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

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

Firstly, one approach could be the inhibition of transcription of the TA pair so that autoregulation would not take place and synthesis of the TA would be hindered. By use of the dif-ferent half-lives of the two proteins, the likelihood of degradation of the antitoxin and release of the toxin could be increased. How to achieve this goal? One possibility could be the use of a mutant of the antitoxin with enhanced DNA binding affinity ('super-repressor') but devoid of the ability to complex to its cognate toxin. This could be achieved as usually the binding site of the antitoxin to the DNA is at the N-terminal moiety whereas to its cognate toxin is at the C-terminus. Perhaps the challenge would be the binding affinity, as the antitoxins are, in general, weak repressors; exceptions have been reported as in the case of the TA pairs mqsA-mqsR from E. coli (Brown et al., 2013) and parDE from plasmid RK2 (Davis, Helinski and Roberts 1992; Oberer et al., 2002 Oberer et al., , 2007 . Characterization of these features could be easily followed by a novel technique based on differential repression of the green fluorescent protein expression (Chan et al., 2014) .