BACTERIOPHAGE-DERIVED ENDOLYSINS AS NEXT-GENERATION ANTIBACTERIALS: A COMPREHENSIVE REVIEW

Abstract

As antimicrobial resistance has become increasingly problematic, there is a growing need for new therapeutic approaches and bacteriophage-derived endolysins are a new generation of antibacterial agents. The peptidoglycan hydrolases have remarkable features such as potent bactericidal activity, high specificity of the target molecule and low tendency to induce bacterial resistance and have great potential for developing alternatives to antibiotics. Endolysins have a modular structure with catalytic domains that hydrolyse specific bonds of the bacterial cell wall and cell wall binding domains that provide target specificity to selectively lyse pathogenic bacteria whilst sparing beneficial commensal bacteria. Their action against biofilms and persister cells overcome important drawbacks of traditional antibiotics and the protein engineering methods such as domain shuffling, directed evolution and artificial intelligence-guided design have increased their therapeutic potential. Clinical development has made great strides and a number of candidates have advanced into clinical trials for infections from multi-drug-resistant pathogens. Although still a few hurdles remain, such as the barrier of the outer membrane in Gram-negative bacteria and the need for optimizing the system for delivery, endolysins offer a revolution in the field of antibacterial therapy. The present review discusses the biology, mechanisms, engineering strategies, clinical application, and future perspectives of bacteriophage-derived endolysins, as well as their potential to overcome antimicrobial resistance as a global crisis by precision antibacterial therapy.