# Targeting Type II Toxin-Antitoxin Systems as Antibacterial Strategies
## 2 Type II TA Systems in Pathogenic Bacteria  
Since 2011, the studies of TA systems have been assisted by the Toxin-Antitoxin Database (TADB) [23], updated to version 2.0 in 2017 [24]. Currently, TADB 2.0 lists 6194 type II TA _loci_[24] categorized, where possible, in two partially interdependent ways. The first classification scheme uses a system based on the structural and functional characteristics of the toxin proteins [25; 26]. There are 11 families of two-component type II TA systems: _cd_, _hicBA_, _hipBA_, _mazEF_, _parD(PemKl)_, _parDE_, _phd-doc_, _relBE_ (with 5 subfamilies--_relBE_, _higBA_, _yfeM-yoeB_, _ygiTU(mqsAR)_ and _prlF-yhaV_), _vapBC_, _mosAT_ and _yeeU_. The less numerous three-component type II TA systems are _o-c-c_, _pasABC_ and _paaR-paaA-parE_. The second classification scheme is based on a set of 44 conserved toxin-antitoxin protein domain pairings and better reflects the versatility and modularity of TA systems [27]. Figure 1 summarizes the variety of type II TA systems identified in bacterial species commonly associated with pathogenesis in humans. Among type II TA system (sub)families, four are most frequently encountered: _vapBC_, _relBE_, _mazEF_ and _higBA_, and these account for \(\sim\)80% of the listed _loci_. (An expanded list of type II TA systems of bacterial pathogens, organized into toxin-antitoxin domain pair groupings, is given in Supplementary Figure S1.) Due to their widespread occurrence within the accessory genomes of human pathogens, their probable role in pathogenicity and potential as therapeutic targets, type II TA systems have been a subject of growing interest in recent years. Several systematic reviews have focused on the distribution and roles of the TA systems in clinically relevant pathogenic bacteria, including _Escherichia coli_, _Mycobacterium tuberculosis_, _Neisseria gonorrhoeae_, _Streptococcus_ spp., _Burkholderia_ spp. and species of the ESKAPE group (_Enterococcus faecium_, _Staphylococcus aureus_, _Klebsiella pneumoniae_, _Acinetobacter baumannii_, _Pseudomonas aeruginosa_ and _Enterobacter_ spp.) [19; 28; 29; 30; 31; 32]. An increasing number of studies are being undertaken to describe the repertoire of TA systems in pathogenic bacteria at the level of a given strain or of a whole taxon. Not only do such approaches shed light on the importance of overall TA system networks with respect to the physiology, virulence and evolution of pathogens, but thanks to the large-scale genome comparisons involved, they also lead to the discovery of novel TA _loci_. M tuberculosis_ is notable for its abundance of TA systems, especially of the _vapBC_, _mazEF_ and _relBE_ families (Figure 1), and their activity has been linked to the regulation of adaptive responses to stress caused by interaction with the host and drug treatment [33]. Predictably, _M. tuberculosis_ has been the object of studies on the common expression patterns of TA _loci_[34; 35; 36], as well as cross-activation between homologous systems [37; 38], and putative interaction between non-cognate toxin-antitoxin pairs, which remains controversial [39; 40; 41]. Furthermore, comparative studies of the distribution of TA systems in mycobacteria have demonstrated the variability of TA _loci_ between different _M. tuberculosis_ lineages, and led to the discovery of putative novel TA systems [42; 43]. Similarly, the body of knowledge about the TA systems of _S. aureus_[44] was recently expanded by several studies providing insights into the association between the TA systems landscape and strain phenotypes [45; 46; 47; 48]. A recent in-depth analysis of the diversity and distribution of type II and type IV TA systems in the genomes of  
Figure 1: Type II toxin–antitoxin (TA) systems identified in human pathogenic bacteria according to the toxin family classification system [25; 26] as collected in the Toxin–Antitoxin Database (TADB) 2.0 [24]. The number given for an individual species is the sum of the values for all strains of a given taxon.