Toxin-Antitoxin Systems in Clinical Pathogens

Abstract

Toxin-antitoxin (TA) systems are prevalent in bacteria and archaea. Although not essential for normal cell growth, TA systems are implicated in multiple cellular functions associated with survival under stress conditions. Clinical strains of bacteria are currently causing major human health problems as a result of their multidrug resistance, persistence and strong pathogenicity. Here, we present a review of the TA systems described to date and their biological role in human pathogens belonging to the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) and others of clinical relevance (Escherichia coli, Burkholderia spp., Streptococcus spp. and Mycobacterium tuberculosis). Better understanding of the mechanisms of action of TA systems will enable the development of new lines of treatment for infections caused by the above-mentioned pathogens.

Keywords: Toxin-Antitoxin; chromosome; clinical; pathogens; persistance; plasmids; resistance; virulence.

Figure 1

Models representing the interaction between toxins and antitoxins in the different types of toxin-antitoxin (TA) systems. (A) Type I: the antitoxin mRNA binding to toxin mRNA, which prevents toxin protein formation; (B) type II: a TA complex is formed by the union of toxin and antitoxin proteins; (C) type III: a TA complex is formed by the union of toxin protein with antitoxin mRNA; (D) type IV: the antitoxin protein binds to the toxin target, blocking its action; (E) type V: the antitoxin mRNA encodes an RNAse that degrades the toxin mRNA.

Figure 2

Model of MazEFSa regulation. Transcription of the operon mazES-rsbUVW-sigB is initiated by the mazEF promoter, and transcription of the rsbUVW-sigB genes depends on the activity of the transcriptional terminator downstream of the mazE and mazF genes. This system is negatively regulated by the σB, encoded by sigB, which represses the mazEF promoter. Toxin MazF is an RNAse that degrades the mRNA in the UACAU site. The antitoxin MazE binds and inactivates the toxin MazF. This system is negatively regulated by the σB encoded by sigB.