2. Academic Validation
  3. The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection

The natural product chlorotonil A preserves colonization resistance and prevents relapsing Clostridioides difficile infection

  • Cell Host Microbe. 2023 Apr 18;S1931-3128(23)00147-6. doi: 10.1016/j.chom.2023.04.003.
Arne Bublitz 1,  Madita Brauer 2,  Stefanie Wagner 3,  Walter Hofer 4,  Mathias Müsken 5,  Felix Deschner 4,  Till R Lesker 1,  Meina Neumann-Schaal 6,  Lena-Sophie Paul 3,  Ulrich Nübel 7,  Jürgen Bartel 8,  Andreas M Kany 4,  Daniela Zühlke 9,  Steffen Bernecker 10,  Rolf Jansen 10,  Susanne Sievers 9,  Katharina Riedel 2,  Jennifer Herrmann 11,  Rolf Müller 11,  Thilo M Fuchs 12,  Till Strowig 13
Affiliations

Affiliations

  • 1 Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany.
  • 2 Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany; Institute of Marine Biotechnology e.V., Greifswald, Germany.
  • 3 Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis, Jena, Germany.
  • 4 Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany.
  • 5 Central Facility for Microscopy, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany.
  • 6 Bacterial Metabolomics, Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany; Braunschweig Integrated Center of Systems Biology (BRICS), Technical University, Braunschweig, Germany.
  • 7 Braunschweig Integrated Center of Systems Biology (BRICS), Technical University, Braunschweig, Germany; Microbial Genome Research, Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany.
  • 8 Institute of Microbiology, Department of Microbial Proteomics, University of Greifswald, Greifswald, Germany.
  • 9 Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany.
  • 10 Department of Microbial Drugs, Helmholtz Center for Infection Research (HZI), Braunschweig, Germany.
  • 11 Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarbrücken, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany; Department of Pharmacy, Saarland University, Saarbrücken, Germany.
  • 12 Friedrich-Loeffler-Institut, Institute of Molecular Pathogenesis, Jena, Germany. Electronic address: thilom.fuchs@fli.de.
  • 13 Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany; German Center for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Braunschweig, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany; Centre for Individualised Infection Medicine (CiiM), Hannover, Germany. Electronic address: till.strowig@helmholtz-hzi.de.
PMID: 37098342 DOI: 10.1016/j.chom.2023.04.003
Abstract

Clostridioides difficile infections (CDIs) remain a healthcare problem due to high rates of relapsing/recurrent CDIs (rCDIs). Breakdown of colonization resistance promoted by broad-spectrum Antibiotics and the persistence of spores contribute to rCDI. Here, we demonstrate antimicrobial activity of the natural product class of chlorotonils against C. difficile. In contrast to vancomycin, chlorotonil A (ChA) efficiently inhibits disease and prevents rCDI in mice. Notably, ChA affects the murine and porcine microbiota to a lesser extent than vancomycin, largely preserving microbiota composition and minimally impacting the intestinal metabolome. Correspondingly, ChA treatment does not break colonization resistance against C. difficile and is linked to faster recovery of the microbiota after CDI. Additionally, ChA accumulates in the spore and inhibits outgrowth of C. difficile spores, thus potentially contributing to lower rates of rCDI. We conclude that chlorotonils have unique antimicrobial properties targeting critical steps in the Infection cycle of C. difficile.

Keywords

Clostridioides difficile; chlorotonil; colonization resistance; gut microbiota; spores.

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