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

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

The classification of type II TA pairs is not an easy task as the toxin homologues that share sequence similarities can pair with different antitoxins with little sequence similarities (e.g. the yefM-yoeB TA genes encode antitoxin from the Phd family and toxin from the RelE family) (Anantharaman and Aravind 2003; Grady and Hayes 2003; Hayes and Van Melderen 2011) . Toxins that share similar structures, despite no notable sequence Inhibition of translation by phosphorylating the translation elongation factor EF-Tu similarities, bind to different targets (e.g. CcdB binds to DNA gyrase but Kid, which has similar structure as CcdB, cleaves free mRNAs) (Hargreaves et al., 2002) . Further, toxins that were thought to belong to different families have similar mode of actions (e.g. ParE and CcdB act on DNA gyrase) (Jiang et al., 2002; van Melderen 2002) . To complicate the picture more, a toxin might have more than one target: for instance, toxin MazF-mt6 from Mycobacterium tuberculosis cleaves free mRNA at the sequence 5 -UU↓CCU-3 (being ↓ the cleaving site), but also cleaves 23S rRNA at a single 5 -UUCCU-3 sequence in the ribosomal A site that contacts tRNA and ribosome recycling factor (Zhu et al., 2009; Schifano et al., 2013) . Thus, instead of classifying the TA gene pair, 12 toxin superfamilies (Table 3) and 20 antitoxin superfamilies have been identified (Hayes and Van Melderen 2011; Leplae et al., 2011) based on sequence similarities. However, the number of the TA genes that we know up to date seems to be still below the actual number (Sberro et al., 2013) .