Antimicrobial bacteriophage-derived proteins and therapeutic applications

Abstract

Antibiotics have the remarkable power to control bacterial infections. Unfortunately, widespread use, whether regarded as prudent or not, has favored the emergence and persistence of antibiotic resistant strains of human pathogenic bacteria, resulting in a global health threat. Bacteriophages (phages) are parasites that invade the cells of virtually all known bacteria. Phages reproduce by utilizing the host cell's machinery to replicate viral proteins and genomic material, generally damaging and killing the cell in the process. Thus, phage can be exploited therapeutically as bacteriolytic agents against bacteria. Furthermore, understanding of the molecular processes involved in the viral life cycle, particularly the entry and cell lysis steps, has led to the development of viral proteins as antibacterial agents. Here we review the current preclinical state of using phage-derived endolysins, virion-associated peptidoglycan hydrolases, polysaccharide depolymerases, and holins for the treatment of bacterial infection. The scope of this review is a focus on the viral proteins that have been assessed for protective effects against human pathogenic bacteria in animal models of infection and disease.

Keywords: antibiotic resistance; antimicrobial; bacteriophage; endolysin; holin; peptidoglycan hydrolase; polysaccharide depolymerase.

Figure 1.

Schematic of Gram-positive bacterial cell lysis by exogenously applied endolysins. Endolysin cleave bonds within the peptidoglycan and the high internal pressure of cell protrudes the plasma membrane resulting in osmolysis (lysis from without). A generalized peptidoglycan structure illustrates cleavage sites by endolysin types: glycocidases (namely glucosaminidase and muramidases), amidases, and endopeptidases (dotted box).

Figure 2.

Schematic of bacterial cell envelope attacked by phage-encoded proteins during lytic replication. (A) Endolysins and holins work in concert for cell lysis during the final stages of replication. (B) Virion-associated peptidoglycan hydrolases are used by certain phage to puncture through the bacterial cell envelope. (C) Depolymerases degrade the extracellular polysaccharides and lipopolysaccharides that can be barriers to viral cell surface adsorption.

Figure 3.

Schematic of bacteriophage-encoded peptidoglycan hydrolase structures. Typically, an enzymatically active domain (EAD) that retains the catalytic activity is connected to cell wall binding domain (CBD) by a short linker region (blue bar). The catalytic activity, number, proximity, and orientation of domains are not conserved. (Top) streptococcal endolysin; (Middle) staphylococcal endolysin; (Bottom) staphylococcal virion-associated peptidoglycan hydrolase. Not drawn to scale.