# Structure, Biology, and Therapeutic Application of Toxin-Antitoxin Systems in Pathogenic Bacteria
###### Abstract  
Bacterial toxin-antitoxin (TA) systems have received increasing attention for their diverse identities, structures, and functional implications in cell cycle arrest and survival against environmental stresses such as nutrient deficiency, antibiotic treatments, and immune system attacks. In this review, we describe the biological functions and the auto-regulatory mechanisms of six different types of TA systems, among which the type II TA system has been most extensively studied. The functions of type II toxins include mRNA/tRNA cleavage, gyrase/ribosome poison, and protein phosphorylation, which can be neutralized by their cognate antitoxins. We mainly explore the similar but divergent structures of type II TA proteins from 12 important pathogenic bacteria, including various aspects of protein-protein interactions. Accumulating knowledge about the structure-function correlation of TA systems from pathogenic bacteria has facilitated a novel strategy to develop antibiotic drugs that target specific pathogens. These molecules could increase the intrinsic activity of the toxin by artificially interfering with the intermolecular network of the TA systems. toxins-antitoxin system; type II; structure-function correlation; pathogenic bacteria; novel antibiotic target +
Footnote †: journal: _Journal of the Royal Society Interface_  
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to diverse stressful environments such as nutrient deficiency, antibiotic treatment, bacteriophage infection, immune system attack, oxidative stress, and high temperature [11; 12]. Depending on the types of TA systems, the activation of the toxin can eventually cause slow cell growth or cell cycle arrest, as is most frequently found in dormant persister cells [6; 13; 14; 15]. Cell death, which is caused by excessive expression of the toxin, might benefit the maintenance of the whole population. A more widely accepted hypothesis is that the toxin is responsible for the cell arrest overcoming the temporary adversity. The hypothesis could be supported by the findings that later expression of the antitoxin can neutralize the virulence of the toxin and that organisms that are able to grow slowly or be dormant carry a large number of TA operons. For example, _Mycobacterium tuberculosis_ harbours at least 30 functional TA operons covering five families of toxins, whereas its non-pathogenic counterpart, the faster-growing _Mycobacterium smegmatis_, has only three functional TA operons [16; 17; 18; 19]. The dormant cell that has a low metabolic activity becomes partly or fully insensitive to the mechanism of action of antibiotic drugs, rendering many pathogenic bacteria resistant to multidrug. This physiological state can switch back to a growing state once the drugs are eliminated. Therefore, this phenomenon, referred to as bacterial persistence, has been an obstacle to effective antibiotic treatment for many infectious diseases. The persistent cell is physiologically different from antibiotic-resistant mutants that proliferate in the presence of antibiotic drugs. It was initially proposed that in _Escherichia coli_, a high level of bacterial persistence is induced by high-persistence protein A (HipA) [20], which is later known to be encoded by the type II _hipBA_ TA locus. HipA facilitates a transition to a persistent, antibiotic-insensitive cell by increasing the basal level of the synthesis of the secondary messenger (p)ppGpp [21], which is extensively distributed throughout bacteria. (p)ppGpp functions as an effector of the stringent response that induces the metabolism of the persistent state [22; 23]. In _E. coli_, the persistence phenotype relies on (p)ppGpp, which activates type I and type II TA systems in a regulatory pathway involving the GTPase Obg, Lon protease, and polyphosphate [22; 24; 25]. (p)ppGpp inhibits the activity of exopolynophatases, causing polyphosphate to accumulate.