Committee: 

Andrés García, Ph.D. (Georgia Institute of Technology) 

Blair Brettmann, Ph.D. (Georgia Institute of Technology) 

Corey Wilson, Ph.D. (Georgia Institute of Technology) 

Julie Champion, Ph.D. (Georgia Institute of Technology) 

DESIGN AND CHARACTERIZATION OF MODIFIED LYTIC ENZYMES AND NANOPARTICLE-BASED VACCINES TO COMBAT S. AUREUS 

There is an imminent threat posed by the expanding list of “superbugs” or antibiotic-resistant bacteria that cause life-threatening infections. Methicillin-Resistant Staphylococcus aureus (MRSA) is one such superbug that is easily spread in hospitals and within communities. Many therapeutics fail to adequately treat infections caused by MRSA, leaving clinicians and patients with few options such as last resort antibiotics. The rapid pace of evolution of antimicrobial resistance to new and last resort antibiotics necessitates research and development of viable alternative strategies for preventing and treating infections. Our approach for tackling this growing public health concern involves three aims: incorporation of reactive handles into lytic enzymes, modification of lytic enzymes to reduce their immunogenicity, and designing vaccines that elicit broadly protective antibodies against S. aureus. 

First, lytic enzymes such as lysostaphin are modular antimicrobials that could have activity against antibiotic-resistant bacteria. Engineering these enzymes with reactive moieties can greatly broaden their potential applications to include incorporation in wound-healing biomaterials. 

Second, the efficacy of lytic enzymes in vivo is stymied by their low half-life and the potential to elicit an immune response. We offer two different approaches for reducing the immunogenicity of lytic enzymes: using site-specific pegylation or using site-specific glycosylation. 

Third, S. aureus has an arsenal of toxins and mechanisms that facilitate evasion of the host immune system. A vaccine that can elicit broad protection against multiple S. aureus toxins is needed to reduce infections and disease severity. We aim to design and characterize a protein-based vaccine against S. aureus that can elicit antibodies that can neutralize multiple members of a family of S. aureus toxins.