更新于：2024-11-01

toxB x TcdA

更新于：2024-11-01

基本信息

关联

项与 toxB x TcdA 相关的药物

PF-6425090

靶点

TcdA x toxB

作用机制

TcdA抑制剂 [+1]

在研机构-

原研机构

Pfizer Inc.

在研适应症-

非在研适应症

艰难梭菌结肠炎 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 toxB x TcdA 相关的临床试验

NCT03918629 / Completed临床3期

A PHASE 3, RANDOMIZED OBSERVER-BLINDED STUDY TO EVALUATE THE IMMUNOGENICITY, SAFETY, AND TOLERABILITY OF 2 DOSES COMPARED TO 3 DOSES OF CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER

This study will investigate a Clostridium difficile vaccine in adults 50 years of age and older. In half the adults, all 3 doses given are the Clostridium difficile vaccine, and in half the adults, 2 of the 3 doses are the Clostridium difficile vaccine with the other dose containing no active ingredients. The study will look at the subjects' immune response to the vaccine and assess the safety and tolerability of a 2-dose regimen of Clostridium difficile vaccine compared to a 3-dose regimen of Clostridium difficile vaccine.

开始日期2019-04-01

申办/合作机构

Pfizer Inc.

NCT03579459 / Completed临床3期

A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE LOT CONSISTENCY, SAFETY, TOLERABILITY, AND IMMUNOGENICITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN HEALTHY ADULTS 65 TO 85 YEARS OF AGE

This study will investigate a Clostridium difficile vaccine in healthy adults 65 to 85 years of age, who will each receive 3 doses of vaccine. The study will assess the lot consistency, safety, and tolerability of the vaccine, and also look at the subjects' immune response to the vaccine.

开始日期2018-07-31

申办/合作机构

Pfizer Inc.

NCT03090191 / Completed临床3期

A PHASE 3, PLACEBO-CONTROLLED, RANDOMIZED, OBSERVER-BLINDED STUDY TO EVALUATE THE EFFICACY, SAFETY, AND TOLERABILITY OF A CLOSTRIDIUM DIFFICILE VACCINE IN ADULTS 50 YEARS OF AGE AND OLDER

The Clover trial is evaluating an investigational vaccine that may help to prevent Clostridium difficile infection. Participants in the study are adults 50 years of age and older, who are at risk of developing Clostridium difficile infection. The study will assess whether the vaccine prevents the disease, and whether it is safe and well tolerated.
Each subject will receive 3 doses of Clostridium difficile vaccine or placebo and be followed for up to 3 years after vaccination for potential Clostridium difficile infection.

开始日期2017-03-29

申办/合作机构

Pfizer Inc.

100 项与 toxB x TcdA 相关的临床结果

登录后查看更多信息

100 项与 toxB x TcdA 相关的转化医学

登录后查看更多信息

0 项与 toxB x TcdA 相关的专利（医药）

登录后查看更多信息

项与 toxB x TcdA 相关的文献（医药）

2024-07-01·Veterinary Microbiology

Molecular Characterization and Potential Host-switching of Swine Farm associated Clostridioides difficile ST11

Article

作者: Li, Qingtian ; Huang, Jiewen ; Ni, Peihua ; Guo, Xiaokui ; Dong, Ke ; Li, Tinghua ; Kuo, Chih-Jung ; Zhu, Yongzhang ; Wei, Beiwen

OBJECTIVETo conduct molecular prevalence and genetic polymorphism analysis of 24 Swine Farm associated C. difficile ST11 strains, in addition to other representative sequenced ST strains.METHODSThe collected C. difficile strains underwent whole genome sequencing and bioinformatic analysis using the illumina NovaSeq platform, SPAdes, Prokka, MOB-suite, and FastTree. Virulence and antibiotic resistance genes were identified through NCBI Pathogen Database. Cytotoxicity tests were conducted on HT-29 cells and Vero cells to verify the function of toxin A and toxin B.RESULTSThe most prevalent resistance genes in ST11 were found to be against β-lactamases, aminoglycosides, and tetracycline. A C. difficile isolate (strain 27) with tcdA deletion and high antibiotic resistance genes was far apart from other swine farm associated ST11 isolates in the phylogenetic branch. The remarkable genetic similarity between animal and human C. difficile strains suggests potential transmission of ST11 strains between animals and humans. The plasmid replicon sequences repUS43 were identified in all ST11 strains except one variant (strain 27), and 91.67% (22/24) of these were assessed by MOB-typer as having mobilizable plasmids.CONCLUSIONSwine farm associated C. difficile ST11 carried fewer virulence genes than ST11 strains collected from NCBI database. It is critical to monitor the evolution of C. difficile strains to understand their changing characteristics, host-switching, and develop effective control and prevention strategies.

