A Systematic Overview of Type II and III Toxin-Antitoxin Systems with a Focus on Druggability

Abstract

Toxin-antitoxin (TA) systems are known to play various roles in physiological processes, such as gene regulation, growth arrest and survival, in bacteria exposed to environmental stress. Type II TA systems comprise natural complexes consisting of protein toxins and antitoxins. Each toxin and antitoxin participates in distinct regulatory mechanisms depending on the type of TA system. Recently, peptides designed by mimicking the interfaces between TA complexes showed its potential to activate the activity of toxin by competing its binding counterparts. Type II TA systems occur more often in pathogenic bacteria than in their nonpathogenic kin. Therefore, they can be possible drug targets, because of their high abundance in some pathogenic bacteria, such as Mycobacterium tuberculosis. In addition, recent bioinformatic analyses have shown that type III TA systems are highly abundant in the intestinal microbiota, and recent clinical studies have shown that the intestinal microbiota is linked to inflammatory diseases, obesity and even several types of cancer. We therefore focused on exploring the putative relationship between intestinal microbiota-related human diseases and type III TA systems. In this paper, we review and discuss the development of possible druggable materials based on the mechanism of type II and type III TA system.

VapC21 Toxin Contributes to Drug-Tolerance and Interacts With Non-cognate VapB32 Antitoxin in Mycobacterium tuberculosis

“…However, the exact molecular switches that enable M. tuberculosis to slow down metabolism and enter into dormant or latent state still remains unknown. Toxin-antitoxin (TA) systems, initially referred as addiction systems, are auto-regulatory operon encoding for a labile antitoxin and stable toxin (Lobato-Marquez et al, 2016;Page and Peti, 2016;Harms et al, 2018;Holden and Errington, 2018;Kang et al, 2018). The toxin-mediated growth arrest is mostly bacteriostatic, reversible and regulated by the expression levels of cognate antitoxins (Muthuramalingam et al, 2016).…”

Targeting Type II Toxin–Antitoxin Systems as Antibacterial Strategies

“…and species of the ESKAPE group (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.) [19,[28][29][30][31][32]. An increasing number of studies are being undertaken to describe the repertoire of TA systems in pathogenic bacteria at the level of a given strain or of a whole taxon.…”

Competent but complex communication: The phenomena of pheromone-responsive plasmids

“…Kang and colleagues discussed the design of small molecules to interfere with the TA complex, allowing for activation of the toxin and leading to cell death. The authors also suggest an approach to starve cells of antitoxin by preventing transcription of the TA system through binding of a molecule to the system promoter [132]. Importantly, TA mechanisms are not homologous with any human systems, reinforcing their possible therapeutic exploitation.…”