title: Inhibition of the calcineurin pathway by two tannins, chebulagic acid and chebulanin, isolated from Harrisonia abyssinica Oliv.
abstract: In order to discover and develop novel signaling inhibitors from plants, a screening system was established targeting the two-component system of Cryptococcus neoformans by using the wild type and a calcineurin mutant of C. neoformans, based on the counter-regulatory action of high-osmolarity glycerol (Hog1) mitogen-activated protein kinase and the calcineurin pathways in C. neoformans. Among 10,000 plant extracts, that from Harrisonia abyssinica Oliv. exhibited the most potent inhibitory activity against C. neoformans var. grubii H99 with fludioxonil. Bioassay-guided fractionation was used to isolate two bioactive compounds from H. abyssinica, and these compounds were identified as chebulagic acid and chebulanin using spectroscopic methods. These compounds specifically inhibited the calcineurin pathway in C. neoformans. Moreover, they exhibited potent antifungal activities against various human pathogenic fungi with minimum inhibitory concentrations ranging from 0.25 to over 64 µg/ml.
authors.affiliation: Division of Biosystems Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-806, Republic of Korea.
authors.forename: Won Jeong
authors.initials: WJ
authors.lastname: Lee
authors.forename: Jae Sun
authors.initials: JS
authors.lastname: Moon
authors.forename: Sung In
authors.initials: SI
authors.lastname: Kim
authors.forename: Young Tae
authors.initials: YT
authors.lastname: Kim
authors.forename: Oyekanmi
authors.initials: O
authors.lastname: Nash
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Bahn
authors.forename: Sung Uk
authors.initials: SU
authors.lastname: Kim
mesh_terms: D000935:Antifungal Agents / Q000302:isolation & purification / Q000378:metabolism; D001578:Benzopyrans / Q000302:isolation & purification / Q000378:metabolism*; D001681:Biological Assay / Q000379:methods; D019703:Calcineurin / Q000378:metabolism*; D003455:Cryptococcus neoformans / Q000187:drug effects / Q000201:enzymology*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000302:isolation & purification / Q000378:metabolism*; D005960:Glucosides / Q000302:isolation & purification / Q000378:metabolism*; D047348:Hydrolyzable Tannins / Q000302:isolation & purification / Q000378:metabolism*; D029641:Simaroubaceae / Q000737:chemistry*; D013057:Spectrum Analysis
chemical_list: D000935:Antifungal Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D005960:Glucosides; D047348:Hydrolyzable Tannins; C000608100:chebulanin; C076178:chebulagic acid; D019703:Calcineurin