9EKQ

Inhibiting the Virulence of Gut Bacteria through Blocking the Activation of a Two-component Lanthipeptide Toxin

Summary for 9EKQ

• Entry DOI: 10.2210/pdb9ekq/pdb
• Descriptor: Lantibiotic leader peptide processing serine protease CylA (2 entities in total)
• Functional Keywords: serine protease, cytolysin a, hydrolase
• Biological source: Enterococcus faecalis
• Total number of polymer chains: 1
• Total formula weight: 44567.52

Authors

Chakraborty, B.,Nair, S.K. (deposition date: 2024-12-03, release date: 2025-06-25, Last modification date: 2025-09-03)

Primary citation

Moreira, R.,Chakraborty, B.,Yang, Y.,Padhi, C.,Gilmore, M.S.,Nair, S.K.,van der Donk, W.A.
Combatting virulent gut bacteria by inhibiting the biosynthesis of a two-component lanthipeptide toxin.
Nat Commun, 16:6936-6936, 2025

PubMed Abstract: The enterococcal cytolysin is a toxic, two-component ribosomally synthesized and post-translationally modified peptide (RiPP) produced by pathogenic Enterococcus faecalis. Cytolysin-producing (C+) E. faecalis resides in the gut microbiome in a commensal role, but results in negative clinical outcomes in alcoholic hepatitis patients. To potentially combat cytolysin virulence, we report inhibitors of its maturation. An extracellular serine protease CylA that is essential for toxin activation is chosen as target. A series of α-aminopeptide boronic acids are designed and synthesized that block cytolysin maturation at low micromolar to nanomolar concentrations in vitro. A crystal structure of CylA provides insights into substrate recognition, autocatalytic activation of the enzyme, and toxin maturation. The inhibitors block hemolytic activity, reduce the amount of cytolysin, and attenuate expression of the cytolysin biosynthetic gene cluster without impeding cell growth. These studies provide a potential route to the development of treatments for cytolysin-induced disease states.

PubMed: 40721579
DOI: 10.1038/s41467-025-62161-7

Experimental method

X-RAY DIFFRACTION (1.3 Å)