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.
Highlights
Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails [1] and are the most common fungal infections [2]
Delivery of water-soluble prodrugs that are converted to the active form at the site of infection would, be a desirable property. In this manuscript we demonstrate the proof-of-principle that an inactive water-soluble coumarin glycoside can be converted to the active antifungal coumarin by b– glucosidase activity, an enzyme produced by the target dermatophytes
Determination of the MIC and minimum fungicidal concentration (MFC) of selected coumarin glycones and aglycones The antifungal effect (MIC100) of selected coumarins against fungi isolated from human dermal infections were determined (Table 1)
Summary
Superficial mycoses are fungal infections of the outer layers of the skin, hair and nails [1] and are the most common fungal infections [2]. Other fungi, including Scopulariopsis brevicaulis, Malassezia spp., Alternaria spp., Fusarium spp. and Candida spp. can cause or be isolated from superficial mycoses [1]. Treatment of superficial mycoses is generally by topical therapeutics in the first instance, including azoles, polyenes and allylamines [3]. Topical treatments have advantages over systemic treatments; fewer and less severe adverse effects, improved patient compliance and lower overall cost of treatment [3,4,5,6]. A new topical antifungal would be fungicidal rather than fungistatic so treatment cycles can be shorter, higher cure rates attained, the chance of resistance reduced and the chance of relapse lowered [4]. The use of water-soluble antifungal agents would be preferable to facilitate ease of formulation and ameliorate potential irritant effects of solvents
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