Combatting virulent gut bacteria by inhibiting the biosynthesis of a two-component lanthipeptide toxin

Ryan Moreira, Bidisha Chakraborty, Yi Yang, Chandrashekhar Padhi, Michael S. Gilmore, Satish K. Nair () and Wilfred A. Donk ()
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Ryan Moreira: University of Illinois at Urbana-Champaign
Bidisha Chakraborty: University of Illinois at Urbana-Champaign
Yi Yang: University of Illinois at Urbana-Champaign
Chandrashekhar Padhi: University of Illinois at Urbana-Champaign
Michael S. Gilmore: Harvard Medical School
Satish K. Nair: University of Illinois at Urbana-Champaign
Wilfred A. Donk: University of Illinois at Urbana-Champaign

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62161-7

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