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

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

Many alternatives to the classical treatments have been proposed (Kaplan and Mason 1998 , Mandell et al., 2007 , Imamovic and Sommer 2013 . There is not a single drug that can cure all infections, and combination of different therapies seem to be the more contingency, if not the only, approach especially when development of new antimicrobials seems to be still far ahead. We can envisage some variants of the classical alternatives (Table 2) , such as (i) development of chemical derivatives of the known antibiotics by chemical modification of the active molecule; (ii) alternate use of available antibiotics, the so-called antibiotic cycling, in which one category of antibiotics is rotated with one or more different antibiotic classes that exhibit comparable activity, although cautions have been raised against this approach (Brown and Nathwani 2005) , and (iii) implementation of more biologic approaches like phage therapy (reviewed in Deresinski 2009), new vaccines and antimicrobial peptides. More novel approaches include (i) development of entirely novel classes of antibiotics; (ii) the use of new small molecules as antivirulence or antipersisters drugs (Conlon et al., 2013) ; (iii) employment of virulence factors as antibacterials (Marra 2004 ) and (iv) search for novel targets (Alonso et al., 2007) . The finding that bacteria that have developed resistance to one antibiotic may display a greater sensitivity to a second one from a distinct structural class (a phenomenon known as collateral sensitivity) has opened new and exciting approaches to design antibiotic treatments (Imamovic and Sommer 2013) . Furthermore, the identification of virulence genes which are associated with the bacterial mobilome (plasmids, bacteriophages and integrative and conjugative elements, ICEs) has thrown light on mechanism of spread of AbR among pathogenic bacteria and on how these bacteria are able to evolve very rapidly as to adapt to new niches and environments (Wellington et al., 2013) . It is clear that the mobilome as a joint bacterial response to the selective pressure posed by humans plays a central role in the 'arms race' between pathogens and humans. Thus, an interesting strategy that would be worth exploring further was initiated with the identification of inhibitors that target the transfer of DNA among bacteria, which were termed conjugation inhibitors (Fernandez-Lopez et al., 2005) .