Calcofluor White Combination Antifungal Treatments for Trichophyton rubrum and Candida albicans

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 UV 365 nm and bind specifically to fungal cell walls, we tested whether CFW combined with UV 365 nm irradiation would be synergistic to fungi and provide a novel photodynamic treatment option. However, while both treatments individually were cytocidal, UV 365 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.

Neutralization of Pathogenic Fungi with Small‐Molecule Immunotherapeutics

“…Our design of a candidate antifungal ARM (called ARM‐F) started with calcofluor white as the TBT (Figure ). Calcofluor white is a well‐studied fungal whitening agent known to possess high specificity for chitin and antifungal properties at high doses . Because ARM‐F needs to bind simultaneously to fungal chitin and anti‐DNP antibodies, we sought a site for linker attachment on calcofluor white that would not compromise chitin‐binding activity.…”

Genome-wide profiling identifies Saccharomyces cerevisiae response in PKC-SLT2 signaling and glycogen metabolic pathways to antifungal compound calcofluor white

“…However, its clinical application in treating fungal infection is hampered by its limited efficacy, owing to fungal cells' effective compensatory responses. A full understanding of its compensation mechanism is the basis to further develop this drug into an effective treatment approach, used either alone or in combination with other drugs [8] . In this study, we have used microarray analysis to dissect the responses of saccharomyces cerevisiae when treated by CFW to identify cellular pathways important for cell survival.…”

“…Calcofluor white (CFW), extensively used in the paper industry and clinical histology over many decades [7] , is also known as a broad spectrum antifungal compound. For example, CFW has already been used to treat dermatophytosis [8] . Theoretically, CFW's low toxicity to humans should make it an ideal candidate to explore for treating fungal infections [8] .…”

“…For example, CFW has already been used to treat dermatophytosis [8] . Theoretically, CFW's low toxicity to humans should make it an ideal candidate to explore for treating fungal infections [8] . However, limited efficacy has hindered CFW to be applied in clinical treatments.…”

Preparation, and Assessment of Antidermatophyte Activity of Miconazole–Urea Water-Soluble Film

“…Several studies have investigated the effect of different drugs, either synthetic or natural products, on T. rubrum, but there are no reports about the use of miconazole/urea combination against the test fungus (Smijs et al, 2008;Pereira et al, 2011;Kingsbury et al, 2012;Aala et al, 2014;Song et al, 2018). Interestingly, Mady et al (2018) developed novel buccal mucoadhesive patches against Candida albicans, which have the ability to attach to the buccal cavity, exerting a local effect on the infected site.…”