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.
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.
Mariangela
M
Tabone
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.
Virginia S
VS
Lioy
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.
Silvia
S
Ayora
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.
Cristina
C
Machón
Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.
Juan C
JC
Alonso
D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000992:Antitoxins / Q000096:biosynthesis / Q000235:genetics; D001412:Bacillus subtilis / Q000187:drug effects* / Q000235:genetics* / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics* / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D005798:Genes, Bacterial; D006159:Guanosine Tetraphosphate / Q000172:deficiency; D006160:Guanosine Triphosphate / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D014158:Transcription, Genetic
D000900:Anti-Bacterial Agents; D000992:Antitoxins; D001427:Bacterial Toxins; D006159:Guanosine Tetraphosphate; D006160:Guanosine Triphosphate