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

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

Secondly, we could envisage the inhibition of translation of the antitoxin by antisense molecules. Even though both TA genes are co-transcribed as a single mRNA transcript, the toxin gene usually carries its own Shine-Dalgarno sequence that is embedded within its upstream antitoxin gene (Chan et al., 2012) . Thus, antisense RNA silencing of the antitoxin could be achieved by the binding of short RNA sequences (or specific oligonucleotides) to the antitoxin coding region or to the initiation of translation signals of the antitoxin, without Figure 5 . Proposed strategies to use TA as antimicrobials. A few approaches have been suggested to make use of the toxin (crescent) of the pathogen itself for self-killing: Inhibition of TA transcription (I) or inhibition of antitoxin (oval) translation (II), thus antitoxin cannot be replenished and once the remaining antitoxin is degraded, the toxin will be free to act on the bacterial cell; Activation of host proteases (III) to rapidly degrade the labile antitoxin proteins and disruption of TA protein complex by i-PPI (IV) to liberate the toxin, as well as triggering activation of TA by quorum sensors (V). affecting translation of the toxin. However, a few factors have to be considered, such as the efficiency of the antisense to bind to the mRNA, the length of the antisense molecule, possible interference of the translation of the toxin protein, the stability of the antisense molecule (i.e. degradation by bacterial RNases) and also the double-stranded nature of the generated RNA after binding to the mRNA target.