A new series of natural antifungals that inhibit P450 lanosterol C-14 demethylase. II. Mode of action.
From a Penicillium sp. we identified a new series of antifungals having a tetrahydropyran skeleton with an alkenyl side chain. We elucidated the mode of action of Ro 09-1470, the most active compound of the series. Treatment of Candida albicans with the compound caused an accumulation of C-14 methyl intermediates of ergosterol at concentrations of which no significant interference with the biosyntheses of other macromolecules and respiration was observed. P450 lanosterol C-14 demethylase (P450(14DM)) activity was inhibited and furthermore, the binding of Ro 09-1470 to the heme of the enzyme was demonstrated by a difference spectrum. We conclude that Ro 09-1470 is the first natural antifungal that inhibits the P450(14DM) of fungi.
Aoki
Y
Y
Nippon Roche Research Center, Kamakura, Japan.
Yamazaki
T
T
Kondoh
M
M
Sudoh
Y
Y
Nakayama
N
N
Sekine
Y
Y
Shimada
H
H
Arisawa
M
M
D002176:Candida albicans / Q000187:drug effects; D065607:Cytochrome P-450 Enzyme Inhibitors; D004271:DNA, Fungal / Q000096:biosynthesis; D005656:Fungal Proteins / Q000096:biosynthesis; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007810:Lanosterol / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D011714:Pyrans / Q000494:pharmacology; D012331:RNA, Fungal / Q000096:biosynthesis; D013053:Spectrophotometry; D058886:Sterol 14-Demethylase; D013261:Sterols / Q000032:analysis
D065607:Cytochrome P-450 Enzyme Inhibitors; D004271:DNA, Fungal; D005656:Fungal Proteins; D011714:Pyrans; D012331:RNA, Fungal; D013261:Sterols; C069635:restricticin; D007810:Lanosterol; D010088:Oxidoreductases; D058886:Sterol 14-Demethylase; D005998:Glycine