A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity

ABSTRACT Clostridium difficile is a leading cause of nosocomial infections worldwide and has become an urgent public health threat requiring immediate attention. Epidemic lineages of the BI/NAP1/027 strain type have emerged and spread through health care systems across the globe over the past decade...

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Autores principales:	Dana Gebhart, Stephen Lok, Simon Clare, Myreen Tomas, Mark Stares, Dean Scholl, Curtis J. Donskey, Trevor D. Lawley, Gregory R. Govoni
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/56d6053b8e4743aea292009135fb17f2
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spelling	oai:doaj.org-article:56d6053b8e4743aea292009135fb17f22021-11-15T15:41:34ZA Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity10.1128/mBio.02368-142150-7511https://doaj.org/article/56d6053b8e4743aea292009135fb17f22015-05-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02368-14https://doaj.org/toc/2150-7511ABSTRACT Clostridium difficile is a leading cause of nosocomial infections worldwide and has become an urgent public health threat requiring immediate attention. Epidemic lineages of the BI/NAP1/027 strain type have emerged and spread through health care systems across the globe over the past decade. Limiting person-to-person transmission and eradicating C. difficile, especially the BI/NAP1/027 strain type, from health care facilities are difficult due to the abundant shedding of spores that are impervious to most interventions. Effective prophylaxis for C. difficile infection (CDI) is lacking. We have genetically modified a contractile R-type bacteriocin (“diffocin”) from C. difficile strain CD4 to kill BI/NAP1/027-type strains for this purpose. The natural receptor binding protein (RBP) responsible for diffocin targeting was replaced with a newly discovered RBP identified within a prophage of a BI/NAP1/027-type target strain by genome mining. The resulting modified diffocins (a.k.a. Avidocin-CDs), Av-CD291.1 and Av-CD291.2, were stable and killed all 16 tested BI/NAP1/027-type strains. Av-CD291.2 administered in drinking water survived passage through the mouse gastrointestinal (GI) tract, did not detectably alter the mouse gut microbiota or disrupt natural colonization resistance to C. difficile or the vancomycin-resistant Enterococcus faecium (VREF), and prevented antibiotic-induced colonization of mice inoculated with BI/NAP1/027-type spores. Given the high incidence and virulence of the pathogen, preventing colonization by BI/NAP1/027-type strains and limiting their transmission could significantly reduce the occurrence of the most severe CDIs. This modified diffocin represents a prototype of an Avidocin-CD platform capable of producing targetable, precision anti-C. difficile agents that can prevent and potentially treat CDIs without disrupting protective indigenous microbiota. IMPORTANCE Treatment and prevention strategies for bacterial diseases rely heavily on traditional antibiotics, which impose strong selection for resistance and disrupt protective microbiota. One consequence has been an upsurge of opportunistic pathogens, such as Clostridium difficile, that exploit antibiotic-induced disruptions in gut microbiota to proliferate and cause life-threatening diseases. We have developed alternative agents that utilize contractile bactericidal protein complexes (R-type bacteriocins) to kill specific C. difficile pathogens. Efficacy in a preclinical animal study indicates these molecules warrant further development as potential prophylactic agents to prevent C. difficile infections in humans. Since these agents do not detectably alter the indigenous gut microbiota or colonization resistance in mice, we believe they will be safe to administer as a prophylactic to block transmission in high-risk environments without rendering patients susceptible to enteric infection after cessation of treatment.Dana GebhartStephen LokSimon ClareMyreen TomasMark StaresDean SchollCurtis J. DonskeyTrevor D. LawleyGregory R. GovoniAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 2 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Dana Gebhart Stephen Lok Simon Clare Myreen Tomas Mark Stares Dean Scholl Curtis J. Donskey Trevor D. Lawley Gregory R. Govoni A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
description	ABSTRACT Clostridium difficile is a leading cause of nosocomial infections worldwide and has become an urgent public health threat requiring immediate attention. Epidemic lineages of the BI/NAP1/027 strain type have emerged and spread through health care systems across the globe over the past decade. Limiting person-to-person transmission and eradicating C. difficile, especially the BI/NAP1/027 strain type, from health care facilities are difficult due to the abundant shedding of spores that are impervious to most interventions. Effective prophylaxis for C. difficile infection (CDI) is lacking. We have genetically modified a contractile R-type bacteriocin (“diffocin”) from C. difficile strain CD4 to kill BI/NAP1/027-type strains for this purpose. The natural receptor binding protein (RBP) responsible for diffocin targeting was replaced with a newly discovered RBP identified within a prophage of a BI/NAP1/027-type target strain by genome mining. The resulting modified diffocins (a.k.a. Avidocin-CDs), Av-CD291.1 and Av-CD291.2, were stable and killed all 16 tested BI/NAP1/027-type strains. Av-CD291.2 administered in drinking water survived passage through the mouse gastrointestinal (GI) tract, did not detectably alter the mouse gut microbiota or disrupt natural colonization resistance to C. difficile or the vancomycin-resistant Enterococcus faecium (VREF), and prevented antibiotic-induced colonization of mice inoculated with BI/NAP1/027-type spores. Given the high incidence and virulence of the pathogen, preventing colonization by BI/NAP1/027-type strains and limiting their transmission could significantly reduce the occurrence of the most severe CDIs. This modified diffocin represents a prototype of an Avidocin-CD platform capable of producing targetable, precision anti-C. difficile agents that can prevent and potentially treat CDIs without disrupting protective indigenous microbiota. IMPORTANCE Treatment and prevention strategies for bacterial diseases rely heavily on traditional antibiotics, which impose strong selection for resistance and disrupt protective microbiota. One consequence has been an upsurge of opportunistic pathogens, such as Clostridium difficile, that exploit antibiotic-induced disruptions in gut microbiota to proliferate and cause life-threatening diseases. We have developed alternative agents that utilize contractile bactericidal protein complexes (R-type bacteriocins) to kill specific C. difficile pathogens. Efficacy in a preclinical animal study indicates these molecules warrant further development as potential prophylactic agents to prevent C. difficile infections in humans. Since these agents do not detectably alter the indigenous gut microbiota or colonization resistance in mice, we believe they will be safe to administer as a prophylactic to block transmission in high-risk environments without rendering patients susceptible to enteric infection after cessation of treatment.
format	article
author	Dana Gebhart Stephen Lok Simon Clare Myreen Tomas Mark Stares Dean Scholl Curtis J. Donskey Trevor D. Lawley Gregory R. Govoni
author_facet	Dana Gebhart Stephen Lok Simon Clare Myreen Tomas Mark Stares Dean Scholl Curtis J. Donskey Trevor D. Lawley Gregory R. Govoni
author_sort	Dana Gebhart
title	A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
title_short	A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
title_full	A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
title_fullStr	A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
title_full_unstemmed	A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity
title_sort	modified r-type bacteriocin specifically targeting <named-content content-type="genus-species">clostridium difficile</named-content> prevents colonization of mice without affecting gut microbiota diversity
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/56d6053b8e4743aea292009135fb17f2
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A Modified R-Type Bacteriocin Specifically Targeting <named-content content-type="genus-species">Clostridium difficile</named-content> Prevents Colonization of Mice without Affecting Gut Microbiota Diversity

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