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Altered P450 activity associated with direct selection for fungal azole resistance
Author(s) -
Joseph-Horne T.,
Hollomon D.,
Loeffler R.S.T.,
Kelly S.L.
Publication year - 1995
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(95)01102-k
Subject(s) - azole , ergosterol , lanosterol , itraconazole , microbiology and biotechnology , chemistry , mutant , sterol , biology , pharmacology , antifungal , biochemistry , cholesterol , gene
Azole antifungals inhibit CYP51A1‐mediated sterol 14α‐demethylation and the mechanism(s) of resistance to such compounds in Ustilago maydis were examined. The inhibition of growth was correlated with the accumulation of the substrate, 24‐methylene‐24,25‐dihydrolanosterol (eburicol), and depletion of ergosterol. Mutants overcoming the effect of azole antifungal treatment exhibited a unique phenotype with leaky CYP51A1 activity which was resistant to inhibition. The results demonstrate that alterations at the level of inhibitor binding to the target site can produce azole resistance. Similar changes may account for fungal azole resistance phenomena in agriculture, and also in medicine where resistance has become a problem in immuno‐compromised patients suffering from AIDS.