Article
Biochemistry & Molecular Biology
Florian Stieglitz, Ralf Gerhard, Rabea Hoenig, Klaudia Giehl, Andreas Pich
Summary: A Clostridioides difficile infection (CDI) is a common hospital-acquired infection worldwide. The virulence factors TcdA and TcdB inhibit small Rho-GTPases, leading to cytopathic effects, colon epithelium barrier dysfunction, and inflammation. A large-scale phosphoproteomic study revealed the central role of RAS in the glucosyltransferase-independent effect of TcdB, and identified apolipoprotein C-III (APOC3) as a potential crucial factor in CDI-induced inflammation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Sebastian Heber, Lara Barthold, Jan Baier, Panagiotis Papatheodorou, Giorgio Fois, Manfred Frick, Holger Barth, Stephan Fischer
Summary: C. difficile produces toxins TcdA and TcdB, which cause CDAD by targeting small GTPases and disrupting intestinal epithelial barrier. Conventional antibiotics do not target these toxins, therefore directly targeting the exotoxins provides a promising treatment approach. Recent findings show that ambroxol reduces toxin-induced cytotoxicity and glucosylation, and could be considered as a therapeutic option for CDAD.
FRONTIERS IN PHARMACOLOGY
(2022)
Review
Immunology
Kosuke Fujimoto, Satoshi Uematsu
Summary: Clostridioides difficile is a bacterium that can be found in the intestinal tract of healthy individuals, but it can also cause infections, particularly hospital-acquired diarrhea following antibiotic treatment. The emergence of highly virulent strains and resistance to antibiotics have led to treatment failures and relapses. Fecal microbiota transplantation (FMT) is considered effective, although safety concerns exist due to antibiotic-resistant bacterial infections. Therefore, the development of specific treatments for C. difficile is urgently needed.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Biology
Baohua Chen, Sujit Basak, Peng Chen, Changcheng Zhang, Kay Perry, Songhai Tian, Clinton Yu, Min Dong, Lan Huang, Mark E. Bowen, Rongsheng Jin
Summary: This study reports the crystal structure of Clostridioides difficile toxin A (TcdA), revealing its dynamic structure and pH-dependency. The study also identifies a small globular subdomain and the CROPs domain that protect the pore-forming region of TcdA at neutral pH. Furthermore, a rationally designed mutation drastically reduces the cytotoxicity of the toxin.
LIFE SCIENCE ALLIANCE
(2022)
Article
Multidisciplinary Sciences
Akihiro Kawamoto, Tomohito Yamada, Toru Yoshida, Yusui Sato, Takayuki Kato, Hideaki Tsuge
Summary: Some bacteria have a toxin delivery system that transports enzymes into host cells. The bacterium Clostridioides difficile has a clinically important system with CDTa and CDTb proteins as therapeutic targets. The cryo-EM structure of CDTa bound to CDTb-pore was reported, revealing structural changes induced by CDTa binding and the involvement of an NSS-loop in substrate translocation. The dynamic information obtained provides insights for drug design against hypervirulent C. difficile strains.
NATURE COMMUNICATIONS
(2022)
Article
Biochemistry & Molecular Biology
Methinee Pipatthana, Phurt Harnvoravongchai, Pisut Pongchaikul, Somsak Likhitrattanapisal, Matthew Phanchana, Surang Chankhamhaengdecha, Tavan Janvilisri
Summary: This study analyzed the sequence-function relationship of ABC proteins in Clostridioides difficile, revealing different protein domains associated with the ABC system and the gene organization within the genome. The classification and genetic structure of ABC transporters were identified, with a focus on the significant role of these proteins in antibiotic resistance, providing insights into the function and evolutionary relationships of ABC proteins in this pathogen.
