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

Koon, Hon Wai; Wang, Jiani; Mussatto, Caroline C.; Ortiz, Christina; Lee, Elaine C.; Tran, Diana; Chen, Xinhua; Kelly, Ciarán P.; Pothoulakis, Charalabos

doi:10.1128/aac.01513-17

Cited by 12 publications

(11 citation statements)

References 48 publications

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“…The release of TNF-a and IL-1b that has been found to be important mediators of intestinal inflammation was significantly increased by TcdB at concentrations ranging from 50 to 600 ng/ml. These findings were in agreement with those published previously [15,35]. and DUSP1 was detected by Co-immunoprecipitation.…”

Section: Discussionsupporting

confidence: 94%

RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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Clostridium difficile (C. difficile) infection results in toxin-induced epithelial injury and marked colonic inflammation. Mitogen-activated protein kinase (MAPK) and NF-jB which regulated by MAP kinase phosphatase (MKP, also known as dual specificity phosphatases, DUSP) are fundamental signalling pathways that mediate multiple cellular processes. However, the regulation of DUSP/MAPKs and NF-jB pathway in C. difficile-induced colonic inflammation remains unclear. Here, we report that TcdB significantly inhibits cell viability and induces production of IL-1b and TNF-a and activation of MAPKs and NF-jB. An E3-ubiquitin ligase, TRIM46, ubiquitinates DUSP1, and its knockdown significantly inhibit TcdB-induced activation of MAPKs and NF-jB and production of IL-1b and TNF-a. Moreover, TRIM46 overexpression induced production of IL-1b and TNF-a also reversed by DUSP1 overexpression. We further found that promoter of TRIM46 also demonstrated binding to NF-jBp65, leading to regulate TRIM46 expression. In addition, the increased colonic inflammation induced by C. difficile administration was inhibited by TRIM46 knockdown in vivo. Taken together, the present study shows that TRIM46, as a new regulator of DUSP1/MAPKs and NF-jB signalling pathway, plays an important role in TcdBinduced colonic inflammation.

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Section: Discussionsupporting

confidence: 94%

RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

et al. 2020

Artificial Cells, Nanomedicine, and Biotechnology

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“…The severe pathogenesis of CDI is accompanied by an upregulation of cytokines, especially interleukin IL-1β, IL-6, and IL-8. Interestingly, vancomycin upregulates IL-1β and IL-6, which correlate with CDI severity, while fidaxomicin reduces the production of IL-1β, thereby exerting a cytoprotective effect. Such an effect may be linked to the lower rates of CDI recurrence with fidaxomicin compared to vancomycin (15.4% vs 25.3%, respectively) .…”

Section: Resultsmentioning

confidence: 96%

Micrococcin P2 Targets Clostridioides difficile

Son

Kim

et al. 2022

J. Nat. Prod.

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Clostridioides dif ficile infection is a global public health threat. Extensive in vitro assays using clinical isolates have identified micrococcin P2 (MP2, 1) as a particularly effective anti-C. diff icile agent. MP2 possesses a mode of action that differs from other antibiotics and pharmacokinetic properties that render it especially promising. Its time−kill studies have been investigated using hypervirulent C. dif f icile ribotype 027. DSS (dextran sulfate sodium)-induced in vivo mouse studies with that strain indicate that 1 is better than vancomycin and fidaxomicin. Thus, micrococcin P2 is a valuable platform to be exploited for the development of new anti-C. dif f icile antibiotics.Clostridioides dif f icile is a Gram-positive, spore-forming, toxinproducing, anaerobic bacteria that is becoming a serious health threat. 1 The organism causes severe diarrhea with lifethreatening complications, 2 such as toxic megacolon, pseudomembranous colitis, and systemic inflammatory response syndrome. 3 The prevalence of the hypervirulent strain of C. diff icile PCR ribotype 027 4 adds additional clinical concerns due to its severe disease presentation. C. dif ficile is thus designated as an urgent threat by the U.S. Centers for Disease Control and Prevention (CDC). 5 In the U.S. alone, more than 220 000 cases of C. diff icile infection (CDI), with 12 800 deaths, were reported in 2019. In South Korea, the estimated CDI rate is as high as in the U.S., but the lack of national-level support for antimicrobial stewardship undermines public awareness. 6 Currently, only two antibiotics, vancomycin and fidaxomicin, are approved by the FDA for the treatment of CDI. 7 However, vancomycin suffers from high rates of relapse (25% to 30%), 8 and its broad antibiotic spectrum against Gram-positive bacteria leads to an undesirable reduction in microbiome diversity. 9 Fidaxomicin has lower recurrence rates because of its better selectivity toward C. dif f icile, but its high price limits its usage. On the other hand, vancomycin is an antibiotic of last resort against a number of deadly human pathogens, and its use must be limited in order to prevent the development of resistance. 10 In the latter respect, the emergence of bacteria that are resistant to all currently available antibiotics is a health threat of great concern. 11 It is estimated that antimicrobial resistance (AMR) will cause 700 000 deaths per year by 2050, if no immediate action is taken. 12 The financial burden of such illnesses is anticipated to be significant. Clearly, the development of new antibiotics is an urgent need. 13

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“…As shown in toxin A-mediated enteritis model (Supplementary Figure 3A and B), direct cytoprotective and anti-inflammatory effects of CSA13 against toxin A is limited. Inflammasome (Pycard/ASC) and NF-κB inhibition is linked to prevention of cell death and tissue damages in response to C. difficile toxins 10, 24–26 . The involvement of NF-κB and inflammasome in the CSA13-mediated cytoprotective and anti-inflammatory effect is unknown and beyond the scope of this investigation.…”

Section: Discussionmentioning

confidence: 99%

Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites

Wang

Ghali

et al. 2018

Gastroenterology

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

Cited by 12 publications

References 48 publications

RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

RETRACTED ARTICLE: Clostridium difficile toxin B induces colonic inflammation through the TRIM46/DUSP1/MAPKs and NF-κB signalling pathway

Micrococcin P2 Targets Clostridioides difficile

Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites

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