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<p>The enterococcal cytolysin is a toxic, two-component ribosomally synthesized and post-translationally modified peptide (RiPP) produced by pathogenic <i>Enterococcus faecalis</i>. Cytolysin-producing (C+) <i>E. faecalis</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月28日

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  • Ryan Moreira,
  • Bidisha Chakraborty,
  • Yi Yang,
  • Chandrashekhar Padhi,
  • Michael S. Gilmore,
  • Satish K. Nair,
  • Wilfred A. van der Donk

摘要

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.