Abstract
While persisters are a health threat due to their transient antibiotic tolerance, little is known about their phenotype and what actually causes persistence. Using a new method for persister generation and high‐throughput methods, we comprehensively mapped the molecular phenotype of Escherichia coli during the entry and in the state of persistence in nutrient‐rich conditions. The persister proteome is characterized by σS‐mediated stress response and a shift to catabolism, a proteome that starved cells tried to but could not reach due to absence of a carbon and energy source. Metabolism of persisters is geared toward energy production, with depleted metabolite pools. We developed and experimentally verified a model, in which persistence is established through a system‐level feedback: Strong perturbations of metabolic homeostasis cause metabolic fluxes to collapse, prohibiting adjustments toward restoring homeostasis. This vicious cycle is stabilized and modulated by high ppGpp levels, toxin/anti‐toxin systems, and the σS‐mediated stress response. Our system‐level model consistently integrates past findings with our new data, thereby providing an important basis for future research on persisters.
Highlights
Bacterial persistence is a phenotypic state of transient antibiotic tolerance that threatens human and animal health (Cohen et al, 2013; Grant & Hung, 2013)
We performed the same analyses on cells that we switched from glucose to medium without a carbon source, generating starved cells, which allowed us to investigate the effect of nutrient presence on the persister phenotype
Using a recently proposed way to generate persisters in large quantities, and high-throughput analytical methods, we comprehensively mapped the molecular phenotype of cells during the entry and in the state of persistence in nutrient-rich conditions
Summary
Bacterial persistence is a phenotypic state of transient antibiotic tolerance that threatens human and animal health (Cohen et al, 2013; Grant & Hung, 2013) This state is typically associated with dormancy in nutrient-rich environments and with absent or low antibiotic target activity, which renders most antibiotics ineffective (Lewis, 2010) and can cause recurrence of infections with, for example, Mycobacterium, Staphylococcus, or Pseudomonas species (Dawson et al, 2011; Fauvart et al, 2011; Cohen et al, 2013). One persistence model are the antibiotic-tolerant cells that are formed stochastically in growing cultures (Maisonneuve et al, 2013; Feng et al, 2014) Another model for persistence are starved cells (i.e. cells in stationary phase) (Nguyen et al, 2011), which have diminished or absent antibiotic target activity due to the absence of nutrients (Fung et al, 2010). A third model for persistence was recently proposed: It was found that after certain nutrient shifts (i.e. abrupt shifts or gradual shifts resembling diauxie) a large number of non-/ slow-growing and antibiotic-tolerant cells (i.e. persisters) emerge in nutrient-rich conditions (Amato & Brynildsen, 2014; Kotte et al, 2014)
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