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

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

Taken together, all the above features make the exploitation of TAs as antibacterials a major challenge: due to their redundancy, target validation as well as the specificity and selectivity (off-target activity) of any drug candidate targeting a specific TA would be very difficult to assess. Despite of that, the toxins of the TA pairs could be an attractive antibacterial targets to be used as stand-alone drugs or in combination with classical antibiotics (Mutschler and Meinhart 2011; Park, Mann and Li 2013; Unterholzner, Poppenberger and Rozhon 2013) . However, it seems that the combination with current approved antibiotics would have, at least at present, another major challenge in terms of matching the formulation to generate a combination product. The route to approach these problems can vary depending upon the way the toxin effect is envisaged. In the first place, if the toxin is going to be the candidate itself, then the fact that TAs are absent in human is irrelevant. The toxins of the TA pairs as all novel targets to be considered for drug discovery must comply with a set of requirements, such as lack of toxicity to eukaryotic cells and target only the infecting bacteria. However, the toxins of TA genes are also harmful to the human cells unless there is a careful monitoring of the toxin dosage (as mentioned above in the antiviral tests) and safe delivery systems are applied, in addition to provision for the replenishment of commensal flora. If, however, the TA is going to be used as a target for drug ligands, then all of the above arguments are relevant, keeping in mind the challenges related to redundancy. Several strategies to disrupt the interface between antitoxins and their cognate toxins by inhibitors of PPI have been envisaged as well as the possible use of the toxins in combined strategies (Alonso et al., 2007; Mutschler and Meinhart 2011) . We will summarize below some of the reported studies as well as our views on whether employ-ment of TAs could be considered as promising candidates for future use in the biopharmaceutical industry. We will also discuss the pros and cons of the use of these toxins as druggable antimicrobial targets.