Enzybiotics: Endolysins and Bacteriocins

Abstract

The growing prevalence within community and healthcare settings of antibiotic resistant Gram-positive and Gram-negative bacterial pathogens is alarming. Particularly concerning are reports of bacteria that are resistant to last-resort antibiotics such as carbapenems and vancomycin. Thus, novel concepts are needed to face the serious challenge posed by multidrug-resistant bacterial infections. A promising alternative antimicrobial approach to conventional antibiotics involves the use of bacteriophage-derived protein(s), generically known as “enzybiotics.” Endolysins, one type of enzybiotic, are cell-wall enzymes, i.e., peptidoglycan hydrolases that act on the host bacterium late in the phage replication cycle. These enzymes hydrolyze critical covalent bonds essential for maintaining cell wall structural integrity. Due to the absence of an outer membrane, extrinsically applied recombinant endolysins have direct access to the bacterial cell wall to lyse susceptible Gram-positive pathogens. Highlighting their therapeutic potential, the efficacy of endolysins has been validated in vitro and/or in vivo against a variety of Gram-positive pathogens, and in less than 15 years since their first documented use as an antimicrobial in 2001, endolysins are now being commercially developed and undergoing clinical trials. Alternatively, phage-like or particulate bacteriocins comprise a second class of enzybiotics that can be used therapeutically. These multiprotein structures resemble bacteriophage tail-like assemblies and are produced by both Gram-negative and Gram-positive bacteria. Unlike fully functional bacteriophages, bacteriocins are incapable of replicating, though they nonetheless possess a pseudo-injection mechanism that results in loss of bacterial membrane integrity and subsequent bacterial death.