Using a Novel Lysin To Help Control Clostridium difficile Infections.

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.

• Authors: Qiong Wang, Chad W Euler, Aurelia Delaune, Vincent A Fischetti
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 59 Issue 12 Pg. 7447-57 (Dec 2015) ISSN: 1098-6596 [Electronic] United States
• PMID: 26392484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Anti-Bacterial Agents
• Recombinant Proteins
• Viral Proteins
• Vancomycin
• Endopeptidases
• endolysin
• Amidohydrolases

Topics

• Amidohydrolases (genetics, pharmacology)
• Amino Acid Sequence
• Animals
• Anti-Bacterial Agents (pharmacology, therapeutic use)
• Catalytic Domain
• Clostridioides difficile (drug effects, genetics)
• Colon (drug effects, microbiology)
• Drug Resistance, Multiple, Bacterial (genetics)
• Endopeptidases (genetics, pharmacology)
• Enterocolitis, Pseudomembranous (drug therapy)
• Female
• Hydrogen-Ion Concentration
• Mice, Inbred C57BL
• Molecular Sequence Data
• Prophages (genetics)
• Recombinant Proteins (genetics, pharmacology, therapeutic use)
• Vancomycin (pharmacology)
• Viral Proteins (genetics, pharmacology, therapeutic use)