# Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria
## 2 Functions of Six Different Types of Bacterial TA Systems
### Type I  
Type I TA systems have a non-coding RNA antitoxin that complementarily binds to the toxin-encoding mRNA, which results in toxin mRNA degradation or inhibits toxin translation [74; 75; 76]. Type I toxin and antitoxin genes are independently transcribed from their own promoters, whereas other type TA operons are commonly co-transcribed from a single promoter upstream of the antitoxin gene. Most of type I toxins are small hydrophobic peptides that disrupt bacterial membrane integrity and thereby cause defects in membrane potential and cell division. They are predicted to have a conserved \(\alpha\)-helical transmembrane domain for pore formation, but their cellular functions and action mechanisms are highly diverse [74; 75; 77]. It remains to be investigated whether the pore formation provokes a detergent-like effect, as is found in many antibacterial peptides [78].  
Type I TA systems are not well characterized relative to type II TA systems, probably because current genomic techniques have not yet identified a large number of type I TA systems on plasmids and chromosomes. These systems were initially discovered on the par locus of plasmid pAD1 and the _sok-hok_ pair of plasmid R1 [43; 79]. The par system is the most extensively studied type I TA system, which has several homologues on plasmids and on chromosomes of Gram-positive bacteria [80]. The par locus on pAD1 can be transcribed into two small RNAs: toxin-encoding RNA I and antisense RNA II [81]. They form a complex by various complementary interactions. The _sok-hok_ module participates in the extension of bacterial lag phase to adapt to stressful environments such as high temperature and antibiotic treatment [82]. The interaction between (p)ppGpp and Obg induces the expression of the Hok toxin through an unknown mechanism, which leads to membrane depolarization and a persistent state [24]. In addition, there are chromosomal type I TA systems in _E. coli_ that include _oltsC-shoB_[46; 83], _istR-tisB_[41], _rdID-ldrD_[84], _agrB-dinQ_[85], _sibC-libS_[86], _orzO-zorO_[86], and _symR-symE_ pairs [51]. Intriguingly, among these pairs, the DinQ and LdrD toxins of the _agrB-dinQ_ and _rdID-ldrD_ systems can induce nucleoid condensation, and the SymE toxin of the _symR-symE_ system lacks putative transmembrane domain and cleaves cellular mRNA. Similar to SymE, RalR encoded by the _ralA-ralR_ type I TA locus of the _E. coli_ racophage act as a non-specific endonuclease that cleaves methylated or non-methylated DNAs [87]. In _B. subtilis_, since the _ratA-txpA_ pair was initially identified as the type I TA module located on the chromosome [48], four type I toxin families, TxpA/BsrG, BsrH/BsrE, YonT, and YhzE, have been proposed on the basis of sequence similarities between the different toxins of _B. subtilis_[88]. Most of the type I toxins from _B. subtilis_ reside in prophage elements and are proposed to be required for prophage maintenance. In _Staphylococcus aureus_, the SprF1-SprG1 system was identified as an unconventional type I TA system that utilizes two initiation codons in a single reading frame to produce two SprG1 toxic peptides. The function of SprG1 is suppressed by SprF1, which is dual-acting antisense RNA [89]. Toxic peptides can be extracellularly secreted and then lyse human host erythrocytes and competing bacteria with different strengths [89]. Recently, a regulatory crosstalk between the type I TA system _ratA-txpA_ and its adjacent type II TA system _mazEF_ was discovered in the human pathogen _Enterococcus faecalis_[77]. The MazeF complex can not only function as an autorepressors but also increase transcription levels of antitoxin-encoding _ratA_ by using different promoters. RatA decreases the stability of the toxin-encoding _txpA_ mRNA.