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AN INVESTIGATION ON A BACTERIOPHAGE ENDOLYSIN POSSESSING ANTIMICROBIAL ACTIVITY AGAINST ANTIBIOTIC-RESISTANT STAPHYLOCOCCUS AUREUS

dc.contributor.advisorNelson, Daniel Cen_US
dc.contributor.authorLinden, Sara Bethen_US
dc.date.accessioned2017-01-24T06:31:48Z
dc.date.available2017-01-24T06:31:48Z
dc.date.issued2016en_US
dc.identifierhttps://doi.org/10.13016/M2R83C
dc.identifier.urihttp://hdl.handle.net/1903/18938
dc.description.abstractStaphylococcus aureus is one of the most common causes of nosocomial (i.e. hospital-acquired) infection. Significantly, over 90% of S. aureus strains are resistant to penicillin, and since the mid-1980’s, methicillin-resistant S. aureus (MRSA) strains have become prevalent in hospitals worldwide, with resistance rates approaching 70%. In the U.S. alone, MRSA is responsible for over 100,000 invasive life threatening infections, such as necrotizing fasciitis, and causes 20,000 deaths annually. More worrisome, a variant known as community-acquired MRSA (CA-MRSA) is spreading in schools, gymnasiums, and even professional sports teams, where it infects otherwise healthy adolescents and young adults. Vancomycin is often considered the last antibiotic of choice against MRSA and other Gram-positive pathogens. However, rates of vancomycin-resistant enterococci (VRE) have already reached 30% and it is widely believed that emergence of vancomycin-resistant S. aureus (VRSA) is due to gene transfer during co-colonization of MRSA and VRE. Thus, alternative antimicrobial approaches are desperately needed. Endolysins, or peptidoglycan hydrolases, are phage-derived enzymes that actively lyse bacterial cells upon direct contact and may be considered such an alternative option. Moreover, the inability of bacteria to evolve resistance to endolysins is due to the specificity of the N-terminal catalytic domain, which cleaves a conserved peptidoglycan bond, and the C-terminal cell wall binding domain, which binds a cell surface moiety. This thesis represents an investigation into the endolysin PlyGRCS, which displays potent bacteriolytic activity against all antibiotic-resistant strains of S. aureus tested. This enzyme is active in physiologically relevant conditions (pH, NaCl, temperature), and its activity is greatly enhanced in the presence of calcium. PlyGRCS is the first endolysin with a single catalytic domain that cleaves two distinct sites in the peptidoglycan. Unlike antibiotics, PlyGRCS displays anti-biofilm activity, preventing, removing, and killing biofilms grown on abiotic and biotic surfaces. Engineering efforts were made to create an enzyme with a variable binding domain, which unfortunately displayed less activity than the wild type endolysin in the conditions tested. The antimicrobial efficacy of PlyGRCS was validated in a mouse model of S. aureus septicemia. The results from this study indicate that the endolysin PlyGRCS is a revolutionary therapeutic that should be further pursued for subsequent translational development.en_US
dc.language.isoenen_US
dc.titleAN INVESTIGATION ON A BACTERIOPHAGE ENDOLYSIN POSSESSING ANTIMICROBIAL ACTIVITY AGAINST ANTIBIOTIC-RESISTANT STAPHYLOCOCCUS AUREUSen_US
dc.typeDissertationen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.contributor.departmentMolecular and Cell Biologyen_US
dc.subject.pqcontrolledBiologyen_US
dc.subject.pqcontrolledBiochemistryen_US
dc.subject.pqcontrolledMicrobiologyen_US
dc.subject.pquncontrolledBacteriophageen_US
dc.subject.pquncontrolledEndolysinen_US
dc.subject.pquncontrolledEnzybioticen_US
dc.subject.pquncontrolledMRSAen_US
dc.subject.pquncontrolledPeptidoglycan hydrolyaseen_US
dc.subject.pquncontrolledStaphylococcus aureusen_US


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