Clostridioides difficile infections (CDI) remain a major healthcare problem due to high rates of recurrent infections (rCDI). The treatment with broad-spectrum antibiotics often contributes to (r)CDI by sustained damage of the microbiota-mediated colonization resistance. Thus, the development of novel antibiotic candidates with distinct antimicrobial activity profiles against (r)CDI is of high public health interest to combat C. difficile infections.
Within the frame of InfectControl 2020, we investigated the antimicrobial effects of a natural product compound, chlorotonil A (ChA) on C. difficile1. The compound in vitro showed bactericidal activity at concentrations comparable to those of standard antibiotics on a C. difficile strains. In a pilot ChA feeding experiment with pigs, we observed only minor effects on the overall composition of the gut microbiota, whereas the absolute abundance of the genera Terrisporobacter and Clostridium was significantly reduced. A transcriptome analysis of C. difficile revealed the disturbance and re-programming of key cellular functions even at sub-MIC concentrations of ChA.
The notable microbiota-sparing property of ChA was confirmed in non-infected mice. In a CDI mouse model, ChA strikingly outperformed vancomycin in protecting mice against relapsing CDI. Subsequent experiments to characterize differences in anti-microbial activity revealed that ChA in contrast to vancomycin results in faster clearance of C. difficile vegetative cells and spores from the gut, a finding correlates with the faster recovery of the microbiota of ChA-treated C. difficile-infected mice. We also noted an unexpected direct activity of chlorotonils towards C. difficile spores, preventing their germination even after the removal of the antibiotic from the media. Together, chlorotonils act at similar concentrations on both vegetative cells and spores, defining a unique antimicrobial profile compared to existing antibiotics. Chlorotonils constitute a highly interesting compound family for the development as novel antibacterial agents to break the vicious cycle of rCDI.
1Bublitz et al. (2023). Cell Host & Microbe. doi: 10.1016/j.chom.2023.04.003.