Current Status of Endolysin-Based Treatments against Gram-Negative Bacteria

Abstract

The prevalence of multidrug-resistant Gram-negative bacteria is a public health concern. Bacteriophages and bacteriophage-derived lytic enzymes have been studied in response to the emergence of multidrug-resistant bacteria. The availability of tRNAs and endolysin toxicity during recombinant protein expression is circumvented by codon optimization and lower expression levels using inducible pET-type plasmids and controlled cultivation conditions, respectively. The use of polyhistidine tags facilitates endolysin purification and alters antimicrobial activity. Outer membrane permeabilizers, such as organic acids, act synergistically with endolysins, but some endolysins permeate the outer membrane of Gram-negative bacteria per se. However, the outer membrane permeation mechanisms of endolysins remain unclear. Other strategies, such as the co-administration of endolysins with polymyxins, silver nanoparticles, and liposomes confer additional outer membrane permeation. Engineered endolysins comprising domains for outer membrane permeation is also a strategy used to overcome the current challenges on the control of multidrug-resistant Gram-negative bacteria. Metagenomics is a new strategy for screening endolysins with interesting antimicrobial properties from uncultured phage genomes. Here, we review the current state of the art on the heterologous expression of endolysin, showing the potential of bacteriophage endolysins in controlling bacterial infections.

A Lysozyme Murein Hydrolase with Broad-Spectrum Antibacterial Activity from Enterobacter Phage myPSH1140

“…However, as with all other endolysins acting on Gram-negative bacteria, cells were treated with EDTA which binds and removes divalent ions that stabilize the surface structure of cells, thus resulting in a partially destabilized outer membrane. Other published studies have reported the use of such compounds to study the activity of the enzymes against Gram-negative bacteria ( 31 ). While the use of chemicals such as EDTA is medically not possible, the key aspect of studies such as ours and previously reported research is the activity of the enzyme per se , albeit in concert with EDTA.…”

In vitro bacterial vaginosis biofilm community manipulation using endolysin therapy

“…This finding may lend itself to the use of endolysin cocktails which can target several BV-associated anaerobes, in a similar fashion to the approach used in bacteriophage therapy [ 40 ]. However the development of endolysins against P. bivia and other Gram-negative bacteria represents a continual challenge in the field [ 41 ].…”

A Lysozyme Murein Hydrolase with Broad-spectrum Antibacterial Activity from Enterobacter Phage myPSH1140

“…However, as with all other endolysins acting on Gram-negative bacteria, cells were treated with EDTA which binds and removes divalent ions that stabilize the surface structure of cells, thus resulting in a partially destabilized outer membrane. Other studies reported have also employs such compounds to study the activity of the enzymes against Gram-negative bacteria (33).…”

“…However, as with all other endolysins acting on Gram-negative bacteria, cells were treated with EDTA which binds and removes divalent ions that stabilize the surface structure of cells, thus resulting in a partially destabilized outer membrane. Other studies reported have also employs such compounds to study the activity of the enzymes against Gram-negative bacteria (33). While the use of chemicals such as EDTA is medically not possible, the key aspect of studies such as ours and previously reported research is the activity of the enzyme per se, albeit in concert with EDTA.…”