Chlorotonil A (ChA) has antimicrobial activity against Clostridioides difficile
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ChA prevents relapsing C. difficile infection in a mouse model
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Unlike vancomycin, ChA preserves colonization resistance against C. difficile
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ChA is retained in C. difficile spores, preventing outgrowth of vegetative cells
Summary
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.
16S rRNA gene sequencing data from mice have been deposited in the NCBI (Bioproject Database) under the accession number: PRJNA809685. 16S rRNA gene sequencing data from piglets are available at the Sequence read archive (SRA) under the BioProject accession number PRJNA800240. The RNA sequencing data from the in vitro experiments are available at the Sequence read archive (SRA) under the BioProject accession number PRJNA949940. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifiers PXD029243.
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This paper does not report original code.
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Any additional information required to reanalyze the data reported in this work is available from the lead contact upon request.
