Chemical probes of surface layer biogenesis in Clostridium difficile.
Clostridium difficile, a leading cause of hospital-acquired infection, possesses a dense surface layer (S-layer) that mediates host-pathogen interactions. The key structural components of the S-layer result from proteolytic cleavage of a precursor protein, SlpA, into high- and low-molecular-weight components. Here we report the discovery and optimization of the first inhibitors of this process in live bacteria and their application for probing S-layer processing. We also describe the design and in vivo application of activity-based probes that identify the protein Cwp84 as the cysteine protease that mediates SlpA cleavage. This work provides novel chemical tools for the analysis of S-layer biogenesis and for the potential identification of novel drug targets within clostridia and related bacterial pathogens.
Dang
T H Tam
TH
Department of Chemistry, Imperial College London, UK.
de la Riva
Lucia
L
Fagan
Robert P
RP
Storck
Elisabeth M
EM
Heal
William P
WP
Janoir
Claire
C
Fairweather
Neil F
NF
Tate
Edward W
EW
D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D016360:Clostridioides difficile / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D054884:Host-Pathogen Interactions; D006801:Humans
D001426:Bacterial Proteins; C070683:surface layer protein A, Bacteria; C524258:Cwp84 protein, Clostridium difficile; D003546:Cysteine Endopeptidases