One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan, Wai Ting; Balsa, Dolors; Espinosa, Manuel

We will analyse the potential use of type II TAs as antimicrobial targets since they are the most abundant and better studied among TAs, and their mechanisms of action have been generally unveiled. Type II TAs exhibit typical features ( Fig. 1 ) such as (i) the antitoxin gene is usually preceding the toxin gene; (ii) both genes are co-transcribed from a promoter located upstream of the antitoxin gene and (iii) they are translationally coupled. The operon is negatively autoregulated by the antitoxin upon binding to an operator region that overlaps the single promoter of the operon, whereas the toxin acts as an efficient co-repressor. The antitoxin protein is labile and more susceptible to degradation by the host proteases, while the toxin protein is much more stable. The ratio of the toxin to antitoxin is important to determine the stoichiometry of the TA protein complex and also to regulate the transcription of the operon, so that the antitoxin is replenished to shield the toxicity in normal condition Cataudella et al., 2012) . However, under certain stressful circumstances such as nutritional stress, colonization of new hosts, DNA-damaging agents, etc., transcription of the TA will be triggered, and the labile antitoxin will be degraded more rapidly, unleashing the toxin protein to act on their targets.