Journal of Antimicrobial Chemotherapy (1992) 30, 781-790
© 1992 The British Society for Antimicrobial Chemotherapy
research-article |
A non-azole inhibitor of lanosterol l4
-methy1 demethylase in Candida albicans
aAnti-infective Research Division One Abbott Park Road, Abbott Park, Illinois 60064-3500, USA bAnti.hypertensive Research Division, Abbott Laboratories One Abbott Park Road, Abbott Park, Illinois 60064-3500, USA
Received 6 March 1992; accepted 13 July 1992
6-Hydroxy-N-methyl-N-(2-[4-phenylphenyl] ethyl)-1,2,3,4-tetrahydro-1-napthalene methanamine (A60586), a new non-azole inhibitor of ergosterol biosynthesis in Candida albicans ATCC62376 has been identified. In whole cells A60586 produced a dose related reduction of [14C]acetate incorporation into ergosterol and a concurrent increase in the radiolabelling of 4,4-dimethylated sterols. Similar observations were made with [14C]mevalonic acid lactone labelled cell free extracts. The IC50s for inhibition of ergosterol in the whole cell and cell free systems were 22 µM(10 mg/L) and 7·8 µM(3·5 mg/L), respectively. Analysis by gas chromatography of sterols from cells previously incubated at 37°C for 24 h with A60586 (200 mg/L) confirmed the presence of lanosterol and 14
-methyl fecosterol. These data indicate that A60586, inhibits the demethylation of the C-14 methyl group of lanosterol. The MIC of A60586 for several candida strains ranged from l2·5 to 50mg/L, and against Cryptococcus albidus and Aspergillus niger ranged from 50 to 100 mg/L. The best in-vitro activity of A60586 was against Torulopsis glabrata (MIC range = 3·12 to 50 mg/L). The membrane permeabilizing effect of this compound (50% leakage of [14C]aminoisobutyric acid at 70 mg/L A60586) may have contributed to its in-vitro antifungal activity.