Olorofim Effectively Eradicates Dermatophytes In Vitro and In Vivo

Abstract

Superficial fungal infections are prevalent worldwide, with dermatophytes, as the most common cause. Various antifungal agents including azoles and allylamines are commonly used to treat dermatophytosis. However, their overuse has yielded drug-resistant strains, calling for the development of novel anti-mycotic compounds. Olorofim, is a newly developed antifungal compound, which targets pyrimidine biosynthesis in molds. The purpose of this study was to determine the in vitro and in vivo antifungal effects of olorofim against common dermatophytes. The in vitro activity of olorofim against dermatophytes was assessed by microtiter broth dilution method. Bioinformatic analysis of olorofim binding to dihydroorotate dehydrogenase (DHODH) of dermatophytes was also performed, using Aspergillus fumigatus DHODH as a template. The in vivo efficacy of the drug was investigated, using a guinea pig model, experimentally infected with Microsporum gypseum. Microtiter assays confirmed the high in vitro sensitivity of dermatophytes to olorofim (MIC= 0.015-0.06 mg/L). Amino acid sequence analysis indicated that DHODH is highly conserved among dermatophytes. The critical residues, in dermatophytes, involved in olorofim binding, were similar to their counterparts in A. fumigatus DHODH, which explains their susceptibility to olorofim. Typical skin lesions of dermatophyte infection, were observed in the guinea pig model, at seven days post-inoculation. Following one week of daily topical administration of olorofim, similar to the clotrimazole group, the skin lesions were resolved and normal hair growth patterns appeared. In light of the in vitro and in vivo activity of olorofim against dermatophytes, this novel agent may be considered as a treatment of choice, against dermatophytosis.

Antifungal Development and the Urgency of Minimizing the Impact of Fungal Diseases on Public Health

“…Olorofim interrupts pyrimidine synthesis by inhibiting the enzyme dihydroorotate dehydrogenase. , Dihydroorotate dehydrogenase participates in the de novo pyrimidine biosynthesis pathway, which is required for DNA, RNA, protein, and cell wall syntheses . This drug is a potential anti- Aspergillus candidate, being active against azole resistant strains. ,,− Olorofim also presents activity at relatively low MICs against L. prolificans and species of Scedosporium , Histoplasma , Blastomyces , and Coccidioides . , The drug is also active against dermatophytes species such as Trichophyton spp., Epidermophyton spp., and Microsporum spp . Olorofim lacks activity against Candida , Cryptococcus , and Mucorales species.…”

“… 28 , 128 The drug is also active against dermatophytes species such as Trichophyton spp., Epidermophyton spp., and Microsporum spp. 129 Olorofim lacks activity against Candida , Cryptococcus , and Mucorales species. Currently, olorofim is in phase 2 trial for invasive fungal infections in patients without other alternatives, and in phase 3 trial for comparison with amphotericin B for invasive aspergillosis.…”

“…28,128 The drug is also active against dermatophytes species such as Trichophyton spp., Epidermophyton spp., and Microsporum spp. 129 phase 2 trial for invasive fungal infections in patients without other alternatives, and in phase 3 trial for comparison with amphotericin B for invasive aspergillosis. 28,113,125 ATI-2307 (T-2307) is an arylamidine that presents antifungal activity against Cryptococcus spp., 130,131 Candida spp.…”

The Role of Olorofim in the Treatment of Filamentous Fungal Infections: A Review of In Vitro and In Vivo Studies

“…Furthermore, olorofim's efficacy was tested in animal models of dermatophytosis. Mirbzadeh et al created an immunosuppressed model of guinea pigs through corticosteroid therapy and infected them with a Microsporum gypseum strain [28]. Olorofim was topically administered to the created lesions, and the scales were analyzed by optical microscopy on day 7 of treatment.…”

Novel agents in the treatment of invasive fungal infections in solid organ transplant recipients

“…was demonstrated in murine models of neutropenia and chronic granulomatous disease [91 ▪▪ ]. It was shown to have good in-vitro activity against Madurella mycetomatis [92 ▪▪ ,93] and dermatophytes such as Microsporum [94] and terbinafine-resistant and azole-resistant Trichophyton [77 ▪▪ ,79 ▪▪ ]. In-vitro activity was observed against Exophiala dermatitidis [84 ▪▪ ] but not Alternaria alternata [77 ▪▪ ].…”