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

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

Most of the known toxins from TAs act as endoribonucleases that cleave mRNAs associated or not to translating ribosomes, independently of the mRNA origin, prokaryotic or eukaryotic. Thus, the toxin could act as an antitumoural agent and, in fact, it was proposed that the Kid toxin from plasmid R1 could be used as an efficient anti-cancer compound (de la Cueva Méndez et al., 2003) . One of the approach could be using tumour-specific promoter to direct therapeutic expression of toxin in cancer cells (Yang et al., 2004) . More recently, reversion of induced solid tumours in mice has been reported by employment of an engineered version of the MazF toxin; nevertheless, the rate of success in reversion was around 50%, probably due to loss of functional toxin (Shimazu et al., 2014) . Such a loss of activity was not observed for toxins VapC from M. tuberculosis or PasB from plasmid pTF-FC2 of Thiobacillus ferrooxidans when expressed into human cancer cells (Wieteska et al., 2014) . These findings leave a door open to testing more thoroughly the possibilities of employment of toxins into tumoural cells. However, under the light of possible use of toxins as antibacterials, it is important to consider that if the toxins have to be delivered directly to the patients to kill the pathogens, the adverse effect of the toxins on the normal commensal flora and the human cells could also be difficult to avoid. Perhaps, as shown the antiviral activity of the MazF interferase, the dosage of the toxin is a critical factor when testing its activity on eukaryotic cells (Chono et al., 2011a,b) . The more efficient approaches would include the more specific targeting of the pathogens, or the bacteria that harbour TAs by triggering the release of the toxins, which are not found in human cells.