Therapeutic potential of bacteriophage endolysins for infections caused by Gram-positive bacteria

Abstract

Gram-positive (G+) bacterial infection is a great burden to both healthcare and community medical resources. As a result of the increasing prevalence of multidrug-resistant G+ bacteria such as methicillin-resistant Staphylococcusaureus (MRSA), novel antimicrobial agents must urgently be developed for the treatment of infections caused by G+ bacteria. Endolysins are bacteriophage (phage)-encoded enzymes that can specifically hydrolyze the bacterial cell wall and quickly kill bacteria. Bacterial resistance to endolysins is low. Therefore, endolysins are considered promising alternatives for solving the mounting resistance problem. In this review, endolysins derived from phages targeting G+ bacteria were classified based on their structural characteristics. The active mechanisms, efficacy, and advantages of endolysins as antibacterial drug candidates were summarized. Moreover, the remarkable potential of phage endolysins in the treatment of G+ bacterial infections was described. In addition, the safety of endolysins, challenges, and possible solutions were addressed. Notwithstanding the limitations of endolysins, the trends in development indicate that endolysin-based drugs will be approved in the near future. Overall, this review presents crucial information of the current progress involving endolysins as potential therapeutic agents, and it provides a guideline for biomaterial researchers who are devoting themselves to fighting against bacterial infections.

Engineered endolysin of Klebsiella pneumoniae phage is a potent and broad-spectrum bactericidal agent against “ESKAPEE” pathogens

“…The efficacy of endolysins is subject to various influencing factors, encompassing amino acid composition, polarity, charge distribution, and overall structural configuration ( Plotka et al, 2019 ; Gallego-Páramo et al, 2021 ; Liu et al, 2023 ). Modifying endolysins entails manipulating these factors to optimize their activity against bacteria.…”

“…Some natural endolysins exhibit poor expression levels and solubility ( Lee et al, 2023 ). Moreover, while these “enzybiotics” effectively eliminate Gram-positive bacteria through specific cell wall hydrolysis ( Liu et al, 2023 ), their application is hindered by the protective outer membrane of Gram-negative bacteria ( Rahman et al, 2021 ). Genetic modification of current endolysins offer a solution to tailor their properties and activity against specific bacterial targets.…”

Bacteriophage vB_SepP_134 and Endolysin LysSte_134_1 as Potential Staphylococcus-Biofilm-Removing Biological Agents

“…In addition, these phage lytic enzymes can be used in combination with antibiotics, as they can digest and destroy the biofilm matrix, which enables antibiotics to reach their target cells and, in turn, can lead to a decrease in the dosage of antibiotics used. With a low risk of resistance development [ 68 , 69 , 70 ], endolysins can be administrated both as an independent antimicrobial agent and in combination with phages to treat MDR and, especially, pandrug-resistant bacteria.…”

Endolysin B as a new archetype inM. tuberculosistreatment

“…On the other hand, one of the main limitations to the use of phage and/or phage-derived proteins for therapy stands in the possible immune response that the host could develop in response to exogenous proteins 41,42 . Although the administration of isolated and bioengineered endolysins ensured rapid effects on Gram-positive bacteria that resulted in various clinical trials 43,44 , these proteins have also been associated to the secretion of inflammatory cytokines and neutralizing antibodies, which significantly reduced the endolysin half-life and the loss of its enzymatic lytic activity 43 . Consistent with these findings, mAMs treated with LysB FL tend to polarize towards a pro-inflammatory phenotype.…”