Abstract
Toxin-antitoxin (TA) modules are ubiquitous in bacteria, but their biological importance in stress adaptation remains a matter of debate. The inactive ζ-ε2-ζ TA complex is composed of one labile ε2 antitoxin dimer flanked by two stable ζ toxin monomers. Free toxin ζ reduces the ATP and GTP levels, increases the (p)ppGpp and c-di-AMP pool, inactivates a fraction of uridine diphosphate-N-acetylglucosamine, and induces reversible dormancy. A small subpopulation, however, survives toxin action. Here, employing a genetic orthogonal control of ζ and ε levels, the fate of bacteriophage SPP1 infection was analyzed. Toxin ζ induces an active slow-growth state that halts SPP1 amplification, but it re-starts after antitoxin expression rather than promoting abortive infection. Toxin ζ-induced and toxin-facilitated ampicillin (Amp) dormants have been revisited. Transient toxin ζ expression causes a metabolic heterogeneity that induces toxin and Amp dormancy over a long window of time rather than cell persistence. Antitoxin ε expression, by reversing ζ activities, facilitates the exit of Amp-induced dormancy both in rec+ and recA cells. Our findings argue that an unexploited target to fight against antibiotic persistence is to disrupt toxin-antitoxin interactions.
Highlights
Bacteria have evolved complex regulatory controls and a diverse repertoire of cell transition states in response to various environmental stresses
Our findings argue that an unexploited target to fight against antibiotic persistence is to disrupt toxin-antitoxin interactions
Resistance, tolerance, and persistence are independent solutions used by bacteria to survive an antibiotic action (Supplementary Figure S1) [1]
Summary
Bacteria have evolved complex regulatory controls and a diverse repertoire of cell transition states in response to various environmental stresses. Antitoxin ε reverses the toxic effect exerted by ζ in cell proliferation, and only ~10% of total cells remained stained with propidium iodide [38,42,43] This is consistent with the fact that the toxin ζ action is reversible by nature even in distantly related bacteria, such as E. coli and B. subtilis cells [38,43]. Transient ε expression reverses the negative effect of the toxin and indirectly awakes Amp dormants to levels observed in the rec+ control. This toxin-mediated sensitization of bacterial cells to Amp and the understanding of the conditions that inhibit antitoxin action will facilitate targeted engineering of their activity towards the development of anti-persistence agents
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