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

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

One of the proposed approaches to the druggability of bacterial toxins is to identify peptides or small molecules that are able to disrupt the protein (antitoxin)-protein (toxin) interactions based on their binding interface (PPI-approaches; Labbé et al., 2013) . The binding affinities of the TA pair varies, making it difficult to estimate the dosage of the inhibitors: for instance the PezAT pair exhibited very strong binding affinities (binding constant in the femtomolar range), which is three to eight orders of magnitude higher than other TAs such as Phd-Doc, RelBE, CcdAB and even Epsilon-Zeta, which is a homologue of PezAT (Gazit and Sauer 1999; Camacho et al., 2002; Dao-Thi et al., 2005; Overgaard, Borch and Gerdes 2009; Mutschler, Reinstein and Meinhart 2010) . Even though PPI interfaces are very interesting targets to develop novel molecules, there are still not promising examples of drugs designed against TA interfaces. The use of high-throughput screening techniques to identify hits that act as i-PPIs in conjunction with the development of techniques to optimize the possible hits to discover proper leads (hit-to-lead techniques) is a matter not fully solved yet.