title: Clostridial toxins: sensing a target in a hostile gut environment.
abstract: The current global outbreak of Clostridium difficile infection exemplifies the major public health threat posed by clostridial glucosylating toxins. In the western world, C. difficile infection is one of the most prolific causes of bacterial-induced diarrhea and potentially fatal colitis. Two pathogenic enterotoxins, TcdA and TcdB, cause the disease. Vancomycin and metronidazole remain readily available treatment options for C. difficile infection, but neither is fully effective as is evident by high clinical relapse and fatality rates. Thus, there is an urgent need to find an alternative therapy that preferentially targets the toxins and not the drug-resistant pathogen. Recently, we addressed these critical issues in a Nature Medicine letter, describing a novel host defense mechanism for subverting toxin virulence that we translated into prototypic allosteric therapy for C. difficile infection. In this addendum article, we provide a continued perspective of this antitoxin mechanism and consider the broader implications of therapeutic allostery in combating gut microbial pathogenesis.
authors.affiliation: Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Numan
authors.initials: N
authors.lastname: Oezguen
authors.forename: Trevor D
authors.initials: TD
authors.lastname: Power
authors.forename: Petri
authors.initials: P
authors.lastname: Urvil
authors.forename: Hanping
authors.initials: H
authors.lastname: Feng
authors.forename: Charalabos
authors.initials: C
authors.lastname: Pothoulakis
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Stamler
authors.forename: Werner
authors.initials: W
authors.lastname: Braun
authors.forename: Tor C
authors.initials: TC
authors.lastname: Savidge
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000992:Antitoxins / Q000627:therapeutic use*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001427:Bacterial Toxins / Q000037:antagonists & inhibitors*; D016360:Clostridioides difficile / Q000472:pathogenicity*; D003015:Clostridium Infections / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D003092:Colitis / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D003967:Diarrhea / Q000188:drug therapy / Q000453:epidemiology / Q000382:microbiology; D004768:Enterotoxins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D041981:Gastrointestinal Tract / Q000382:microbiology*; D006801:Humans; D008795:Metronidazole / Q000627:therapeutic use; D014640:Vancomycin / Q000627:therapeutic use; D037521:Virulence Factors / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000992:Antitoxins; D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; D037521:Virulence Factors; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile; D008795:Metronidazole; D014640:Vancomycin