Phage-based enzybiotics

Authors: SHEN, YANG - University Of Maryland; MITCHELL, MICHAEL - University Of Maryland; Donovan, David; NELSON, DANIEL - University Of Maryland

Submitted to: Advances in Cellular and Molecular Microbiology: Bacteriophages in Health and Disease
Publication Type: Book / Chapter
Publication Acceptance Date: 10/20/2011
Publication Date: 1/10/2012
Citation: Shen, Y., Mitchell, M.S., Donovan, D.M., Nelson, D.C. 2012. Phage-based enzybiotics. Advances in Cellular and Molecular Microbiology: Bacteriophages in Health and Disease.

Interpretive Summary: Problem: Ggram positive pathogens have large negative impacts on both agriculture and human health. Staphylococcus and streptococcus are leading causes of bovine mastitis, a 2 billion dollar a year loss, accounting for more than 40% of all cases in one study. Traditional treatments for mastitis, most commonly antibiotics, have been shown to be only marginally effective. Bacteriophage endolysins are a potential source of narrow spectrum antibiotics for treatment of antibiotic resistant pathogens. Accomplishments: The book chapter summarizes the current reported knowledge in the field regarding the use of phage endolysins (peptidoglycan hydrolases) as antimicrobials. Contribution of Accomplishment to Solving the Problem: This work educates the novice as to the benefits and hurdles of using enzyme antimicrobials. It is a current review of the literature. This chapter will aid scientists in the development of similar molecules as antimicrobials.

Technical Abstract: The term “enzybiotic” was coined by Vincent Fischetti’s group in 2001 to describe both the ENZYmatic and antiBIOTIC properties of bacteriophage-encoded endolysins (Nelson et al., 2001). Endolysins are peptidoglycan (i.e. cell wall) hydrolases that function to lyse the bacterial peptidoglycan for release of progeny virions during the phage lytic cycle. Timing of lysis during lytic infection is initiated by holins, which permeabilize the bacterial membrane and allow the cytoplasmically accumulated endolysins access to the peptidoglycan (Wang et al., 2000, Young, 1992). Significantly, in the absence of holins or parental bacteriophage, these enzymes can be used exogenously to lyse the peptidoglycan of susceptible organisms. Once the structural peptidoglycan is compromised, internal turgor pressure, measured at 20-50 atmospheres for Gram-positive organisms (Arnoldi et al., 2000, Doyle and Marquis, 1994, Whatmore and Reed, 1990), causes a rapid osmotic lysis of the bacterial membrane resulting in cell death. Non-endolysin enzybiotics, such as virion associated enzymes, have also been identified (Takac and Blasi, 2005, Rodriguez et al., 2011). With few exceptions, this enzyme-mediated “lysis from without” phenomenon is restricted to Gram-positive species as the Gram-negative peptidoglycan is covered by a protective outer membrane that is not permeable to an exogenous enzyme under normal conditions. Nonetheless, enzybiotics encoded by Gram-positive phage represent an attractive therapeutic option (Fischetti, 2010, Hermoso et al., 2007, Donovan, 2007, Borysowski et al., 2006, Loessner, 2005). While the most comprehensive definition of "enzybiotics" would include all endolysins, autolysins, exolysins, and perhaps other enzymes (i.e. bacteriocins, etc.) we will focus this chapter on the phage-encoded endolysins. Current knowledge about the mechanisms of action for these enzymes, in vitro and in vivo activity, synergy with other enzymes or antibiotics, immune responses, and resistance to these enzymes will be discussed.