Department of Microbial Immune Regulation, Helmholtz Center for Infection Research, Braunschweig, Germany.
Institute of Microbiology, Department of Microbial Physiology and Molecular Biology, University of Greifswald, Greifswald, Germany; Institute of Marine Biotechnology e.V., Greifswald, Germany.
Cell Host Microbe. 2023 May 10;31(5):734-750.e8. doi: 10.1016/j.chom.2023.04.003. Epub 2023 Apr 24.
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.
艰难梭菌感染（CDI）仍然是一个医疗保健问题，因为复发性/持续性 CDI（rCDI）的发生率很高。广谱抗生素导致的定植抵抗的破坏和孢子的持续存在导致了 rCDI。在这里，我们证明了天然产物类氯替酮对艰难梭菌的抗菌活性。与万古霉素不同，氯替酮 A（ChA）能有效抑制疾病并预防小鼠 rCDI。值得注意的是，ChA 对鼠和猪的微生物群的影响小于万古霉素，在很大程度上保持了微生物群的组成，对肠道代谢组的影响最小。相应地，ChA 治疗不会破坏对艰难梭菌的定植抵抗，并且与 CDI 后微生物群更快恢复有关。此外，ChA 在孢子中积累并抑制艰难梭菌孢子的生长，从而可能导致 rCDI 的发生率降低。我们得出结论，氯替酮具有针对艰难梭菌感染周期关键步骤的独特抗菌特性。
