title: Molecular basis of Streptococcus mutans sortase A inhibition by the flavonoid natural product trans-chalcone.
abstract: Sortase A (SrtA) from Gram positive pathogens is an attractive target for inhibitors due to its role in the attachment of surface proteins to the cell wall. We found that the plant natural product trans-chalcone inhibits Streptococcus mutans SrtA in vitro and also inhibited S. mutans biofilm formation. Mass spectrometry revealed that the trans-chalcone forms a Michael addition adduct with the active site cysteine. The X-ray crystal structure of the SrtA H139A mutant provided new insights into substrate recognition by the sortase family. Our study suggests that chalcone flavonoids have potential as sortase-specific oral biofilm inhibitors.
authors.affiliation: EastChem School of Chemistry, The University of Edinburgh, David Brewster Road, Edinburgh, EH9 3FJ, UK. Dominic.Campopiano@ed.ac.uk.
authors.forename: Daynea J
authors.initials: DJ
authors.lastname: Wallock-Richards
authors.forename: Jon
authors.initials: J
authors.lastname: Marles-Wright
authors.forename: David J
authors.initials: DJ
authors.lastname: Clarke
authors.forename: Amarnath
authors.initials: A
authors.lastname: Maitra
authors.forename: Michael
authors.initials: M
authors.lastname: Dodds
authors.forename: Bryan
authors.initials: B
authors.lastname: Hanley
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Campopiano
mesh_terms: D019881:Aminoacyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013295:Streptococcus mutans / Q000201:enzymology*
chemical_list: D001426:Bacterial Proteins; D001688:Biological Products; D004791:Enzyme Inhibitors; D002599:Chalcone; D019881:Aminoacyltransferases; C120542:sortase A; D003546:Cysteine Endopeptidases