COMPUTATIONAL AND STRUCTURAL BIOTECHNOLOGY JOURNAL
(2021)
Article
Multidisciplinary Sciences
Alexander B. Smith, Matthew L. Jenior, Orlaith Keenan, Jessica L. Hart, Jonathan Specker, Arwa Abbas, Paula C. Rangel, Chao Di, Jamal Green, Katelyn A. Bustin, Jennifer A. Gaddy, Maribeth R. Nicholson, Clare Laut, Brendan J. Kelly, Megan L. Matthews, Daniel R. Evans, Daria Van Tyne, Emma E. Furth, Jason A. Papin, Frederic D. Bushman, Jessi Erlichman, Robert N. Baldassano, Michael A. Silverman, Gary M. Dunny, Boone M. Prentice, Eric P. Skaar, Joseph P. Zackular
Summary: Enterococci can shape the metabolic environment in the gut and enhance the fitness and pathogenesis of Clostridioides difficile through nutrient restriction and cross-feeding. This microbial interaction plays a role in the susceptibility to and the severity of C. difficile infection.
Article
Chemistry, Medicinal
Jujun Zhou, John R. Horton, Martina Menna, Francesco Fiorentino, Ren Ren, Dan Yu, Taraneh Hajian, Masoud Vedadi, Giulia Mazzoccanti, Alessia Ciogli, Elmar Weinhold, Michael Hueben, Robert M. Blumenthal, Xing Zhang, Antonello Mai, Dante Rotili, Xiaodong Cheng
Summary: Researchers designed 42 analogs of adenosine to inhibit the C. difficile-specific DNA adenine methyltransferase (CamA), which affects persistence in the colon. Among these inhibitors, compound 39 shows high selectivity for CamA against closely related bacterial and mammalian methyltransferases, protein lysine and arginine methyltransferases, and human adenosine receptors.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Pablo Castro-Cordova, Paola Mora-Uribe, Rodrigo Reyes-Ramirez, Glenda Cofre-Araneda, Josue Orozco-Aguilar, Christian Brito-Silva, Maria Jose Mendoza-Leon, Sarah A. Kuehne, Nigel P. Minton, Marjorie Pizarro-Guajardo, Daniel Paredes-Sabja
Summary: Spores produced by Clostridioides difficile during infection play a crucial role in the disease recurrence. Entry of the spores into the intestinal mucosa via host fibronectin and vitronectin pathways, and inhibition of spore entry can lead to reduced recurrence of infection in a mouse model.
NATURE COMMUNICATIONS
(2021)
Review
Microbiology
Shannon L. Kordus, Audrey K. Thomas, D. Borden Lacy
Summary: Clostridioides difficile produces up to three different toxins, which play a key role in the pathogenesis of colon infection. In this Review, Kordus, Thomas, and Lacy discuss the structure and function of these toxins and how this information guides new therapeutic approaches. Understanding the mechanisms of host-toxin interactions provides a foundation for developing novel strategies for the treatment and prevention of C. difficile infection.
NATURE REVIEWS MICROBIOLOGY
(2022)
Review
Microbiology
Heloise Coullon, Thomas Candela
Summary: The cortex and peptidoglycan of Clostridioides difficile have been relatively understudied, but have gained increased interest in recent years due to their highly modified structures. These modifications may play a role in antimicrobial resistance and are crucial for spore cortex synthesis and germination, which are essential in the pathogenesis of the bacterium. Enzymes responsible for these modifications could be potential new drug targets or anti-C. difficile agents.
CURRENT OPINION IN MICROBIOLOGY
(2022)
Review
Microbiology
Wiep Klaas Smits, Anna Maria Roseboom, Jeroen Corver
Summary: Plasmids are common in the enteropathogen Clostridioides difficile and may encode functions relevant to pathogenesis, such as antimicrobial resistance and toxin production.
CURRENT OPINION IN MICROBIOLOGY
(2022)
Article
Plant Sciences
Young-Jin Son, Young-Rok Kim, Sang-Hun Oh, Sungji Jung, Marco A. Ciufolini, Hee-Jong Hwang, Jin-Hwan Kwak, Hyunjoo Pai
Summary: Clostridioides difficile infection is a global health threat and micrococcin P2 (MP2) has shown promising results as an effective antimicrobial agent against the hypervirulent C. difficile strain through in vitro and in vivo studies.
