Abstract
Superficial mycoses caused by dermatophyte fungi are among the most common infections worldwide, yet treatment is restricted by limited effective drugs available, drug toxicity, and emergence of drug resistance. The stilbene fluorescent brightener calcofluor white (CFW) inhibits fungi by binding chitin in the cell wall, disrupting cell wall integrity, and thus entails a different mechanism of inhibition than currently available antifungal drugs. To identify novel therapeutic options for the treatment of skin infections, we compared the sensitivity of representative strains of the dermatophyte Trichophyton rubrum and Candida albicans to CFW and a panel of fluorescent brighteners and phytoalexin compounds. We identified the structurally related stilbene fluorescent brighteners 71, 85, 113 and 134 as fungicidal to both T. rubrum and C. albicans to a similar degree as CFW, and the stilbene phytoalexins pinosylvan monomethyl ether and pterostilbene inhibited to a lesser degree, allowing us to develop a structure-activity relationship for fungal inhibition. Given the abilities of CFW to absorb UV365 nm and bind specifically to fungal cell walls, we tested whether CFW combined with UV365 nm irradiation would be synergistic to fungi and provide a novel photodynamic treatment option. However, while both treatments individually were cytocidal, UV365 nm irradiation reduced sensitivity to CFW, which we attribute to CFW photoinactivation. We also tested combination treatments of CFW with other fungal inhibitors and identified synergistic interactions between CFW and some ergosterol biosynthesis inhibitors in C. albicans. Therefore, our studies identify novel fungal inhibitors and drug interactions, offering promise for combination topical treatment regimes for superficial mycoses.
Highlights
Dermatophytoses, the infections of keratinized tissues such as the skin, hair and nails by the highly specialized dermatophyte fungi such as Trichophyton rubrum, represent the most common type of human infection worldwide, in aging, diabetic or immunocompromised individuals [1,2,3,4,5]
Because calcofluor white (CFW) and the structurally similar fluorescent brightener 220 have been shown to inhibit fungal growth, we tested a panel of related stilbene and non-stilbene fluorescent brighteners (Fig. 1) for the ability to inhibit the growth of the T. rubrum and C. albicans
Modification of the R2 residue from a hydrogen to a sulfate group had a greater impact on function, with at least 10-fold reduced sensitivity of strains to fluorescent brightener 220 compared with CFW, or fluorescent brightener 210 compared with fluorescent brightener 71
Summary
Dermatophytoses, the infections of keratinized tissues such as the skin, hair and nails by the highly specialized dermatophyte fungi such as Trichophyton rubrum, represent the most common type of human infection worldwide, in aging, diabetic or immunocompromised individuals [1,2,3,4,5]. Fluorescent brighteners are typically diaminostilbene derivative compounds that fluoresce upon exposure to UV light, and bind through hydrogen bonding to b-linked fibrillar polymers such as cellulose and chitin [11] Due to these properties, fluorescent brighteners such as calcofluor white (CFW) have been used extensively in the textile, detergent and paper industry for creating a whitening effect, as well as in fungal diagnostics and research [12,13,14,15]. To identify novel dermatologic therapeutic options, we evaluated the inhibition of two divergent, dermatologically-relevant species T. rubrum (the most commonly isolated fungus from dermatophyte infections [3,24,25]), and Candida albicans (the most significant yeast contributor to skin infections [3,4,26]) by a panel of stilbene and non-stilbene fluorescent brighteners, and determined a structure-activity relationship for drug efficacy. We determined drug interactions between CFW and recognized fungal inhibitors for topical drug application
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