Article ; Online: Using a Novel Lysin To Help Control Clostridium difficile Infections.
Antimicrobial agents and chemotherapy
2015 Volume 59, Issue 12, Page(s) 7447–7457
Abstract: As a consequence of excessive antibiotic therapies in hospitalized patients, Clostridium difficile, a Gram-positive anaerobic spore-forming intestinal pathogen, is the leading cause of hospital-acquired diarrhea and colitis. Drug treatments for these ... ...
Abstract | As a consequence of excessive antibiotic therapies in hospitalized patients, Clostridium difficile, a Gram-positive anaerobic spore-forming intestinal pathogen, is the leading cause of hospital-acquired diarrhea and colitis. Drug treatments for these diseases are often complicated by antibiotic-resistant strains and a high frequency of treatment failures and relapse; therefore, novel nonantibiotic approaches may prove to be more effective. In this study, we recombinantly expressed a prophage lysin identified from a C. difficile strain, CD630, which we named PlyCD. PlyCD was found to have lytic activity against specific C. difficile strains. However, the recombinantly expressed catalytic domain of this protein, PlyCD1-174, displayed significantly greater lytic activity (>4-log kill) and a broader lytic spectrum against C. difficile strains while still retaining a high degree of specificity toward C. difficile versus commensal clostridia and other bacterial species. Our data also indicated that noneffective doses of vancomycin and PlyCD1-174 when combined in vitro could be significantly more bactericidal against C. difficile. In an ex vivo treatment model of mouse colon infection, we found that PlyCD1-174 functioned in the presence of intestinal contents, significantly decreasing colonizing C. difficile compared to controls. Together, these data suggest that PlyCD1-174 has potential as a novel therapeutic for clinical application against C. difficile infection, either alone or in combination with other preexisting treatments to improve their efficacy. |
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MeSH term(s) | Amidohydrolases/genetics ; Amidohydrolases/pharmacology ; Amino Acid Sequence ; Animals ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Catalytic Domain ; Clostridium difficile/drug effects ; Clostridium difficile/genetics ; Colon/drug effects ; Colon/microbiology ; Drug Resistance, Multiple, Bacterial/genetics ; Endopeptidases/genetics ; Endopeptidases/pharmacology ; Enterocolitis, Pseudomembranous/drug therapy ; Female ; Hydrogen-Ion Concentration ; Mice, Inbred C57BL ; Molecular Sequence Data ; Prophages/genetics ; Recombinant Proteins/genetics ; Recombinant Proteins/pharmacology ; Recombinant Proteins/therapeutic use ; Vancomycin/pharmacology ; Viral Proteins/genetics ; Viral Proteins/pharmacology ; Viral Proteins/therapeutic use |
Chemical Substances | Anti-Bacterial Agents ; Recombinant Proteins ; Viral Proteins ; Vancomycin (6Q205EH1VU) ; Endopeptidases (EC 3.4.-) ; endolysin (EC 3.4.99.-) ; Amidohydrolases (EC 3.5.-) |
Language | English |
Publishing date | 2015-12 |
Publishing country | United States |
Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't |
ZDB-ID | 217602-6 |
ISSN | 1098-6596 ; 0066-4804 |
ISSN (online) | 1098-6596 |
ISSN | 0066-4804 |
DOI | 10.1128/AAC.01357-15 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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