title: 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.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA Department of Medical Laboratory Sciences, Hunter College, CUNY, New York, New York, USA Department of Microbiology and Immunology, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Chad W
authors.initials: CW
authors.lastname: Euler
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA.
authors.forename: Aurelia
authors.initials: A
authors.lastname: Delaune
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, New York, USA vaf@rockefeller.edu.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Fischetti
mesh_terms: D000581:Amidohydrolases / Q000235:genetics / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use; D020134:Catalytic Domain; D016360:Clostridioides difficile / Q000187:drug effects* / Q000235:genetics; D003106:Colon / Q000187:drug effects / Q000382:microbiology; D024901:Drug Resistance, Multiple, Bacterial / Q000235:genetics; D010450:Endopeptidases / Q000235:genetics / Q000494:pharmacology*; D004761:Enterocolitis, Pseudomembranous / Q000188:drug therapy; D005260:Female; D006863:Hydrogen-Ion Concentration; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D039002:Prophages / Q000235:genetics*; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D014640:Vancomycin / Q000494:pharmacology; D014764:Viral Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000900:Anti-Bacterial Agents; D011994:Recombinant Proteins; D014764:Viral Proteins; D014640:Vancomycin; D010450:Endopeptidases; C001143:endolysin; D000581:Amidohydrolases