|SCHMELCHER, MATHIAS - Eth Zurich|
|SHEN, YANG - University Of Maryland|
|NELSON, DANIEL - University Of Maryland|
|EUGSTER, MARCEL - Eth Zurich|
|EICHENSEHER, FRITZ - Eth Zurich|
|HANKE, DANIELA - Eth Zurich|
|LOESSNER, MARTIN - Eth Zurich|
|DONG, SHENGLI - University Of Alabama|
|PRITCHARD, DAVID - University Of Alabama|
|LEE, JEAN - Channing Laboratory|
Submitted to: Antimicrobial Chemotherapy
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/9/2014
Publication Date: 1/27/2015
Citation: Schmelcher, M., Shen, Y., Nelson, D.C., Eugster, M.R., Eichenseher, F., Hanke, D.C., Loessner, M.J., Dong, S., Pritchard, D.G., Lee, J.C., Becker, S.C., Donovan, D.M. 2015. Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection. Antimicrobial Chemotherapy. 70(5):1453-1465.
Interpretive Summary: In this age of multi-drug resistant pathogens (including Staphylococcus aureus ) in both human and animal infectious disease, there is a need for novel antimicrobials that are refractory to resistance development. Bacteriophage are viruses that infect and kill bacteria. Bacteriophage endolysins are proteins that the bacteriophage use to escape their host bacteria. The endolysin degrades the bacterial cell wall and have co-evolved with their host bacteria such that they target specific sites within the bacterial cell wall that the bacteria can not readily change, and thus are highly refractory to resistance development by the host. We have characterized a range of phage endolysins [that all share similar protein architecture but very different (<50% identical) amino acid sequence] for the cut sites in the cell wall and ability to eradicate Staphylococcus aureus in both biofilms and in a mouse model of sepsis. We present evidence that these endolysins are effective in reducing or eradicating Staphylococcus aureus in animal models of infectious disease. This is the first step toward commercializing our novel antimicrobials. Once commercialized, this will eventually benefit both human and animal health care workers to avoid and cure multi-drug resistant staphylococcal diseases.
Technical Abstract: Staphylococcus aureus is a Gram-positive pathogen relevant for both human and animal health. With multi-drug resistant S. aureus strains becoming increasingly prevalent, alternative therapeutics are urgently needed. Bacteriophage endolysins (peptidoglycan hydrolases, PGH) are capable of killing Gram-positive S. aureus when exposed externally and are therefore promising antimicrobials against these pathogens. In this work, we compare nine SH3b (cell wall binding domain) containing staphylolytic PGHs representing multiple homology groups. Despite a similar modular architecture and conserved cut sites in the peptidoglycan (as determined by mass spectrometry), the enzymes displayed varying degrees of in vitro lytic activity against numerous staphylococcal strains including cell surface mutants, drug-resistant strains, and mastitis isolates, and proved effective against static biofilms. In a mouse model of systemic methicillin-resistant S. aureus infection, six of the nine PGHs provided 100% protection from death by bacteremia and animals were free of clinical signs at the end of the experiment, whereas only ~25 - 30% of animals treated with buffer or oxacillin survived 48 hours post infection. Overall, our results demonstrate the potential of bacteriophage endolysins as effective antimicrobials for the treatment of staphylococcal infections/contaminations, and reveal evolutionary conservation of catalytic specificity within this diverse group of PGHs.