Role of toxin ζ and starvation responses in the sensitivity to antimicrobials

• Published in: PloS one Vol. 9; no. 1; p. e86615
• Main Authors: Tabone, Mariangela, Lioy, Virginia S, Ayora, Silvia, Machón, Cristina, Alonso, Juan C
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 2014; Public Library of Science (PLoS)
• Subjects: Anti-Bacterial Agents - pharmacology; Antibiotics; Antiinfectives and antibacterials; Antimicrobial agents; Antitoxins - biosynthesis; Antitoxins - genetics; Bacillus subtilis; Bacillus subtilis - drug effects; Bacillus subtilis - genetics; Bacillus subtilis - metabolism; Bacteria; Bacterial Toxins - genetics; Bacterial Toxins - metabolism; Biology; Cell growth; Drug Resistance, Bacterial - genetics; E coli; Escherichia coli; Firmicutes; Gene expression; Gene Expression Regulation, Bacterial; Genes, Bacterial; Guanosine Tetraphosphate - deficiency; Guanosine triphosphate; Guanosine Triphosphate - metabolism; Metabolism; Metabolites; Microbial Sensitivity Tests; Protein synthesis; Proteobacteria; Toxins; Transcription, Genetic; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0086615

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.