Toxin-Antitoxins (TAs) of Streptococcus pneumoniae

Type II (proteic) Toxin-Antitoxins (TAs) are usually present as two genes organized in an operon. The antitoxin neutralizes the toxicity of the cognate toxin by tight protein:protein interactions. TAs are ubiquitous in bacteria and archaea, redundant (several copies per chromosome), and absent in eukaryotes. When bacteria are subjected to stress, TA synthesis is triggered, the unstable antitoxin is degraded by proteases and the stable toxin is freed to exert its role. As a consequence, the bacterial population enters into ‘persistence’, resisting antibiotic treatments. We study the four TAs from S. pneumoniae, and analyse whether they can be druggable by disruption of the T:A association and toxin release. We proposed the design of antibacterial drugs able to increase the intracellular amounts of toxins by different approaches: i) transcriptional inhibition of TA synthesis, so that the intracellular antitoxin is degraded releasing the already synthesized toxin; ii) design of antisense RNAs to specifically inhibit antitoxin translation; iii) activation of bacterial proteases that degrade the antitoxin, and iv) drugs that disrupt the T:A interactions.