title: A prodrug approach to the use of coumarins as potential therapeutics for superficial mycoses.
abstract: Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails that affect 20-25% of the world's population, with increasing incidence. Treatment of superficial mycoses, predominantly caused by dermatophytes, is by topical and/or oral regimens. New therapeutic options with improved efficacy and/or safety profiles are desirable. There is renewed interest in natural product-based antimicrobials as alternatives to conventional treatments, including the treatment of superficial mycoses. We investigated the potential of coumarins as dermatophyte-specific antifungal agents and describe for the first time their potential utility as topical antifungals for superficial mycoses using a prodrug approach. Here we demonstrate that an inactive coumarin glycone, esculin, is hydrolysed to the antifungal coumarin aglycone, esculetin by dermatophytes. Esculin is hydrolysed to esculetin β-glucosidases. We demonstrate that β-glucosidases are produced by dermatophytes as well as members of the dermal microbiota, and that this activity is sufficient to hydrolyse esculin to esculetin with concomitant antifungal activity. A β-glucosidase inhibitor (conduritol B epoxide), inhibited antifungal activity by preventing esculin hydrolysis. Esculin demonstrates good aqueous solubility (<6 g/l) and could be readily formulated and delivered topically as an inactive prodrug in a water-based gel or cream. This work demonstrates proof-of-principle for a therapeutic application of glycosylated coumarins as inactive prodrugs that could be converted to an active antifungal in situ. It is anticipated that this approach will be applicable to other coumarin glycones.
authors.affiliation: NovaBiotics Ltd, Craibstone, Bucksburn, Aberdeen, United Kingdom.
authors.forename: Derry K
authors.initials: DK
authors.lastname: Mercer
authors.forename: Jennifer
authors.initials: J
authors.lastname: Robertson
authors.forename: Kristine
authors.initials: K
authors.lastname: Wright
authors.forename: Lorna
authors.initials: L
authors.lastname: Miller
authors.forename: Shane
authors.initials: S
authors.lastname: Smith
authors.forename: Colin S
authors.initials: CS
authors.lastname: Stewart
authors.forename: Deborah A
authors.initials: DA
authors.lastname: O Neil
mesh_terms: D000935:Antifungal Agents / Q000494:pharmacology / Q000627:therapeutic use*; D003883:Arthrodermataceae / Q000201:enzymology / Q000378:metabolism; D001419:Bacteria / Q000378:metabolism; D003374:Coumarins / Q000494:pharmacology / Q000627:therapeutic use*; D003881:Dermatomycoses / Q000188:drug therapy*; D029721:Drosophila Proteins; D004929:Esculin / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008826:Microbial Sensitivity Tests; D064307:Microbiota; D011355:Prodrugs / Q000494:pharmacology / Q000627:therapeutic use*; D012867:Skin / Q000382:microbiology; D014468:Umbelliferones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001617:beta-Glucosidase / Q000378:metabolism
chemical_list: D000935:Antifungal Agents; D003374:Coumarins; D029721:Drosophila Proteins; D011355:Prodrugs; D014468:Umbelliferones; C529564:rudhira protein, Drosophila; D004929:Esculin; C030123:coumarin; D001617:beta-Glucosidase; C007628:esculetin