STEREOSELECTIVE INTERACTION OF THE AZOLE ANTIFUNGAL AGENT SCH39304 WITH THE CYTOCHROME-P-450 MONOOXYGENASE SYSTEM ISOLATED FROM CRYPTOCOCCUS-NEOFORMANS

Citation
Dc. Lamb et al., STEREOSELECTIVE INTERACTION OF THE AZOLE ANTIFUNGAL AGENT SCH39304 WITH THE CYTOCHROME-P-450 MONOOXYGENASE SYSTEM ISOLATED FROM CRYPTOCOCCUS-NEOFORMANS, Antimicrobial agents and chemotherapy, 41(7), 1997, pp. 1465-1467
Citations number
15
Categorie Soggetti
Pharmacology & Pharmacy",Microbiology
ISSN journal
00664804
Volume
41
Issue
7
Year of publication
1997
Pages
1465 - 1467
Database
ISI
SICI code
0066-4804(1997)41:7<1465:SIOTAA>2.0.ZU;2-W
Abstract
We investigated the stereoselective inhibition of growth and ergostero l biosynthesis by SCH39304 in the pathogenic fungus Cryptococcus neofo rmans obtained from four AIDS patients who failed fluconazole therapy and compared the results to those obtained with a wild-type strain, Fo r all strains, the MICs of the RR isomer were approximately half those of the racemate, with the SS enantiomer showing no inhibitory activit y. The 50% inhibitory concentrations for in vitro ergosterol biosynthe sis correlated with the MIC data, indicating stereo-selective inhibiti on of their target P-450 enzyme, sterol 14 alpha-demethylase, as the c ause of this difference, The RR enantiomer produced classical type II spectra on addition to microsomal extracts of the strains, whereas the SS enantiomer showed an absence of binding, Stereo- and regio-specifi c localization of N-1 substituent groups of SCH39304 within the active site of the enzyme determined the unique discrimination between its t wo enantiomers, and the inability to bind to sterol 14 alpha-demethyla se is also true of other P-450 enzymes contained in the microsomal fra ction, As previously observed for other antifungal azoles, isolates ob tained following failure of fluconazole therapy showed resistance to S CH39304 and its RR enantiomer, This resistance could be associated,vit h an alteration in the sensitivity of ergosterol biosynthesis in vitro . These alterations did not cause any changes allowing the SS enantiom er to bind to the P-450 mediating sterol 14 alpha-demethylation.