Toxin-Antitoxin Systems of Staphylococcus aureus

Abstract

Toxin-antitoxin (TA) systems are small genetic elements found in the majority of prokaryotes. They encode toxin proteins that interfere with vital cellular functions and are counteracted by antitoxins. Dependent on the chemical nature of the antitoxins (protein or RNA) and how they control the activity of the toxin, TA systems are currently divided into six different types. Genes comprising the TA types I, II and III have been identified in Staphylococcus aureus. MazF, the toxin of the mazEF locus is a sequence-specific RNase that cleaves a number of transcripts, including those encoding pathogenicity factors. Two yefM-yoeB paralogs represent two independent, but auto-regulated TA systems that give rise to ribosome-dependent RNases. In addition, omega/epsilon/zeta constitutes a tripartite TA system that supposedly plays a role in the stabilization of resistance factors. The SprA1/SprA1AS and SprF1/SprG1 systems are post-transcriptionally regulated by RNA antitoxins and encode small membrane damaging proteins. TA systems controlled by interaction between toxin protein and antitoxin RNA have been identified in S. aureus in silico, but not yet experimentally proven. A closer inspection of possible links between TA systems and S. aureus pathophysiology will reveal, if these genetic loci may represent druggable targets. The modification of a staphylococcal TA toxin to a cyclopeptide antibiotic highlights the potential of TA systems as rather untapped sources of drug discovery.

Keywords: MazEF; Omega-Epsilon-Zeta; RNase; SprA1-SprA1AS; SprFG; Staphylococcus aureus; TenpIN; YefM-YoeB; plasmid addiction; toxin-antitoxin system.

Figure 1

Type I toxin-antitoxin systems in S. aureus (A) The SprA1-SprA1_AS toxin-antitoxin system. Toxin (SprA1) and antitoxin (SprA1_AS) RNAs are transcribed from convergent promoters. The toxin RNA (SprA1) gives rise to a cytotoxic peptide PepA1 that is able to disrupt the host membrane and erythrocytes. The antitoxin RNA is able to inhibit toxin synthesis by interactions with the non-overlapping areas; (B) The SprFG1 toxin-antitoxin system. Similar to (A) but from one toxin RNA two peptides of different lengths (SprG1-short, SprG1-long) are produced. In addition, the toxin-antitoxin RNA interaction occurs via the overlapping region. Not drawn to scale.

Figure 2

Type II toxin-antitoxin systems in S. aureus (A) The MazEF toxin-antitoxin system is embedded in the rsbUVWsigB locus. One promoter drives mazEF transcription, which can comprise the downstream rsbUVWsigB genes depending on a weak transcriptional terminator and transcriptional read-through. Free toxin MazF cleaves available mRNA at UACAU sites and can be inhibited by the antitoxin protein MazE. The system is negatively regulated by the sigB encoded σ^B; (B) The toxin YoeB of the YefM-YoeB toxin-antitoxin system is a ribosome dependent RNase that cleaves close to the start codon. The antitoxin YefM inhibits the toxin by protein-protein interactions and can auto-regulate its own operon; (C) The Omega-Epsilon-Zeta system. In contrast to many other type II TA-operons, this is a tripartite system, where the regulation of the operon is separate from the antitoxin protein. The Omega protein is thought to auto-regulate its own operon, whereas the antitoxin Epsilon is supposed to inhibit toxicity from the Zeta toxin. This system has not been studied in depth, therefore most elements depicted here are based on predictions and homology to closely related systems. Unclear elements and functions are indicated by faint color. Systems are not drawn to scale.

Figure 3

Model of the type III toxin-antitoxin system TenpIN in S. aureus. The antitoxin TenpI is predicted to possess three repeats that are proposed to be processed by the toxin TenpN. Presumably the processed TenpI RNA fragments are able to bind the toxin protein forming an RNA/protein complex. Note that this system has not been tested experimentally in S. aureus and the figure presented here is solely a model based on the predicted chromosomal regions and orthologous systems. Not drawn to scale.