2(2), 31; https://doi.org/10.3390/mps2020031
Received: 20 March 2019 / Revised: 9 April 2019 / Accepted: 12 April 2019 / Published: 17 April 2019
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, wherein combined application of a second compound (viz., chemosensitizer) with a conventional, non-antifungal drug could greatly enhance the antifungal activity of the co-applied drug. 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 in the enhancement of antifungal efficacy of bithionol. Bithionol 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 a high efficiency drug repurposing design, which enhances the susceptibility of pathogens to drugs, reduces time and costs for new antifungal development, and abates drug or fungicide resistance. View Full-Text
Keywords: antifungal intervention; antioxidant system; Aspergillus; chemosensitization; drug repurposing; drug resistance; mutants; pathogen control antifungal intervention; antioxidant system; Aspergillus; chemosensitization; drug repurposing; drug resistance; mutants; pathogen control
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Kim, J.H.; Chan, K.L.; Cheng, L.W.; Tell, L.A.; Byrne, B.A.; Clothier, K.; Land, K.M. High Efficiency Drug Repurposing Design for New Antifungal Agents. Methods Protoc. 2019, 2, 31.

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