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High Efficiency Drug Repurposing for New Antifungal Agents
Jong H. Kim * 1 , Kathleen L. Chan 1 , Luisa W. Cheng 1 , Lisa A. Tell 2 , Barbara A. Byrne 3 , Kristin Clothier 4 , Kirkwood M. Land 5
1  Foodborne Toxin Detection & 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
3  Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA
4  Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine & 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

Published: 03 November 2018 by MDPI AG in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4
10.3390/ecmc-4-05620
Abstract:

There has been a persistent effort 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 chemosensitization as a new screening strategy, where combined application of a second compound, viz., chemosensitizer, with a conventional drug could 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 could lead to high efficiency drug repurposing, which enhances the drug susceptibility of targeted fungal pathogens.

Keywords: Antifungal; Aspergillus fumigatus; Chemosensitization; Drug repurposing; Drug resistance; Signaling pathway
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