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, 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.
Highlights
There have been continuous efforts to develop new antifungal agents or to improve the efficacy of conventional antifungal methods [1,2]
Among the several types of aspergillosis documented (such as allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, aspergilloma, chronic pulmonary aspergillosis, invasive aspergillosis (IA), and cutaneous aspergillosis) [10], IA is a devastating infection triggered by environmental Aspergillus species, wherein Aspergillus fumigatus is the leading agent of IA followed by A. flavus, A. terreus, A. niger, and A. nidulans [9,10]
Antifungal activities of test compounds were examined in the wild type and two antioxidant mutants of the human pathogen Aspergillus fumigatus AF293 and two mycotoxigenic fungi, Aspergillus parasiticus 2999 and A. parasiticus 5862 (National Center for Agricultural Utilization and Research, USDA-ARS, Peoria, IL, USA)
Summary
There have been continuous efforts to develop new antifungal agents or to improve the efficacy of conventional antifungal methods [1,2]. Among the several types of aspergillosis documented (such as allergic bronchopulmonary aspergillosis, allergic Aspergillus sinusitis, aspergilloma, chronic pulmonary aspergillosis, invasive aspergillosis (IA), and cutaneous aspergillosis) [10], IA is a devastating infection triggered by environmental Aspergillus species, wherein Aspergillus fumigatus is the leading agent of IA followed by A. flavus, A. terreus, A. niger, and A. nidulans [9,10] Certain azole fungicides, such as propiconazole or tebuconazole, that are applied to agricultural fields have the same mode of antifungal action as clinical azole drugs. We applied a previously developed chemosensitization strategy by including redox-active natural compounds or a structural analog as sensitizers, and used fungal mutants lacking key genes in the antioxidant system This resulted in the enhancement of the efficacy of the repurposed pro-oxidant drug bithionol. Results indicated that the sensitivity of the drug repurposing process could be augmented by the chemosensitization method and/or inclusion of fungal mutants lacking key genes in the cellular targets
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