Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB

ABSTRACT Clostridium difficile infection (CDI) is a major cause of hospital-associated, antibiotic-induced diarrhea, which is largely mediated by the production of two large multidomain clostridial toxins, TcdA and TcdB. Both toxins coordinate the action of specific domains to bind receptors, enter...

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Autores principales:	Jason L. Larabee, Sarah J. Bland, Jonathan J. Hunt, Jimmy D. Ballard
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Clostridium difficile TcdB exotoxins peptides Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/60cd3efb34cd49579b838667ca9e17c7
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spelling	oai:doaj.org-article:60cd3efb34cd49579b838667ca9e17c72021-11-15T15:51:29ZIntrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB10.1128/mBio.00503-172150-7511https://doaj.org/article/60cd3efb34cd49579b838667ca9e17c72017-07-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.00503-17https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile infection (CDI) is a major cause of hospital-associated, antibiotic-induced diarrhea, which is largely mediated by the production of two large multidomain clostridial toxins, TcdA and TcdB. Both toxins coordinate the action of specific domains to bind receptors, enter cells, and deliver a catalytic fragment into the cytosol. This results in GTPase inactivation, actin disassembly, and cytotoxicity. TcdB in particular has been shown to encode a region covering amino acids 1753 to 1851 that affects epitope exposure and cytotoxicity. Surprisingly, studies here show that several peptides derived from this region, which share the consensus sequence 1769NVFKGNTISDK1779, protect cells from the action of TcdB. One peptide, PepB2, forms multiple interactions with the carboxy-terminal region of TcdB, destabilizes TcdB structure, and disrupts cell binding. We further show that these effects require PepB2 to form a higher-order polymeric complex, a process that requires the central GN amino acid pair. These data suggest that TcdB1769–1779 interacts with repeat sequences in the proximal carboxy-terminal domain of TcdB (i.e., the CROP domain) to alter the conformation of TcdB. Furthermore, these studies provide insights into TcdB structure and functions that can be exploited to inactivate this critical virulence factor and ameliorate the course of CDI. IMPORTANCE Clostridium difficile is a leading cause of hospital-associated illness that is often associated with antibiotic treatment. To cause disease, C. difficile secretes toxins, including TcdB, which is a multidomain intracellular bacterial toxin that undergoes conformational changes during cellular intoxication. This study describes the development of peptide-based inhibitors that target a region of TcdB thought to be critical for structural integrity of the toxin. The results show that peptides derived from a structurally important region of TcdB can be used to destabilize the toxin and prevent cellular intoxication. Importantly, this work provides a novel means of toxin inhibition that could in the future develop into a C. difficile treatment.Jason L. LarabeeSarah J. BlandJonathan J. HuntJimmy D. BallardAmerican Society for MicrobiologyarticleClostridium difficileTcdBexotoxinspeptidesMicrobiologyQR1-502ENmBio, Vol 8, Iss 3 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Clostridium difficile TcdB exotoxins peptides Microbiology QR1-502
spellingShingle	Clostridium difficile TcdB exotoxins peptides Microbiology QR1-502 Jason L. Larabee Sarah J. Bland Jonathan J. Hunt Jimmy D. Ballard Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
description	ABSTRACT Clostridium difficile infection (CDI) is a major cause of hospital-associated, antibiotic-induced diarrhea, which is largely mediated by the production of two large multidomain clostridial toxins, TcdA and TcdB. Both toxins coordinate the action of specific domains to bind receptors, enter cells, and deliver a catalytic fragment into the cytosol. This results in GTPase inactivation, actin disassembly, and cytotoxicity. TcdB in particular has been shown to encode a region covering amino acids 1753 to 1851 that affects epitope exposure and cytotoxicity. Surprisingly, studies here show that several peptides derived from this region, which share the consensus sequence 1769NVFKGNTISDK1779, protect cells from the action of TcdB. One peptide, PepB2, forms multiple interactions with the carboxy-terminal region of TcdB, destabilizes TcdB structure, and disrupts cell binding. We further show that these effects require PepB2 to form a higher-order polymeric complex, a process that requires the central GN amino acid pair. These data suggest that TcdB1769–1779 interacts with repeat sequences in the proximal carboxy-terminal domain of TcdB (i.e., the CROP domain) to alter the conformation of TcdB. Furthermore, these studies provide insights into TcdB structure and functions that can be exploited to inactivate this critical virulence factor and ameliorate the course of CDI. IMPORTANCE Clostridium difficile is a leading cause of hospital-associated illness that is often associated with antibiotic treatment. To cause disease, C. difficile secretes toxins, including TcdB, which is a multidomain intracellular bacterial toxin that undergoes conformational changes during cellular intoxication. This study describes the development of peptide-based inhibitors that target a region of TcdB thought to be critical for structural integrity of the toxin. The results show that peptides derived from a structurally important region of TcdB can be used to destabilize the toxin and prevent cellular intoxication. Importantly, this work provides a novel means of toxin inhibition that could in the future develop into a C. difficile treatment.
format	article
author	Jason L. Larabee Sarah J. Bland Jonathan J. Hunt Jimmy D. Ballard
author_facet	Jason L. Larabee Sarah J. Bland Jonathan J. Hunt Jimmy D. Ballard
author_sort	Jason L. Larabee
title	Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
title_short	Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
title_full	Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
title_fullStr	Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
title_full_unstemmed	Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB
title_sort	intrinsic toxin-derived peptides destabilize and inactivate <italic toggle="yes">clostridium difficile</italic> tcdb
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/60cd3efb34cd49579b838667ca9e17c7
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Intrinsic Toxin-Derived Peptides Destabilize and Inactivate <italic toggle="yes">Clostridium difficile</italic> TcdB

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