Molecular mechanisms of multiple toxin–antitoxin systems are coordinated to govern the persister phenotype

Toxin-antitoxin systems are ubiquitous and have been implicated in persistence, the multidrug tolerance of bacteria, biofilms, and, by extension, most chronic infections. However, their purpose, apparent redundancy, and coordination remain topics of debate. Our model relates molecular mechanisms to...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-07, Vol.110 (27), p.10891-10891
Main Authors: Fasani, Rick A., Savageau, Michael A.
Format: Article
Language:English
Subjects:
Anti-Bacterial Agents - pharmacology
Antitoxins - biosynthesis
Antitoxins - genetics
Antitoxins - physiology
Bacteria - genetics
Bacteria - growth & development
Bacteria - metabolism
Bacterial Toxins - antagonists & inhibitors
Bacterial Toxins - biosynthesis
Bacterial Toxins - genetics
Biofilms
Biological Sciences
Drug resistance
Genotype & phenotype
Models, Biological
Molecular biology
Phenotype
PNAS Plus
PNAS PLUS: SIGNIFICANCE STATEMENTS
Signal transduction
Systems Biology
Toxins
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Summary:Toxin-antitoxin systems are ubiquitous and have been implicated in persistence, the multidrug tolerance of bacteria, biofilms, and, by extension, most chronic infections. However, their purpose, apparent redundancy, and coordination remain topics of debate. Our model relates molecular mechanisms to population dynamics for a large class of toxin-antitoxin systems and suggests answers to several of the open questions. The generic architecture of toxin-antitoxin systems provides the potential for bistability, and even when the systems do not exhibit bistability alone, they can be coupled to create a strongly bistable, hysteretic switch between normal and toxic states. Stochastic fluctuations can spontaneously switch the system to the toxic state, creating a heterogeneous population of growing and nongrowing cells, or persisters, that exist under normal conditions, rather than as an induced response. Multiple toxin-antitoxin systems can be cooperatively marshaled for greater effect, with the dilution determined by growth rate serving as the coordinating signal. The model predicts and elucidates experimental results that show a characteristic correlation between persister frequency and the number of toxin-antitoxin systems.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1301023110