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

Mariangela Tabone; Virginia S Lioy; Silvia Ayora; Cristina Machón; Juan C Alonso

doi:10.1371/journal.pone.0086615

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

PLoS One. 2014 Jan 29;9(1):e86615. doi: 10.1371/journal.pone.0086615. eCollection 2014.

Authors

Mariangela Tabone¹, Virginia S Lioy¹, Silvia Ayora¹, Cristina Machón¹, Juan C Alonso¹

Affiliation

¹ Departamento de Biotecnología Microbiana, Centro Nacional de Biotecnología, (CNB-CSIC), Madrid, Spain.

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / pharmacology*
Antitoxins / biosynthesis
Antitoxins / genetics
Bacillus subtilis / drug effects*
Bacillus subtilis / genetics*
Bacillus subtilis / metabolism
Bacterial Toxins / genetics*
Bacterial Toxins / metabolism
Drug Resistance, Bacterial / genetics
Gene Expression Regulation, Bacterial*
Genes, Bacterial
Guanosine Tetraphosphate / deficiency
Guanosine Triphosphate / metabolism
Microbial Sensitivity Tests
Transcription, Genetic

Substances

Anti-Bacterial Agents
Antitoxins
Bacterial Toxins
Guanosine Tetraphosphate
Guanosine Triphosphate

Grants and funding

The research was partially financed by the European Union (Grant Health-F3-2009-223111) and by the Ministerio de Economia y Competividad (MINECO) (BFU2012-39879-C02-01) to J.C.A., by the MINECO (BFU2012-39879-C02-02) and by the Comunidad de Madrid (CM-BIO0260-2006) to S.A. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.