## 1 Introduction  
Microbial type II toxin-antitoxin (TA) systems, which are stress regulators, are generally composed of two genes organized in an operon, encoding a toxin (T) and an antitoxin (A) protein [1; 2; 3]. RelE and \(\zeta\) are the most abundant prokaryotic toxins in nature [4], with \(\zeta\) been the most ubiquitous toxin in Firmicutes [5; 6]. The plasmid- or chromosomal-encoded TA complexes (\(\zeta\)-\(\varepsilon\) or PezT-PezA) consist of two monomeric long-living \(\zeta\) (PezT) toxins separated by a dimeric short-living \(\varepsilon_{2}\) (PezA\({}_{2}\)) antitoxin, forming a \(\zeta\)\(\varepsilon_{2}\zeta\) (PezTPEzA\({}_{2}\)PezT) inactive complex [7; 8]. The toxins of the \(\zeta\) family are highly conserved, \(\zeta\) (286 amino acids long polypeptide) shares 42% of sequence identity with PezT (253 amino acids long). Both toxins have a very similar three-dimensional structure, and mutations in equivalent positions show similar phenotypes [7; 8]. However, antitoxin \(\varepsilon\) (90 amino acids long polypeptide) only shares 17% of sequence identity with the C-terminal region of antitoxin PezA (158 amino acids long). Despite this low sequence identity, the C-terminal region of PezA folds into a three helix bundle similar to that of \(\varepsilon\)[7; 8]. Both Firmicutes toxins, \(\zeta\) and PezT might interact with ATP-Mg\({}^{2^{+}}\) or GTP-Mg\({}^{2^{+}}\), with uridine diphosphate-\(N\)-acetylglucosamine (UNAG) and with \(\varepsilon_{2}\) (PezA) antitoxin [7; 9]. These toxins, as part of the biological non-toxic heterotetrameric (\(\zeta\)\(\varepsilon_{2}\zeta\) or PezTPEzA\({}_{2}\)PezT) complex, interact with UNAG [9]. However, in this inactive complex, the toxin cannot interact with ATP-Mg\({}^{2+}\)/GTP-Mg\({}^{2^{+}}\), because the antitoxin helixes block the entry of the nucleotide cofactor into the binding pocket of the toxin through steric hindrance [7; 8; 10]. Toxin PezT phosphorylates the 3'-OH group, which is an essential precursor of bacterial cell wall biosynthesis, leading to phosphorylated, unreactive, UNAG-3P [9]. Toxin PezT was specific for UNAG, because it failed to phosphorylate uridine diphosphate-\(N\)-acetylgalactosamine [9]. Hence, \(\zeta\)/PezT toxin blocks the first committed step in the peptidoglycan synthesis pathway, that is the transfer of an enolpyruvate residue from phosphoenolpyruvate to position 3 of UNAG [9]. Toxin \(\zeta\), under various stress stimuli, can be activated as a result of \(\varepsilon_{2}\) antitoxin degradation by stress-induced proteases or under conditions that prevent TA gene expression [8; 11; 12; 13]. Such activation permits free wt \(\zeta\) (or its short-living variant (\(\zeta\)Y83C, half-life \(\sim\)28 min)) to trigger a heterogeneous set of protective responses, and the expression of \(\sim\)2% of total _Escherichia coli_ or _Bacillus subtilis_ genes, so that these toxins show a bacteriostatic, rather than a bactericidal behavior [12; 14]. In _B. subtilis_ cells, \(\zeta\)Y83C toxin expression increases RelA expression, reduces expression of lipid metabolism genes, and decreases the GTP pool without apparent alteration of the proteome within the first 15 min upon induction [12; 14; 15]. Within the 15-60 min interval, \(\zeta\)Y83C expression reduces the synthesis of macromolecules, decreases ATP levels, increases the alarmone guanosine (penta)tetraphosphate ([p] ppGpp) pool, and alters the membrane potential without affecting the SOS response [14; 15]. Within 60-90 min, \(\zeta\)Y83C expression decreases the pool of a novel metabolite, probably UNAG [14]. Finally, expression of \(\zeta\) for 120-240 min leads to a fraction (25%-35%) of the population stained with propidium iodide (PI), suggesting a membrane compromise; but subsequent expression of the \(\varepsilon_{2}\) antitoxin facilitates the exit from the dormant state and a fraction of cells recover their membrane \"alteration\" [12; 14; 15]. A different effect is observed if _B.