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