ALTERED P450 ACTIVITY ASSOCIATED WITH DIRECT SELECTION FOR FUNGAL AZOLE RESISTANCE

Azole antifungals inhibit CYP51A1-mediated sterol 14 alpha-demethylati on and the mechanism(s) of resistance to such compounds in Ustilago ma ydis were examined, The inhibition of growth was correlated with the a ccumulation of the substrate, 24-methylene-24,25-dihydrolanosterol (eb uricol), and depletion of ergosterol, Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CY P51A1. activity which was resistant to inhibition, The results demonst rate that alterations at the level of inhibitor binding to the target site can produce azole resistance, Similar changes may account for fun gal azole resistance phenomena in agriculture, and also in medicine wh ere resistance has become a problem in immunocompromised patients suff ering from AIDS.