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.
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