title: Discovery of two new inhibitors of Botrytis cinerea chitin synthase by a chemical library screening.
abstract: Chitin synthases polymerize UDP-GlcNAC to form chitin polymer, a key component of fungal cell wall biosynthesis. Furthermore, chitin synthases are desirable targets for fungicides since chitin is absent in plants and mammals. Two potent Botrytis cinerea chitin synthase inhibitors, 2,3,5-tri-O-benzyl-d-ribose (compound 1) and a 2,5-functionalized imidazole (compound 2) were identified by screening a chemical library. We adapted the wheat germ agglutinin (WGA) test for chitin synthase activity detection to allow miniaturization and robotization of the screen. Both identified compounds inhibited chitin synthases in vitro with IC50 values of 1.8 and 10μM, respectively. Compounds 1 and 2 were evaluated for their antifungal activity and were found to be active against B. cinerea BD90 strain with MIC values of 190 and 100μM, respectively. Finally, we discovered that both compounds confer resistance to plant leaves against the attack of the fungus by reducing the propagation of lesions by 37% and 23%, respectively. Based on the inhibitory properties found in different assays, compounds 1 and 2 can be considered as antifungal hit inhibitors of chitin synthase, allowing further optimization of their pharmacological profile to improve their antifungal properties.
authors.affiliation: UPMC Univ Paris 06, CNRS UMR 7203, Laboratoire des Biomolécules, 75005 Paris, France.
authors.forename: Hervé
authors.initials: H
authors.lastname: Magellan
authors.forename: Martine
authors.initials: M
authors.lastname: Boccara
authors.forename: Thierry
authors.initials: T
authors.lastname: Drujon
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Soulié
authors.forename: Catherine
authors.initials: C
authors.lastname: Guillou
authors.forename: Joëlle
authors.initials: J
authors.lastname: Dubois
authors.forename: Hubert F
authors.initials: HF
authors.lastname: Becker
mesh_terms: D000935:Antifungal Agents / Q000737:chemistry* / Q000494:pharmacology; D017360:Arabidopsis / Q000382:microbiology; D020171:Botrytis / Q000187:drug effects / Q000201:enzymology* / Q000472:pathogenicity; D002687:Chitin Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D008904:Miniaturization; D010935:Plant Diseases / Q000382:microbiology; D012266:Ribose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D012371:Robotics; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C586724:2,3,5-tri-O-benzyl-d-ribose; D000935:Antifungal Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D054852:Small Molecule Libraries; D012266:Ribose; D002687:Chitin Synthase
keywords: Antifungal compounds; Botrytis cinerea; Chitin synthase; Glycosyltransferase; Inhibitor