Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> 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 prod...

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Autores principales:	Charles Darkoh, Herbert L. DuPont, Steven J. Norris, Heidi B. Kaplan
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/263772918a024d19ae13b70b76a1d3b4
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spelling	oai:doaj.org-article:263772918a024d19ae13b70b76a1d3b42021-11-15T15:41:34ZToxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling10.1128/mBio.02569-142150-7511https://doaj.org/article/263772918a024d19ae13b70b76a1d3b42015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02569-14https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.Charles DarkohHerbert L. DuPontSteven J. NorrisHeidi B. KaplanAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Charles Darkoh Herbert L. DuPont Steven J. Norris Heidi B. Kaplan Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
description	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. IMPORTANCE 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.
format	article
author	Charles Darkoh Herbert L. DuPont Steven J. Norris Heidi B. Kaplan
author_facet	Charles Darkoh Herbert L. DuPont Steven J. Norris Heidi B. Kaplan
author_sort	Charles Darkoh
title	Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
title_short	Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
title_full	Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
title_fullStr	Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
title_full_unstemmed	Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling
title_sort	toxin synthesis by <named-content content-type="genus-species">clostridium difficile</named-content> is regulated through quorum signaling
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/263772918a024d19ae13b70b76a1d3b4
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Toxin Synthesis by <named-content content-type="genus-species">Clostridium difficile</named-content> Is Regulated through Quorum Signaling

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