Altered P450 activity associated with direct selection for fungal azole resistance.
Azole antifungals inhibit CYP51A1-mediated sterol 14 alpha-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 immunocompromised patients suffering from AIDS.
Joseph-Horne
T
T
Krebs Institute for Biomolecular Research, Department of Molecular Biology and Biotechnology, University of Sheffield, UK.
Hollomon
D
D
Loeffler
R S
RS
Kelly
S L
SL
D001393:Azoles / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004352:Drug Resistance, Microbial; D015394:Molecular Structure; D009154:Mutation; D010088:Oxidoreductases / Q000378:metabolism*; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000378:metabolism; D013379:Substrate Specificity; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology; D014588:Ustilago / Q000187:drug effects* / Q000201:enzymology*
D001393:Azoles; D002250:Carbon Radioisotopes; D013261:Sterols; D014230:Triazoles; C032910:triadimefon; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase