Remodeling of the fungal cell wall contributes to Fludioxonil and Ambruticin resistance in the dermatophyte Trichophyton rubrum.

PERES NT; GRAS DE; SANCHES PR; ROSSI A; PRADE RA; MARTINEZ-ROSSI NM

California

Conferencia; 26th Fungal Genetics Conference at Asilomar; 2011

Genetics Society of America

Fungal infections have become a health problem worldwide, leading to the need for the development of new efficient antifungal agents. Although dermatophytes do not cause life-threatening diseases, there are reports of deep infections and severe lesions in immunossupressed patients and impairment of living standards of the infected individuals. The antifungal compounds Fludioxonil and Ambruticin present a unique mode of action, interfering with the fungal osmotic signaling pathway. We evaluated the effect of these drugs on Trichophyton rubrum, and low doses of the drugs inhibit growth of this dermatophyte, leading to hyphal-tip swelling, rupture of cell wall, and leakage of cell contents. We isolated Ambruticin/Fludioxonil resistant mutants with UV, which showed enhanced conidiation, altered pigmentation, modified vegetative growth rates, and higher sensitivity to osmotic stress. Using the sib-selection approach we isolated two genes encoding a phospholipid transporter and the glucan 1,3- beta glucosidase protein, which conferred resistance to Ambruticin and Fludioxonil to the wild type strain. Since these enzymes are involved in the remodeling of fungal cell wall, we suggest that this process may be an important mechanism contributing to the resistance to both drugs.