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

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

We have presented here a number of plausible, and sometimes, speculative, approaches to tackle the druggability of TAs. We have also tried to discuss different angles on the subject as well as to present it in a thought-provoking manner. Fortunately, an increasing number of protein TA structures are being solved, which will facilitate the study of the TA interfaces. This, in turn, will permit to perform in silico docking experiments to design molecules that may disrupt the T: A interactions. In our opinion, a fragment-based drug design to deal with the disruption of the TAs interactions seems to be one of the most likely approaches to develop TAs as good candidates to enter into the antibacterials pipeline. Perhaps the most useful approach would be (i) rationale design of the fragments library based on the known structures of the TAs solved so far (Park SJ et al., 2013) , and Figure 6 . What are minicells? Bacterial cells that harbour mutations in some of their genes involved in cell division (like min mutants in E. coli or divIV mutants in B. subtilis) were shown to have a septum abnormally positioned, resulting in a cell of normal size and a minicell. Because of their small size (around 400 nm), minicells can be separated and purified from normal-sized cells by employment of two successive buoyant density sucrose gradients. Purified minicells can be stored with 10% glycerol at -70 o C without loss of their biological activity. Due to the abnormal chromosome segregation, minicells lack chromosomal DNA; however, they are metabolically active and have all the biochemical machinery to synthesize proteins. When a minicell-producing strain harbours a plasmid, these plasmids would segregate into the normal cells and into the minicells. Thus, determination of de novo protein synthesis by minicells has been successfully employed to characterize plasmid-encoded proteins, including TAs (Lacks et al., 1986 , Bravo et al., 1987 , 1988 ).