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

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

Several mechanisms of action of the different toxins have been identified (Table 3 ) via inhibition of replication by targeting the DNA gyrase (e.g. CcdB or ParE) (Jiang et al., 2002; van Melderen 2002) ; inhibition of peptidoglycan synthesis by phosphorylating the peptidoglycan precursor uridine diphosphate-N-acetylglucosamine (e.g. Zeta/PezT) ; and inhibition of translation by several alternative mechanisms such as ( (iv) inhibiting aminoacyl-tRNA synthetase (e.g. HipA) (Germain et al., 2013) , or (v) phosphorylating the conserved threonine of the translation elongation factor EF-Tu (e.g. Doc) (Castro-Roa et al., 2013). The toxic effect could be bacteriostatic or bactericidal, depending upon the type of toxin and time of exposure (Nieto et al., 2010) . TAs operons can reside on chromosomes, on plasmids or on both, in single or multiple copies. In several instances, they are also found within horizontal mobile elements like pathogenic islands, ICEs, integrative mobilizable elements and on large superintegrons (Rowe-Magnus et al., 2003; Szekeres et al., 2007; Wozniak and Waldor 2009; Gerdes 2013) . From the beginning of the discovery of TAs, plasmid-encoded TAs were believed to only function in exerting post-segregational killing (PSK) of daughter cells that do not inherit the parental TA-encoded plasmid (Bravo, de Torrontegui and Díaz 1987; Bravo et al., 1988; López-Villarejo et al., 2012) . However, an additional role of plasmidencoded TA ccd F as a transmissible persistence factor was reported (Tripathi et al., 2012) , indicating that the role of plasmidencoded TAs might be far more complex than envisaged. On the other hand, the functions of the chromosomally encoded TAs are even more debatable (van Melderen and Saavedra De Bast 2009; van Melderen 2010; Makarova et al., 2011) . They have been suggested to be involved in at least the following processes: (i) global stress response leading to inhibition of cell growth under unfavourable condition, but the toxicity is reversible when a normal environment is restored (Christensen et al., 2001) ; (ii) bacterial programmed cell death, i.e. an altruistic behaviour in which some of the cells sacrifice themselves to release nutrients for the benefit of the siblings or community as a whole when nutrients are scarce (Engelberg-Kulka and Glaser 1999); (iii) anti-addiction module: the chromosomally encoded TAs protect the cells against PSK mediated by the plasmid-encoded TA homologues (de Bast, Mine and van Melderen 2008); (iv) persistence leading to inhibition of cells growth mediated by TAs to reduce the susceptibility of the cells to antibiotic (Gerdes and Maisonneuve 2012); (v) biofilm formation (Ren et al., 2004; Kim et al., 2009; Kolodkin-Gal et al., 2009 ); (vi) maintenance of the bacterial mobilome by stabilization of the dispensable chromosomal regions to prevent extensive genetic loss (Rowe-Magnus et al., 2003; Szekeres et al., 2007) ; (vii) increase survival rate and virulence (Ren, Walker and Daines 2012) , and (viii) colonization of niches (Norton and Mulvey 2012).