The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile
Novel therapeutics are needed to treat pathologies associated with the binary toxin (CDT), particularly when infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the l...
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| Veröffentlicht in: | International journal of molecular sciences 2021-03, Vol.22 (6), p.2926 |
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| creator | Abeyawardhane, Dinendra L Godoy-Ruiz, Raquel Adipietro, Kaylin A Varney, Kristen M Rustandi, Richard R Pozharski, Edwin Weber, David J |
| description | Novel therapeutics are needed to treat pathologies associated with the
binary toxin (CDT), particularly when
infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI. |
| doi_str_mv | 10.3390/ijms22062926 |
| format | Article |
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binary toxin (CDT), particularly when
infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.</description><identifier>ISSN: 1422-0067</identifier><identifier>ISSN: 1661-6596</identifier><identifier>EISSN: 1422-0067</identifier><identifier>DOI: 10.3390/ijms22062926</identifier><identifier>PMID: 33805767</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Actin ; Actin Cytoskeleton - drug effects ; Actin Cytoskeleton - metabolism ; Actin Cytoskeleton - ultrastructure ; Actins - deficiency ; Actins - genetics ; ADP-ribosylation ; ADP-Ribosylation - drug effects ; Amino acids ; Anti-Bacterial Agents - therapeutic use ; Antibiotics ; Bacterial Proteins - antagonists & inhibitors ; Bacterial Proteins - chemistry ; Bacterial Proteins - genetics ; Bacterial Proteins - metabolism ; Bacterial Toxins - antagonists & inhibitors ; Bacterial Toxins - chemistry ; Bacterial Toxins - genetics ; Bacterial Toxins - metabolism ; binary toxin ; Binding Sites ; CDT ; CDTa ; Cell death ; Clostridioides difficile ; Clostridioides difficile - drug effects ; Clostridioides difficile - genetics ; Clostridioides difficile - metabolism ; Clostridioides difficile - pathogenicity ; Cross Infection - drug therapy ; Cross Infection - metabolism ; Cross Infection - microbiology ; Cross Infection - pathology ; Cytoplasm ; Cytoskeleton ; Drug resistance ; Endocytosis ; Endocytosis - drug effects ; Enterocolitis, Pseudomembranous - drug therapy ; Enterocolitis, Pseudomembranous - metabolism ; Enterocolitis, Pseudomembranous - microbiology ; Enterocolitis, Pseudomembranous - pathology ; Enterotoxins - antagonists & inhibitors ; Enterotoxins - chemistry ; Enterotoxins - genetics ; Enterotoxins - metabolism ; Enzymes ; Epidemiology ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epithelial Cells - microbiology ; Epithelial Cells - ultrastructure ; Genes ; Hospitals ; Humans ; infectious disease ; Inflammatory bowel disease ; Models, Molecular ; Protein Binding ; Protein Domains ; Protein Interaction Domains and Motifs ; protein structural biology ; Protein Structure, Secondary ; Review ; Ribosylation ; Structure-function relationships ; Toxicity ; Toxin A ; Toxins</subject><ispartof>International journal of molecular sciences, 2021-03, Vol.22 (6), p.2926</ispartof><rights>2021. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c478t-cdd33054a590bebdfb99bce32d6e03b162318950d8873d1b8f3c644dccc58b113</citedby><cites>FETCH-LOGICAL-c478t-cdd33054a590bebdfb99bce32d6e03b162318950d8873d1b8f3c644dccc58b113</cites><orcidid>0000-0002-8824-1110 ; 0000-0001-7012-5376</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001090/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001090/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33805767$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Abeyawardhane, Dinendra L</creatorcontrib><creatorcontrib>Godoy-Ruiz, Raquel</creatorcontrib><creatorcontrib>Adipietro, Kaylin A</creatorcontrib><creatorcontrib>Varney, Kristen M</creatorcontrib><creatorcontrib>Rustandi, Richard R</creatorcontrib><creatorcontrib>Pozharski, Edwin</creatorcontrib><creatorcontrib>Weber, David J</creatorcontrib><title>The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile</title><title>International journal of molecular sciences</title><addtitle>Int J Mol Sci</addtitle><description>Novel therapeutics are needed to treat pathologies associated with the
binary toxin (CDT), particularly when
infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. 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| source | MDPI - Multidisciplinary Digital Publishing Institute; MEDLINE; PubMed Central; EZB Electronic Journals Library |
| subjects | Actin Actin Cytoskeleton - drug effects Actin Cytoskeleton - metabolism Actin Cytoskeleton - ultrastructure Actins - deficiency Actins - genetics ADP-ribosylation ADP-Ribosylation - drug effects Amino acids Anti-Bacterial Agents - therapeutic use Antibiotics Bacterial Proteins - antagonists & inhibitors Bacterial Proteins - chemistry Bacterial Proteins - genetics Bacterial Proteins - metabolism Bacterial Toxins - antagonists & inhibitors Bacterial Toxins - chemistry Bacterial Toxins - genetics Bacterial Toxins - metabolism binary toxin Binding Sites CDT CDTa Cell death Clostridioides difficile Clostridioides difficile - drug effects Clostridioides difficile - genetics Clostridioides difficile - metabolism Clostridioides difficile - pathogenicity Cross Infection - drug therapy Cross Infection - metabolism Cross Infection - microbiology Cross Infection - pathology Cytoplasm Cytoskeleton Drug resistance Endocytosis Endocytosis - drug effects Enterocolitis, Pseudomembranous - drug therapy Enterocolitis, Pseudomembranous - metabolism Enterocolitis, Pseudomembranous - microbiology Enterocolitis, Pseudomembranous - pathology Enterotoxins - antagonists & inhibitors Enterotoxins - chemistry Enterotoxins - genetics Enterotoxins - metabolism Enzymes Epidemiology Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial Cells - microbiology Epithelial Cells - ultrastructure Genes Hospitals Humans infectious disease Inflammatory bowel disease Models, Molecular Protein Binding Protein Domains Protein Interaction Domains and Motifs protein structural biology Protein Structure, Secondary Review Ribosylation Structure-function relationships Toxicity Toxin A Toxins |
| title | The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile |
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