Fungal Glycolipid Hydrolase Inhibitors and Their Effect on Cryptococcus neoformans.
Pathogenic fungi kill an estimated 1.3 million people each year. This number is predicted to rise as drug resistance spreads, thus antifungal drugs with novel modes of action are urgently required. Fungal endoglycoceramidase-related proteins 1 and 2 (EGCrP-1 and -2), which hydrolyse glucosylceramide and ergosteryl β-glucoside, respectively, are important for fungal cell growth and have been identified as potential targets for drug development. A library of iminosugar derivatives was screened against EGCrP-1 and -2, and a number of competitive inhibitors with nanomolar affinities were identified. In addition, a mechanism-based inhibitor was shown to form a covalent derivative with EGCrP-2. Nine of the inhibitors were evaluated against Cryptococcus neoformans. Several showed growth inhibitory activity, but only against a C. neoformans strain lacking the outer fungal polysaccharide capsule; this implies that penetration into the cell is a significant handicap for these inhibitors. Pro-drug versions of these inhibitors could address this issue.
['Santana|Andres G|AG|', 'Tysoe|Christina|C|', 'Hu|Guanggan|G|', 'Kronstad|James|J|', 'Goddard-Borger|Ethan D|ED|', 'Withers|Stephen G|SG|']
D003455:Cryptococcus neoformans D004791:Enzyme Inhibitors D005656:Fungal Proteins D006026:Glycoside Hydrolases D007700:Kinetics D011355:Prodrugs D012233:Rhizopus
Cryptococcus neoformans glucosylceramide iminosugars antimycotic agents glycosidase inhibitors