The Biology of Persister Cells in Escherichia coli

Abstract

Bacterial persisters are dormant, antibiotic-tolerant cells that are phenotypic variants formed within a regularly growing, drug-susceptible population. They differ from genetically or phenotypically resistant cells in that their survival of antibiotic treatment is rooted in a dormant physiology and not in the obstruction of drug–target interactions. In this chapter, I assembled a concise overview of the formation, survival, and evolution of persisters formed by the model organism Escherichia coli. Though the formation of persister cells has stochastic aspects, it is often induced by starvation or stress as a specialized differentiation of part of the population (responsive diversification). Consequently, the phenotypic heterogeneity of persisters and regularly growing cells is commonly interpreted as a bet-hedging strategy that ensures population survival under the threat of catastrophic events and that at the same time optimizes the benefit from favorable conditions. Multiple different molecular mechanisms have been implicated in persister cell formation and can be grouped into two major classes. Non-specific mechanisms affect bacterial physiology on a global scale via, for example, alterations of energy metabolism, or are purely stochastic events that shut down cellular processes by an accidental malfunctioning (persistence as stuff happens). Conversely, specialized mechanisms directly inhibit antibiotic targets often through activation of fine-tuned molecular switches known as toxin-antitoxin modules. In addition, the repair of cellular damage caused by antibiotics is critical for the resuscitation of persister cells. A major obstacle to coherently interpreting these findings is the fragmented nature of the literature and several controversies that should be consolidated by future studies.