2022-09-02·Autophagy1区 · 生物学

Vitamin D₃and carbamazepine protect againstClostridioides difficileinfection in mice by restoring macrophage lysosome acidification

1区 · 生物学

Article

作者: Chan, Matthew Tak Vai ; Chan, Hung ; Li, Qing ; Chen, Huarong ; Zeng, Judeng ; Liu, Xiaodong ; Xie, Chuan ; Wang, Xiansong ; Hu, Wei ; Liu, Wing Yingzhi ; Gin, Tony ; Kwong, Thomas Ngai Yeung ; Zhang, Lin ; Chan, Raphael Chiu Yeung ; Cheng, Alfred Sze Lok ; Ho, Idy Hiu Ting ; Ip, Margaret ; Wong, Sunny Hei ; Wu, William Ka Kei ; Ko, Ho ; Yu, Jun

Clostridioides difficile infection (CDI) is a common cause of nosocomial diarrhea. TcdB is a major C. difficile exotoxin that activates macrophages to promote inflammation and epithelial damage. Lysosome impairment is a known trigger for inflammation. Herein, we hypothesize that TcdB could impair macrophage lysosomal function to mediate inflammation during CDI. Effects of TcdB on lysosomal function and the downstream pro-inflammatory SQSTM1/p62-NFKB (nuclear factor kappa B) signaling were assessed in cultured macrophages and in a murine CDI model. Protective effects of two lysosome activators (i.e., vitamin D₃ and carbamazepine) were assessed. Results showed that TcdB inhibited CTNNB1/β-catenin activity to downregulate MITF (melanocyte inducing transcription factor) and its direct target genes encoding components of lysosomal membrane vacuolar-type ATPase, thereby suppressing lysosome acidification in macrophages. The resulting lysosomal dysfunction then impaired autophagic flux and activated SQSTM1-NFKB signaling to drive the expression of IL1B/IL-1β (interleukin 1 beta), IL8 and CXCL2 (chemokine (C-X-C motif) ligand 2). Restoring MITF function by enforced MITF expression or restoring lysosome acidification with 1α,25-dihydroxyvitamin D₃ or carbamazepine suppressed pro-inflammatory cytokine expression in vitro. In mice, gavage with TcdB-hyperproducing C. difficile or injection of TcdB into ligated colon segments caused prominent MITF downregulation in macrophages. Vitamin D₃ and carbamazepine lessened TcdB-induced lysosomal dysfunction, inflammation and histological damage. In conclusion, TcdB inhibits the CTNNB1-MITF axis to suppress lysosome acidification and activates the downstream SQSTM1-NFKB signaling in macrophages during CDI. Vitamin D₃ and carbamazepine protect against CDI by restoring MITF expression and lysosomal function in mice.Abbreviations: ATP6V0B: ATPase H+ transporting V0 subunit b; ATP6V0C: ATPase H+ transporting V0 subunit c; ATP6V0E1: ATPase H+ transporting V0 subunit e1; ATP6V1H: ATPase H+ transporting V1 subunit H; CBZ: carbamazepine; CDI: C. difficile infection; CXCL: chemokine C-X-X motif ligand; IL: interleukin; LAMP1: lysosomal-associated membrane protein 1; LC3: microtubule-associated protein 1 light chain 3; LEF: lymphoid enhancer binding factor 1; MITF: melanocyte inducing transcription factor; NFKB: nuclear factor kappa B; PMA: phorbol 12-myristate 13-acetate; TcdA: Clostridial toxin A; TcdB: Clostridial toxin B; TFE3: transcription factor E3; TFEB: transcription factor EB.

2022-05-01·Journal of Infection and Chemotherapy4区 · 医学

Rare toxin A-negative and toxin B-positive strain of Clostridioides difficile from Japan lacking a complete tcdA gene

4区 · 医学

Article

作者: Sato, Koichi ; Gabata, Toshifumi ; Yutani, Masahiro ; Otani, Hatsumi ; Wada, Taizo ; Wada, Takashi ; Nakamura, Youko ; Matsumura, Takuhiro ; Fujinaga, Yukako ; Maekawa, Akiko ; Satou, Kenji ; Yoneda-Nakagawa, Shiori ; Iwata, Yasunori ; Senda, Yasuko ; Takemori-Sakai, Yukiko ; Ogura, Hisayuki ; Miyagawa, Taro ; Sakai, Yoshio ; Mori, Mika ; Oe, Hiroyasu ; Oshima, Megumi

INTRODUCTIONClostridioides difficile (C. difficile) produces three kinds of toxins: toxin A (enterotoxin), toxin B (cytotoxin), and C. difficile transferase (CDT), a binary toxin. Some strains show positivity only for toxin B. These strains reportedly possess a gene for toxin A, tcdA. However, toxin A production is inhibited due to a mutated stop codon and/or deletion within the tcdA gene. Here for the first case in Japan, we describe toxin genomes and proteins of a strain possessing only toxin B and lacking a complete tcdA gene, along with clinical manifestations.METHODSC. difficile was isolated from the bloody stool of a 60-year-old female patient treated with meropenem. Although a rapid detection kit of toxins (C. DIFF QUIK CHEK COMPLETE®, TechLab, Blacksburg, VA, USA) showed positivity, Western blotting detected no toxins. Therefore, we explored the strain's toxin genes and their sequences to determine whether the strain possessed a toxin.RESULTSPolymerase chain reaction did not identify toxin genes. Whole-genome sequencing analysis showed that a gene for toxin A, tcdA, was completely deleted in the strain. Moreover, 701 mutations and some deletions/insertions were identified on the tcdB gene.CONCLUSIONSWe isolated a rare strain of C. difficile producing only toxin B and lacking a complete tcdA gene herein Japan. The possibility of a false negative needs to be considered with a genetic method for a diagnose of C. difficile infection.