title: Intravitreal injection of the chimeric phage endolysin Ply187 protects mice from Staphylococcus aureus endophthalmitis.
abstract: The treatment of endophthalmitis is becoming very challenging due to the emergence of multidrug-resistant bacteria. Hence, the development of novel therapeutic alternatives for ocular use is essential. Here, we evaluated the therapeutic potential of Ply187AN-KSH3b, a chimeric phage endolysin derived from the Ply187 prophage, in a mouse model of Staphylococcus aureus endophthalmitis. Our data showed that the chimeric Ply187 endolysin exhibited strong antimicrobial activity against both methicillin-sensitive S. aureus and methicillin-resistant S. aureus (MRSA) strains, as evidenced by MIC determinations, reductions in turbidity, and disruption of biofilms. Moreover, exposure of S. aureus to Ply187 for up to 10 generations did not lead to resistance development. The intravitreal injection of chimeric Ply187 (at 6 or 12 h postinfection) significantly improved the outcome of endophthalmitis, preserved retinal structural integrity, and maintained visual function as assessed by electroretinogram analysis. Furthermore, phage lysin treatment significantly reduced the bacterial burden and the levels of inflammatory cytokines and neutrophil infiltration in the eyes. These results indicate that the intravitreal administration of a phage lytic enzyme attenuates the development of bacterial endophthalmitis in mice. To the best of our knowledge, this is the first study demonstrating the therapeutic use of phage-based antimicrobials in ocular infections.
authors.affiliation: Department of Ophthalmology and Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA.
authors.forename: Pawan Kumar
authors.initials: PK
authors.lastname: Singh
authors.affiliation: BARC, Agricultural Research Service, U.S. Department of Agriculture, Beltsville, Maryland, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Donovan
authors.affiliation: Department of Ophthalmology and Kresge Eye Institute, Wayne State University, Detroit, Michigan, USA Department of Anatomy and Cell Biology, Wayne State University, Detroit, Michigan, USA akuma@med.wayne.edu.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000818:Animals; D018441:Biofilms / Q000187:drug effects* / Q000254:growth & development; D003090:Coliphages / Q000737:chemistry / Q000201:enzymology; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D004195:Disease Models, Animal; D004596:Electroretinography; D010450:Endopeptidases / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D009877:Endophthalmitis / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D058449:Intravitreal Injections; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology / Q000473:pathology; D016896:Treatment Outcome; D014822:Vitreous Body / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology
chemical_list: D016207:Cytokines; D011994:Recombinant Proteins; D010450:Endopeptidases; C001143:endolysin