Fidaxomicin and OP-1118 Inhibit Clostridium difficile Toxin A-and B-Mediated Inflammatory Responses via Inhibition of NF-κB Activity

作者：Koon, Hon Wai; Wang, Jiani; Mussatto, Caroline C.; Ortiz, Christina; Lee, Elaine C.; Diana Hoang-Ngoc Tran; Chen, Xinhua; Kelly, Ciaran P.; Pothoulakis, Charalabos^*

来源：Antimicrobial Agents and Chemotherapy, 2018, 62(1): e01513-17.

DOI：10.1128/AAC.01513-17

• Clostridium difficile infection
• antibiotics
• signaling

Clostridium difficile causes diarrhea and colitis by releasing toxin A and toxin B. In the human colon, both toxins cause intestinal inflammation and stimulate tumor necrosis factor alpha (TNF-alpha) expression via the activation of NF-kappa B. It is well established that the macrolide antibiotic fidaxomicin is associated with reduced relapses of C. difficile infection. We showed that fidaxomicin and its primary metabolite OP-1118 significantly inhibited toxin A-mediated intestinal inflammation in mice in vivo and toxin A-induced cell rounding in vitro. We aim to determine whether fidaxomicin and OP-1118 possess anti-inflammatory effects against toxin A and toxin B in the human colon and examine the mechanism of this response. We used fresh human colonic explants, NCM460 human colonic epithelial cells, and RAW264.7 mouse macrophages to study the mechanism of the activity of fidaxomicin and OP-1118 against toxin A-and B-mediated cytokine expression and apoptosis. Fidaxomicin and OP-1118 dose-dependently inhibited toxin A-and B-induced TNF-alpha and interleukin-1 beta (IL-1 beta) mRNA expression and histological damage in human colonic explants. Fidaxomicin and OP-1118 inhibited toxin A-mediated NF-kappa B phosphorylation in human and mouse intestinal mucosae. Fidaxomicin and OP-1118 also inhibited toxin A-mediated NF-kappa B phosphorylation and TNF-alpha expression in macrophages, which was reversed by the NF-kappa B activator phorbol myristate acetate (PMA). Fidaxomicin and OP-1118 prevented toxin A- and B-mediated apoptosis in NCM460 cells, which was reversed by the addition of PMA. PMA reversed the cytoprotective effect of fidaxomicin and OP-1118 in toxin-exposed human colonic explants. Fidaxomicin and OP-1118 inhibit C. difficile toxin A- and B-mediated inflammatory responses, NF-kappa B phosphorylation, and tissue damage in the human colon.

• 出版日期2018-1
• 单位中国医科大学