# Targeting Type II Toxin-Antitoxin Systems as Antibacterial Strategies
## 1 Introduction  
The emergence of antibiotic-resistant bacteria is a critical issue in modern medicine [1]. Considerable efforts are being made to identify novel antimicrobials to combat infectious diseases caused by evolving multi-resistant pathogens. Bacterial toxin-antitoxin (TA) systems represent promising targets for such compounds. These small genetic modules encode two components: a stable toxin (always a protein) that recognizes a specific cellular target, and a labile antitoxin (protein or RNA molecule), produced in excess, that counteracts the activity of the toxin [2]. TAs have been classified into several groups based on the molecular nature of the antitoxin and their mode of interaction with their cognate toxin. The most prevalent and most extensively studied are type II TA systems, encoding proteic antitoxins which neutralize the toxin by forming TA complexes under optimal growth conditions [3; 4]. These two-gene _loci_ are organized in operons, whose expression is tightly regulated by both the antitoxin and toxin-antitoxin complexes [5; 6]. Degradation of the antitoxin by cellular proteases liberates the toxin, which elicits a bacteriostatic or bactericidal effect [7; 8; 9; 10].  
TA _loci_ were initially identified within bacterial plasmids, where they function as post-segregational cell killing systems (PSK), providing stable maintenance for their carrier replicon in a bacterial population due to the elimination of plasmid-less cells [11]. A surprising observation was that TA systems are also highly abundant and widespread in the chromosomes of free-living bacteria (both Gram-negative and Gram-positive), as well as in archaea [12]. More detailed studies have revealed that these TAs may be involved in important biological processes, such as (i) the stringent response, helping cells to survive stressful conditions by limiting various metabolic activities [13], (ii) programmed cell death [14] and (iii) biofilm formation [15]. In the light of these observations, it seems likely that chromosomal TA _loci_ have been transferred to extrachromosomal replicons and adopted as plasmid stabilization systems.  
The toxins of TA systems target essential cellular processes of bacteria; therefore, they may be considered intracellular \"molecular time bombs\", which are activated under certain environmental conditions [16]. Compounds that can artificially activate TA toxins may form a new class of antimicrobials that could represent an alternative to antibiotics [17]. Type II TA systems are ubiquitous in bacteria [18], and their mechanisms are fairly well characterized [18], so they would appear to be excellent candidates for testing the merits of this idea.  
The potential use of TA systems in combatting bacterial infections has been examined in several valuable reviews [19; 20; 21; 22]. Here, we describe the most promising antibacterial strategies employing type II TA systems and discuss possible undesirable effects of their application, such as the induction of persister cells, biofilm formation and toxicity to eukaryotic cells. In addition, the distribution of type II TA systems among clinically relevant human pathogens is described, which may help to identify appropriate TA candidates for fighting particular infections.