Treatment of Trichophyton rubrum ex vivo skin infection with a new antifungal agent, ambruticin, leads to the activation or repression of several genes, including a putative mitochondrial protein and a subtilisin protease

PERES NT; GRAS DE; SANCHES PR; FALCÃO JP; ROCHA LB; MAZUCATO M; ROSSI A; PRADE RA; MARTINEZ-ROSSI NM

Noordwijkerhout

Conferencia; 10th European Conference on Fungal Genetics; 2010

Federation of European Microbiological Societies

During host infection and treatment with cytotoxic agents, microorganisms must be able to remodel metabolic pathways to scavenge nutrients and to respond to the stress in order to survive in the host milieu. The identification of the mechanisms involved in fungal adaptation to host microenvironment and stress response is essential to understand the pathogenic process of fungal infection, enabling the establishment of new therapeutic measures. The anthropophilic dermatophyte Trichophyton rubrum is one of the most prevalent fungi isolated from cutaneous infections; however, the molecular mechanisms involved in its pathogenicity remain unclear. Moreover, antifungal drugs commonly used in the treatment of fungal infections act upon a limited number of cellular targets, presenting numerous side effects. In this work, an ex vivo human skin infection model was used to identify T. rubrum expressed genes during interaction with human epidermal cells and treatment with the antifungal agent ambruticin, which supposedly interfere with the osmoregulation system. The results show that this drug presents antifungal activities against this dermatophyte, leading to a swelling of the hyphal tip and consequently fungal death, also modulating the expression of several genes. The ex vivo human skin infection model followed by suppressive subtraction hybridization allowed the identification of genes involved in cellular transport and biogenesis of cellular components that were activated or repressed in response to ambruticin. The activation of the gene coding for a mitochondrial protein with unknown function, homolog to the Saccharomyces cerevisiae Tar1p, or repression of the gene coding for a subtilisin protease 5, during treatment of T. rubrum ex vivo skin infection suggests that they might be important for the maintenance of this dermatophyte in the host tissue, especially in the presence of an inhibitory agent.