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Fungal Glycolipid Hydrolase Inhibitors and Their Effect on Cryptococcus neoformans
Author(s) -
Santana Andres G.,
Tysoe Christina,
Hu Guanggan,
Kronstad James,
GoddardBorger Ethan D.,
Withers Stephen G.
Publication year - 2017
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201600538
Subject(s) - iminosugar , cryptococcus neoformans , glycolipid , microbiology and biotechnology , echinocandins , biology , antifungal drug , drug , enzyme , biochemistry , chemistry , candida albicans , pharmacology , antifungal , amphotericin b , caspofungin
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.