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 zeta 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.