Structure, Biology, and Therapeutic Application of Toxin–Antitoxin Systems in Pathogenic Bacteria

Abstract

Bacterial toxin–antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein–protein interactions. Accumulating knowledge about the structure–function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems.

A tripartite toxin‐antitoxin module induced by quorum sensing is associated with the persistence phenotype in Streptococcus mutans

“…Emerging evidence implicates TA modules in bacterial pathogenicity and persister formation. [2][3][4]10,30 Bacterial persistence involves entry into a dormant state in which cells survive unfavourable conditions including killing by antibiotics, which is a significant clinical problem.…”

“…Chromosomal TA modules have been proposed to function as regulators of bacterial cell growth in response to environmental perturbations such as nutrient deprivation, antibiotic treatment, and immune system response . TAs are currently classified into six groups (types I to VI) based on the mechanisms used by the antitoxins to counteract the toxins . While the product of the toxin gene is a protein, that of the antitoxin gene is either a non‐coding RNA (types I and III) or a protein (types II, IV, V, and VI).…”

Identification and characterization of acetyltransferase‐type toxin‐antitoxin locus in Klebsiella pneumoniae

“…TA systems play a critical role in the survival of bacterial populations in response to stresses such as nutrient starvation or antibiotic pressure (Harms et al, 2016). TA systems are commonly composed of a stable toxin and a labile antitoxin encoded by a bicistronic locus (Lee and Lee, 2016). Toxin genes code for proteins, whereas the matching antitoxin genes code for either RNAs or antitoxin proteins, resulting in their classification as type 1-6 TA loci (Gerdes and Maisonneuve, 2012;Page and Peti, 2016;Chan et al, 2016).…”

Crystal structure of proteolyzed VapBC and DNA‐bound VapBC from Salmonella enterica Typhimurium LT2 and VapC as a putative Ca 2+ ‐dependent ribonuclease

“…TA pairs are generally classified into six types, according to the genetic structure and regulation modes of the antitoxin molecules . In the type I and III TA systems, the antitoxins are RNA molecules that directly inhibit translation or regulate toxin activities.…”

“…8,9 TA pairs are generally classified into six types, according to the genetic structure and regulation modes of the antitoxin molecules. [10][11][12] In the type I and III TA systems, the antitoxins are RNA molecules that directly inhibit translation or regulate toxin activities. In the type I TA system, antitoxins are unstable antisense RNAs that directly bind to mRNA molecules of toxin.…”