Role of Toxin ζ and Starvation Responses in the Sensitivity to Antimicrobials

A fraction of otherwise antimicrobial-sensitive Bacillus subtilis cells, called persisters, are phenotypically tolerant of antimicrobial treatment. We report that, independently of B. subtilis' growth phase, transient ζ toxin expression induces a dormant state and alters cellular responses so that cells are more sensitive to antimicrobials with different modes of action. This outcome is modulated by fine tuning (p)ppGpp and GTP levels: i) in the presence of low “dysregulated” (p)ppGpp levels (as in relA (−) cells) hyper-tolerance to both toxin and antimicrobials was observed; ii) physiological or low (p)ppGpp levels (as in the wild-type, sasA (−), sasB (−) and relA (−) sasA (−) context) show a normal toxin and antimicrobial tolerance; and iii) lower levels (in relA (−) sasB (−)) or absence of (p)ppGpp (in the relA (−) sasA (−) sasB (−) context), in concert with elevated GTP levels, potentiate the efficacy of both toxin and antimicrobial action, rendering tolerance vulnerable to eradication.