title: Novel inhibitors of surface layer processing in Clostridium difficile.
abstract: Clostridium difficile, a leading cause of hospital-acquired bacterial infection, is coated in a dense surface layer (S-layer) that is thought to provide both physicochemical protection and a scaffold for host-pathogen interactions. The key structural components of the S-layer are two proteins derived from a polypeptide precursor, SlpA, via proteolytic cleavage by the protease Cwp84. Here, we report the design, synthesis and in vivo characterization of a panel of protease inhibitors and activity-based probes (ABPs) designed to target S-layer processing in live C. difficile cells. Inhibitors based on substrate-mimetic peptides bearing a C-terminal Michael acceptor warhead were found to be promising candidates for further development.
authors.affiliation: Department of Chemistry, Imperial College London, London SW72AZ, United Kingdom.
authors.forename: T H
authors.initials: TH
authors.lastname: Tam Dang
authors.forename: Robert P
authors.initials: RP
authors.lastname: Fagan
authors.forename: Neil F
authors.initials: NF
authors.lastname: Fairweather
authors.forename: Edward W
authors.initials: EW
authors.lastname: Tate
mesh_terms: D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016360:Clostridioides difficile / Q000201:enzymology / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001426:Bacterial Proteins; D010455:Peptides; D011480:Protease Inhibitors; C070683:surface layer protein A, Bacteria; C524258:Cwp84 protein, Clostridium difficile; D003546:Cysteine Endopeptidases