Advisor: Ravi Kane, Ph.D. (Georgia Institute of Technology)
Dr. Blair Brettmann, Ph.D. (Georgia Institute of Technology)
Dr. Julie Champion, Ph.D. (Georgia Institute of Technology)
Dr. Andrés García, Ph.D. (Georgia Institute of Technology)
Dr. Corey Wilson, Ph.D. (Georgia Institute of Technology)
Design and Characterization of Lytic Enzymes with Reduced Immunogenicity
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 bacteria evolving resistance to new and last resort antibiotics necessitates research and development of viable alternative sources of antimicrobial agents.
Lytic enzymes such as lysostaphin are modular antimicrobials that could potentially constitute a viable source for antimicrobial agents that are active against antibiotic-resistant bacteria. Lysostaphin utilizes a mechanism other than methicillin and similar drugs by targeting highly conserved portions of the bacterial cell wall resulting in rapid lysis of MRSA. However, efficacy of lysostaphin in vivo is stymied by its low in vivo half-life and the potential to elicit an immune response.
Conjugation of poly(ethylene glycol) (PEG) is a common approach that has successfully increased the in vivo half-life of different protein therapeutics, but has failed with respect to lytic enzymes due to significant loss of activity. Our approach involves selectively conjugating PEG chains to specific residues that are non-conserved in order to lower immunogenicity while retaining activity. This approach, through designing fusion proteins using domains from lytic enzymes with different specificities, can be extended to design antimicrobial agents with specificity and activity to pathogenic bacteria other than S. aureus.