Nitric Oxide-Releasing Macromolecule Exhibits Broad-Spectrum Antifungal Activity and Utility as a Topical Treatment for Superficial Fungal Infections

Abstract

ABSTRACT Cutaneous and superficial fungal infections affecting the skin, nails, and hair of humans are caused primarily by dermatophytes of the genera Trichophyton and Epidermophyton or by yeasts of the genera Candida and Malassezia. Onychomycosis is a common fungal infection of the nail that frequently coexists with tinea pedis, the most prevalent mycotic skin infection. Efficacy rates for current topical onychomycosis therapies are hampered by low drug penetration across the nail plate, which is theoretically obviated with nitric oxide (NO)-based topical therapies. The Nitricil technology platform is comprised of polysiloxane-based macromolecules that stably release therapeutic levels of NO. In the reported studies, NVN1000, the lead candidate of the platform, was assessed for its spectrum of in vitro activity against a broad range of filamentous fungi and yeast species commonly associated with cutaneous fungal infections. Time-kill assays demonstrated that NVN1000 exhibited fungicidal activity as early as 4 h. Additionally, the penetration of several unique NVN1000 NO-releasing drug product formulations (gel, cream, and lacquer) was evaluated following a single topical application in an in vitro infected human nail assay, with all formulations showing similar inhibition of fungal growth. Repeated topical application in this model demonstrated that a lower-strength dose of NO could achieve the same efficacy as a higher-strength dose after 7 days. Together, these in vitro results demonstrate that NO-releasing treatments rapidly penetrate the nail plate and eradicate the fungal infection, representing promising novel topical therapies for the treatment of onychomycosis and other cutaneous fungal infections.