The Advantages and Challenges of Using Endolysins in a Clinical Setting

Abstract

Antibiotic-resistant pathogens are increasingly more prevalent and problematic. Traditional antibiotics are no longer a viable option for dealing with these multidrug-resistant microbes and so new approaches are needed. Bacteriophage-derived proteins such as endolysins could offer one effective solution. Endolysins are bacteriophage-encoded peptidoglycan hydrolases that act to lyse bacterial cells by targeting their cell's wall, particularly in Gram-positive bacteria due to their naturally exposed peptidoglycan layer. These lytic enzymes have received much interest from the scientific community in recent years for their specificity, mode of action, potential for engineering, and lack of resistance mechanisms. Over the past decade, a renewed interest in endolysin therapy has led to a number of successful applications. Recombinant endolysins have been shown to be effective against prominent pathogens such as MRSA, Listeria monocytogenes, Staphylococcus strains in biofilm formation, and Pseudomonas aeruginosa. Endolysins have also been studied in combination with other antimicrobials, giving a synergistic effect. Although endolysin therapy comes with some regulatory and logistical hurdles, the future looks promising, with the emergence of engineered "next-generation" lysins. This review will focus on the likelihood that endolysins will become a viable new antimicrobial therapy and the challenges that may have to be overcome along the way.

Keywords: antibiotics; bacteriophage; endolysin; multidrug resistance; novel therapy.

Figure 1

Timeline of Phage Therapy. Outlined is the history of phage and endolysin therapy vs. antibiotic therapy, from the discovery of bacteriophage to the present day.

Figure 2

Phage Endolysin Mechanism. The process of a basic phage infection of a Gram-positive bacterial cell, and the role of endolysins and holins in infection.

Figure 3

Next-Generation Lysins. This illustration shows the basic difference in structure between the following: natural endolysins, the engineered chimeric lysin which involves the linking of the catalytic domain of one lysin to a suitable cell wall-binding domain, the Artilysin which involves the fusion of an LPS disrupting molecule to a lysin, VALs which do not possess their own cell wall-binding domain and so are fused to a suitable candidate, and truncated lysins which have the cell wall-binding domain removed to increase activity.