Dermatophytosis is a superficial infection of keratinized structures of the host caused by keratinolytic filamentous fungi named dermatophytes. Its prevalence is estimated around 20% in humans and has been increasing for the last decade. Classical antifungal agents are rather effective against dermatophytosis but their systemic administration is confronted with several problems. Systemic treatments are expensive and long-lasting, leading to a poor patient compliancy, are often associated with toxicity, and are challenged by the emergence of drug resistance. In this context, new antifungal compounds effective against dermatophytes are required. In order to improve the current knowledge about dermatophytosis, and to validate potential antifungal molecules, an in vitro model of reconstructed human epidermis (RHE) infected by the common dermatophyte species Trichophyton rubrum has been developed. This model is representative of dermatophytosis in vivo while fungal elements invade the stratum corneum of RHE. Because p38 mitogen-activated protein kinase (MAPK) had been found activated in RHE, the potential involvement of this signaling pathway was investigated during dermatophytosis by the use of several specific inhibitors of p38 activity. Among them, PD169316 alone was able to protect RHE against fungal invasion after infection by T. rubrum. Moreover, the integrity of the epidermal barrier is protected by PD169316 and is concurrent with a reduced expression of both pro-inflammatory cytokines and antimicrobial peptides usually released during infection. Analyzed on Sabouraud agar, PD169316 was able to directly impair the growth of T. rubrum, as well as of other dermatophyte species. PD169316 is the only p38 MAPK inhibitor that exhibits such impact on dermatophyte growth and invading ability. Thus, data suggest that PD169316 may act on target required for dermatophyte growth itself and might reveal new strategy of antifungal treatment.

Infection by dermatophytes of reconstructed human epidermis is impaired by PD169316 via inhibition of fungal growth