JOURNAL OF NATURAL PRODUCTS
(2022)
Article
Infectious Diseases
Elena Novakova, Zuzana Stofkova, Vladimira Sadlonova, Lukas Hleba
Summary: This study analyzed the phenotypic and genotypic characteristics of C. difficile isolates from patients with CDI in Slovakia, revealing a high prevalence of RT176 and 001.
Article
Microbiology
Jennifer J. Dawkins, Jessica R. Allegretti, Travis E. Gibson, Emma McClure, Mary Delaney, Lynn Bry, Georg K. Gerber
Summary: This study conducted a longitudinal analysis of the gut microbiome and metabolome changes in patients with primary Clostridioides difficile infection (CDI). The results showed that metabolomic data can accurately predict the recurrence of CDI, providing important insights for the development of diagnostic tests and treatments.
Article
Biochemistry & Molecular Biology
Peng Chen, Liang Tao, Zheng Liu, Min Dong, Rongsheng Jin
Article
Microbiology
Liang Tao, Songhai Tian, Jie Zhang, Zhuoming Liu, Lindsey Robinson-McCarthy, Shin-Ichiro Miyashita, David T. Breault, Ralf Gerhard, Siam Oottamasathien, Sean P. J. Whelan, Min Bong
NATURE MICROBIOLOGY
(2019)
Article
Biology
Enhui Shen, Kangli Zhu, Danyang Li, Zhenrui Pan, Yun Luo, Qiao Bian, Liuqing He, Xiaojun Song, Ying Zhen, Dazhi Jin, Liang Tao
COMMUNICATIONS BIOLOGY
(2020)
Article
Microbiology
Zhenrui Pan, Yuanyuan Zhang, Jianhua Luo, Danyang Li, Yao Zhou, Liuqing He, Qi Yang, Min Dong, Liang Tao
Summary: Clostridioides difficile toxin B (TcdB) has four dominant variants (TcdB1-4) with diverse receptor preferences, interacting with CSPG4 and Frizzled proteins. Through mutagenesis studies, it was found that TcdB interacts with CSPG4 across multiple domains. In a mouse model, the TcdB variants induced distinguishable pathological phenotypes, suggesting different disease progression in C. difficile strains.
Letter
Cell Biology
Yao Zhou, Diyin Li, Jianhua Luo, Aizhong Chen, Xingxing Li, Zhenrui Pan, Li Wan, Liuqing He, Danyang Li, Yanyan Li, Min Dong, Liang Tao
Article
Multidisciplinary Sciences
Peng Chen, Ji Zeng, Zheng Liu, Hatim Thaker, Siyu Wang, Songhai Tian, Jie Zhang, Liang Tao, Craig B. Gutierrez, Li Xing, Ralf Gerhard, Lan Huang, Min Dong, Rongsheng Jin
Summary: Chondroitin sulfate proteoglycan 4 (CSPG4) is identified as a potential receptor for C. difficile toxin B (TcdB) during C. difficile infections (CDIs). The cryo-EM structure of a TcdB-CSPG4 complex and CDI mouse models offer insights into the role of CSPG4 in CDIs and suggest a therapeutic strategy targeting TcdB.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Jianhua Luo, Qi Yang, Xiaofeng Zhang, Yuanyuan Zhang, Li Wan, Xiechao Zhan, Yao Zhou, Liuqing He, Danyang Li, Dazhi Jin, Ying Zhen, Jing Huang, Yanyan Li, Liang Tao
Summary: The study identified tissue factor pathway inhibitor (TFPI) as the receptor for TcdB4, a dominant virulence factor of hypervirulent clade 2 Clostridioides difficile. TFPI is highly expressed in the intestinal glands and protects the colonic epithelium from TcdB2/4. These findings reveal new mechanisms for CDI pathogenesis.
