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

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 persis-tence 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 van-comycin, 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.

Automated summary

Clostridium difficile infections (CDIs) are a significant healthcare problem, mainly due to high rates of relapsing/recurrent CDIs (rCDIs). In this study, the antimicrobial activity of chlorotonils against C. difficile is demonstrated. Chlorotonil A (ChA) effectively inhibits disease and prevents rCDI in mice, with minimal impact on the microbiota and intestinal metabolome. ChA also accumulates in the spore and inhibits outgrowth, potentially reducing rates of rCDI. These findings suggest that chlorotonils have unique antimicrobial properties targeting critical steps in the infection cycle of C. difficile.