title: Toxin synthesis by Clostridium difficile is regulated through quorum signaling.
abstract: Clostridium difficile infection (CDI) is dramatically increasing as a cause of antibiotic- and hospital-associated diarrhea worldwide. C. difficile, a multidrug-resistant pathogen, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. Consequently, it produces toxins A and B that directly cause disease. Despite the enormous public health problem posed by this pathogen, the molecular mechanisms that regulate production of the toxins, which are directly responsible for disease, remained largely unknown until now. Here, we show that C. difficile toxin synthesis is regulated by an accessory gene regulator quorum-signaling system, which is mediated through a small (<1,000-Da) thiolactone that can be detected directly in stools of CDI patients. These findings provide direct evidence of the mechanism of regulation of C. difficile toxin synthesis and offer exciting new avenues both for rapid detection of C. difficile infection and development of quorum-signaling-based non-antibiotic therapies to combat this life-threatening emerging pathogen.
  
  
  OBJECTIVE
  Clostridium difficile infection (CDI) is the most common definable cause of hospital-acquired and antibiotic-associated diarrhea in the United States, with the total cost of treatment estimated between 1 and 4.8 billion U.S. dollars annually. C. difficile, a Gram-positive, spore-forming anaerobe, flourishes in the colon after the gut microbiota has been altered by antibiotic therapy. As a result, there is an urgent need for non-antibiotic CDI treatments that preserve the colonic microbiota. C. difficile produces toxins A and B, which are directly responsible for disease. Here, we report that C. difficile regulates its toxin synthesis by quorum signaling, in which a novel signaling peptide activates transcription of the disease-causing toxin genes. This finding provides new therapeutic targets to be harnessed for novel nonantibiotic therapy for C. difficile infections.
authors.affiliation: The University of Texas Health Science Center, School of Public Health, Division of Epidemiology, Human Genetics, and Environmental Sciences, Center For Infectious Diseases, Houston, Texas, USA Charles.darkoh@uth.tmc.edu.
authors.forename: Charles
authors.identifier: http://orcid.org/0000-0003-0063-7856
authors.initials: C
authors.lastname: Darkoh
authors.forename: Herbert L
authors.initials: HL
authors.lastname: DuPont
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Norris
authors.affiliation: The University of Texas Medical School, Department of Microbiology and Molecular Genetics, Houston, Texas, USA.
authors.forename: Heidi B
authors.initials: HB
authors.lastname: Kaplan
mesh_terms: D001426:Bacterial Proteins / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism*; D016360:Clostridioides difficile / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004768:Enterotoxins / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial; D053038:Quorum Sensing; D015398:Signal Transduction
chemical_list: D001426:Bacterial Proteins; D001427:Bacterial Toxins; D004768:Enterotoxins; C041348:tcdA protein, Clostridium difficile; C031815:toxB protein, Clostridium difficile