For example, they showed that YefM could interact only with its cognate toxin YoeB, whereas RelB1 and RelB2 were capable of interacting with any of the RelE1, RelE2, or YoeB toxins. Moreover, YefM is able to bind its promoter on its own, whereas RelB1 and RelB2 need to be part of the TA complex, but not necessarily with their cognate toxin [56]. Such multiple ways to inactivate toxins or to regulate expression of TA genes further emphasizes the complexity of toxin-antitoxin networks in this bacterium. Transcriptional analyses revealed that RelBE2 is among the 10 most induced TA systems in _M. tuberculosis_ drug-tolerant persisters [12]. Furthermore, while the _yefM/yoeB_, _relBE1_, and _relBE2_ genes were all expressed during bacterial growth in Luria-Bertani medium, only _relE1_, _relB2_, and _yoeB_ transcripts could be detected in human macrophages at late stages of infection [55]. All three _relE1_, _relE2_, and _yoeB_ toxin-encoding genes were also up-regulated in response to antibiotic treatment, as well as in lung tissues of infected mice [18], thus, suggesting that such toxins could contribute to persistence. Accordingly, overexpression of each of the three toxins also led to an increased level of drug-tolerant persisters and the deletion of either _relE2_ or _yoeB_, but not _relE1_, reduced the formation of persisters by four- to nine-fold [18]. However, none of the toxin mutants was affected for survival in mice model, indicating that the toxins may not individually contribute to infection _in vivo_[18]. The first identified _higBA_ locus (host inhibition of growth) originates from the Rts1 plasmid of _Proteus vulgaris_ where it functions as an addiction module [57]. TA members of this family encode- for a RelE-like toxin directly followed by an antitoxin that contains a HTH Xre-domain [29, 58]. The HigB toxin from Rts1 plasmid was shown to act as a ribosome-dependent ribonuclease with a mechanism distinct from RelE and YoeB, in which the toxin binds the ribosome 50S subunit and cleaves preferentially at AAA sequences on the processing mRNAs [59]. HigB1 and HigB2 from _V. cholerae_ were also studied and showed different, less specific cleavage patterns [60]. The recently solved crystal structure of HigBA from _P. vulgaris_ revealed a heterotetameric HigB-(HigA)2-HigB complex in which two HigA-HigB heterodimers are assembled via additional HigA-HigA interactions [61]. The structure of HigA in such complex was very similar to that of previously identified HigA-like antitoxin structures obtained in the absence of toxin (_i.e._,: HigA from _Coxiella burnetii_, PDB entry 3 trb and YddM from _E. coli_ CFT073, PDB entries 2 ICT and 2 ICP; [62]), thus, indicating that HigA may not undergo major conformational changes upon toxin binding. Remarkably, the structure also shows that inactivation of HigB may not occur by direct occlusion of its active site by HigA, thus suggesting a novel mechanism of inhibition in which the large HigB-(HigA)2-HigB complex might sterically inhibit interaction of the toxin with ribosome-bound mRNA, as proposed by the authors [61]. _M. tuberculosis_ H37 Rv possesses three TA systems homologous to HigBA, _i.e._, two classical two-component TA pairs HigBA2 (Rv2022c-Rv2021c) and HigBA3 (Rv3182-Rv3183) and one atypical tripartite system, named TAC (Toxin-Antitoxin-Chaperone), composed of a HigBA1 pair (Rv1955-Rv1956) coupled to a molecular chaperone Rv1957 (Figure 1). To date, nothing is known about the involvement of HigBAs in _M. tuberculosis_ pathogenesis. However, it has been shown that both _higBA1_ and _higBA2_ locus, which are located on the same genomic island comprising other genes potentially involved in dormancy, are among the 10 most up-regulated TA systems in _M. tuberculosis_ drug-tolerant persisters [12, 63]. While the effect of HigB2 toxin on bacterial growth was not investigated yet, conditional expression of HigB3 did not significantly affect _M. smegmatis_ growth (Figure 1) [16]. In contrast, HigB1 exhibits a robust toxicity both in _E.