Emerging Roles of Toxin-Antitoxin Modules in Bacterial Pathogenesis

Abstract

Toxin-antitoxin (TA) cassettes are encoded widely by bacteria. The modules typically comprise a protein toxin and protein or RNA antitoxin that sequesters the toxin factor. Toxin activation in response to environmental cues or other stresses promotes a dampening of metabolism, most notably protein translation, which permits survival until conditions improve. Emerging evidence also implicates TAs in bacterial pathogenicity. Bacterial persistence involves entry into a transient semi-dormant state in which cells survive unfavorable conditions including killing by antibiotics, which is a significant clinical problem. TA complexes play a fundamental role in inducing persistence by downregulating cellular metabolism. Bacterial biofilms are important in numerous chronic inflammatory and infectious diseases and cause serious therapeutic problems due to their multidrug tolerance and resistance to host immune system actions. Multiple TAs influence biofilm formation through a network of interactions with other factors that mediate biofilm production and maintenance. Moreover, in view of their emerging contributions to bacterial virulence, TAs are potential targets for novel prophylactic and therapeutic approaches that are required urgently in an era of expanding antibiotic resistance. This review summarizes the emerging evidence that implicates TAs in the virulence profiles of a diverse range of key bacterial pathogens that trigger serious human disease.

Keywords: antibiotic resistance; biofilm formation; pathogenesis; persistence; toxin-antitoxin complexes; virulence.

Figure 1

Action of proteins that belong to a typical type II TA complex. The antitoxin (A; blue) and toxin (T; red) genes are co-expressed from a promoter (p; grey) in a single operon. The TA complex negatively regulates transcription from the promoter by binding specific palindromes within the overlapping operator region. In response to certain environmental conditions, the antitoxin is proteolytically cleaved by Lon or Clp proteases (yellow). The toxin is thereby released to act on its specific intracellular target process (green) to induce cell cycle arrest or death.

Figure 2

Distribution of type I (red), type II (black), type IV (green) and type V (blue) TA genes on the chromosome of E. coli K-12.

Figure 3

Schematic representation of a complex and multilayered protein network engaged in biofilm development in E. coli via TA systems. The central part illustrates Lon protease as an example of antitoxin degrading proteases, which also include ClpXP and ClpAP. Only the relevant, most well-described interactions are displayed. Coloured boxes denote toxins (red), antitoxins (blue), Lon protease (yellow), other proteins (dark grey), small molecules (light grey), and cellular processes and structures (purple). Arrows, stimulation; broken lines ending in balls, inhibition.

Figure 4

Schematic representation of a complex and multilayered protein network engaged in persistence formation in E. coli via TA complexes. The central part illustrates Lon protease as an example of antitoxin degrading proteases, which also include ClpXP and ClpAP. MazEF is shown as an exemplar type II module in which the toxin is an endoribonuclease. Only the relevant, most well-described interactions are displayed. Colored boxes denote toxins (red), antitoxins (blue), Lon protease (yellow), other proteins (dark grey), small molecules (light grey), and cellular processes and structures (purple). Arrows, stimulation; broken lines ending in balls, inhibition.