Enterococcal Cytolysin: A Novel Two Component Peptide System that Serves as a Bacterial Defense Against Eukaryotic and Prokaryotic Cells

Abstract

The cytolysin is a novel, two-peptide lytic toxin produced by some strains of Enterococcus faecalis. It is toxic in animal models of enterococcal infection, and associated with acutely terminal outcome in human infection. The cytolysin exerts activity against a broad spectrum of cell types including a wide range of gram positive bacteria, eukaryotic cells such as human, bovine and horse erythrocytes, retinal cells, polymorphonuclear leukocytes, and human intestinal epithelial cells. The cytolysin likely originated as a bacteriocin involved with niche control in the complex microbial ecologies associated with eukaryotic hosts. However, additional anti-eukaryotic activities may have been selected for as enterococci adapted to eukaryotic cell predation in water or soil ecologies. Cytolytic activity requires two unique peptides that possess modifications characteristic of the lantibiotic bacteriocins, and these peptides are broadly similar in size to most cationic eukaryotic defensins. Expression of the cytolysin is tightly controlled by a novel mode of gene regulation in which the smaller peptide signals high-level expression of the cytolysin gene cluster. This complex regulation of cytolysin expression may have evolved to balance defense against eukaryotic predators with stealth.

Discovery and in vitro biosynthesis of haloduracin, a two-component lantibiotic

“…1). A similar observation has been reported for the two-component systems plantaricin W and cytolysin, in which the peptide undergoes additional proteolytic processing beyond the removal of the leader sequence (10,17). In cytolysin the additional proteolysis by CylA has been shown to be necessary for biological activity (10).…”

“…We show conclusively that these peptides are part of a two-component system. Including haloduracin, seven two-component lantibiotics have now been documented (10,11,17,18,29,30). Interestingly, by searching the nonredundant database for homologs to the haloduracin peptides we discovered another gene cluster in Bacillus lichenformis that encodes two prepeptides, two modification enzymes, and several additional transport, immunity, and regulation proteins involved in lantibiotic biosynthesis.…”

“…In most cases, the sequence similarity of the two prepeptides is rather low (Ϸ25%), and so two different enzymes are thought to be used for the posttranslational modification of each peptide (9). The exception is cytolysin, a two-component lantibiotic that is processed by a single LanM enzyme (10). In this case, the sequence homology of the two peptide substrates is much higher at Ϸ90%.…”

Lantibiotics from Geobacillus thermodenitrificans

“…Although it is not unprecedented that lanthionine-containing peptides do not demonstrate any antimicrobial activity (29-32), we wondered whether perhaps a second proteolytic cleavage event might be required. Removal of six additional N-terminal residues after leader peptide cleavage at a double-glycine site has been reported previously for several class II lantibiotics (33)(34)(35)(36). In some examples, such as cytolysin from Enterococcus faecalis, removal of these additional residues from the N terminus of the modified core peptide is necessary for bioactivity (34), but in other examples (e.g., haloduracin; ref.…”

Determination of Virulence Factors in Clinical Multidrug Resistance Enterococci Isolates at Southeast of Iran

“…They have been distinguished the higher fre- Cytolysin operon is carried through plasmid or bacterial chromosome. The cylA gene processes the peptides and activates other genes in cytolysin operon, also allowing them in order to combine until producing the hemolytic toxin (24). Nevertheless, we found the distribution of this gene in 14.1% of all Enterococci, particularly E. faecalis (two isolates were related to MDRs) that associated with UTIs.…”