Phage endolysins (ELs) as antimicrobial agents to Gram-negative bacteria

Abstract

Endolysins (ELs) are enzymes produced by bacteriophages that disrupt the peptidoglycan layer (PG) compromising cell integrity. Based on catalytic activity, phage ELs are classified into five superfamilies, glucosaminidases, muramidases, transglycosylases, endopeptidases, and amidases. PG is a structure found only in bacteria making it an excellent target for antibiotics such as penicillin. However, the search for new antimicrobials is imperative considering the increasing antimicrobial resistance (AMR) phenotype exhibited by pathogenic bacteria. A recent work estimated that, in 2019, resistant bacteria were associated with 4.95 million deaths, including 1.27 million deaths that were directly attributable to bacterial AMR. Therefore, considering their activity on PG, endolysins are promising candidates to be employed as an antimicrobial agent in the control of infections caused by Gram-positive and Gram-negative bacteria. In nature, the endolysins act from the inside of the cell. Then, the exogenous application of Els particularly to inhibit Gram-negative bacteria is challenging due to the outer membrane barrier. To circumvent this barrier, the use of membrane permeating agents, endolysin encapsulation, and the combination with antibiotics that target bacterial membranes are promising alternatives. In addition, considering that the mechanisms of the exogenous activity of lysins remain unclear, the use of proteins with signal-peptide (SP) or signal-arrest-release (SAR) SP and SAR-containing lysins, respectively, might also represent a good alternative for bacterial control.