Peptidoglycan hydrolase enzyme fusions are uniquely suited for treating multi-drug resistant pathogens

Authors: Donovan, David; Becker, Stephen; DONG, SHENGLI - University Of Alabama; BAKER, JOHN - University Of Alabama; Foster Frey, Juli; PRITCHARD, DAVID - University Of Alabama

Submitted to: Biotech International
Publication Type: Review Article
Publication Acceptance Date: 3/1/2009
Publication Date: 5/1/2009
Citation: Donovan, D.M., Becker, S.C., Dong, S., Baker, J.R., Foster Frey, J.A., Pritchard, D.G. 2009. Peptidoglycan hydrolase enzyme fusions are uniquely suited for treating multi-drug resistant pathogens. Biotech International 21(2):6-10.

Interpretive Summary: C. Problem— Multi drug resistant bacteria are a plague to modern health care. They are similarly becoming a significant problem with animal health. Methicillin resistant staphylococcus aureus is one of the most egregious forms of multi-drug resistant bacteria. These multi-drug resistant forms of bacteria often form biofilms that are much more resistant to antibiotics than planktonic forms of bacteria. There is an immediate need for enzyme antimicrobials that can digest biofilms and prevent the development of drug resistant strains. C. Accomplishment— We have identified synergistic antimicrobial peptidoglycan hydrolases that degrade the major structural component of staphylococcal cell walls, including multi-drug resistant strains. These enzymes are of bacterial origin and in some case harbor multiple lytic activities. In order to create antimicrobials that we feel will be refractory to resistance development, we have created fusions with these antimicrobial proteins that harbor three lytic activities in the same protein. These triple acting fusion proteins maintain three lytic activities in one protein and kill staphylococci in ex vivo rat blood. C. Contribution of Accomplishment to Solving the Problem— The creation of triple acting antimicrobial enzymes that kill both planktonic and biofilm forms of the organism is a major advancement toward developing antimicrobials that are refractory to resistance development.

Technical Abstract: Pathogens with resistance to multiple antibiotics are a world-wide concern for human and animal health. Bacteriophage lytic enzymes are a potent new source of antimicrobials for treating these pathogens. Phage are viruses that infect bacteria. Survival of the phage relies on phage encoded endolysins to degrade host peptidoglycan (PG) for nascent phage particles to escape and reinfect new host cells. PG is a major bacterial cell wall structure. Bacteria-phage co-evolution has yielded endolysins that target immutable PG bonds such that no hosts with resistance to the phage endolysins have been identified. The lysins are modular enzymes with lytic domains that maintain their parental specificities when fused. These qualities and the ability to kill pathogens in biofilms position the PG hydrolases as a potent new class of antimicrobials uniquely suited to eradicate multi-drug resistant pathogens.