Article
Immunology
Liqian Wang, Danyang Li, Zixi Chen, Liuqing He, Xianjun Wang, Liang Tao
Summary: An unusual case of monomicrobial Clostridioides difficile septicemia was reported in a patient without overt gastrointestinal symptoms. The strain isolated from the blood sample was different from the one in the stool, suggesting a potential invasion through the root canal after a recent tooth extraction. Oral C. difficile colonization may be a risk factor for severe C. difficile septicemia.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Article
Genetics & Heredity
Liuqing He, Xinyu Huang, Guoqing Zhang, Ling Yuan, Enhui Shen, Lu Zhang, Xiao-Hua Zhang, Tong Zhang, Liang Tao, Feng Ju
Summary: This study explored the virulence factors and antibiotic resistance in the microbial community of the Mariana Trench using metagenomic approaches. The results revealed that the bottom sediment harbored prosperous microbiota with specific virulence genes and antibiotic resistance. Furthermore, the study identified horizontal gene transfer as the major mechanism for the evolution of bacteria in the trench sediment.
ENVIRONMENTAL MICROBIOME
(2022)
Article
Multidisciplinary Sciences
Xingxing Li, Liuqing He, Jianhua Luo, Yangling Zheng, Yao Zhou, Danyang Li, Yuanyuan Zhang, Zhenrui Pan, Yanyan Li, Liang Tao
Summary: In this study, the importance of TMPRSS2 and surface fucosylation in the actions of Hemorrhagic toxin (TcsH) produced by Paeniclostridium sordellii was revealed. The authors carried out genome-wide screens and identified cell surface fucosylation and TMPRSS2 as host factors involved in the binding and entry of TcsH. It was found that TMPRSS2 and fucosylated glycans can independently mediate the binding/entry of TcsH, acting as redundant receptors. This study provides insights into the host recognition mechanisms for large clostridial toxins.
NATURE COMMUNICATIONS
(2022)
Article
Biology
Yao Zhou, Danyang Li, Diyin Li, Aizhong Chen, Liuqing He, Jianhua Luo, Liang Tao
Summary: In addition to LDLR, Clostridium novyi alpha-toxin (Tcn alpha) can also use LRP1 and Megalin as cellular entry receptors. The expression levels of LDLR and LRP1 vary in different cells, suggesting that the dominant entry receptor for Tcn alpha may be cell-type dependent.
COMMUNICATIONS BIOLOGY
(2022)
Article
Engineering, Electrical & Electronic
Yue Hui, Yuan Yao, Qilin Qian, Jianhua Luo, Hehao Chen, Zheng Qiao, Yetian Yu, Liang Tao, Nanjia Zhou
Summary: This article introduces a method for manufacturing hydrogel electronics using 3D printing technology. By using a special hydrogel supporting matrix and silver-hydrogel ink, complex 3D circuits can be created within the hydrogel matrix. The resulting hydrogel electronics are soft, stretchable, and exhibit high conductivity.
NATURE ELECTRONICS
(2022)
Article
Biology
Yingnan Hou, Tengyu Xie, Liuqing He, Liang Tao, Jing Huang
Summary: The study revealed the presence of topological links in protein complexes predicted by AlphaFold-Multimer, highlighting the significance for protein structure prediction and the study of protein-protein interactions.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemical Research Methods
Qi Yang, Yao Zhou, Liuqing He, Yuanyuan Zhang, Liang Tao
Summary: The article introduces a protocol for conducting a genome-scale CRISPR screen on HeLa cells to identify host factors involved in the action of Clostridioides difficile TcdB4 toxin. The protocol provides detailed instructions on preparing the library, setting up the screen, obtaining gene sequences, and analyzing the results. This protocol can be adapted for other genome-scale libraries, cell lines, and cytotoxins as well.
