Regulation of phenotypic variability by a threshold-based mechanism underlies bacterial persistence

Abstract

In the face of antibiotics, bacterial populations avoid extinction by harboring a subpopulation of dormant cells that are largely drug insensitive. This phenomenon, termed "persistence," is a major obstacle for the treatment of a number of infectious diseases. The mechanism that generates both actively growing as well as dormant cells within a genetically identical population is unknown. We present a detailed study of the toxin-antitoxin module implicated in antibiotic persistence of Escherichia coli. We find that bacterial cells become dormant if the toxin level is higher than a threshold, and that the amount by which the threshold is exceeded determines the duration of dormancy. Fluctuations in toxin levels above and below the threshold result in coexistence of dormant and growing cells. We conclude that toxin-antitoxin modules in general represent a mixed network motif that can serve to produce a subpopulation of dormant cells and to supply a mechanism for regulating the frequency and duration of growth arrest. Toxinantitoxin modules thus provide a natural molecular design for implementing a bet-hedging strategy.single-cell | stochasticity | systems biology

Phenotypic Diversity Using Bimodal and Unimodal Expression of Stress Response Proteins

“…An example of bimodal protein expression in E. coli is persistence, where fewer than 1% of cells in the population are in a resistant, nongrowing state that is tolerant to antibiotics (4). The switch between the growing and latent states is stochastic, and cells can stay in each state for many generations (39,40). The advantage of bimodality in this case may come from the extended time the cells spend in the resistant state.…”

Role of persister cells in chronic infections: clinical relevance and perspectives on anti-persister therapies

“…Recently, this observation was attributed to the presence of reversibly drug-tolerant cells, also called persisters (Sharma et al, 2010). Moreover, as has been shown for bacterial persister cells (Rotem et al, 2010), the cause for this heterogeneity may lie in natural cell-to-cell variations of protein levels, rather than in differences in genotype or cell cycle state (Spencer et al, 2009). It is not unlikely that insights gained by studying either of these seemingly radically different model systems will ultimately lead to advances in controlling both.…”

“…The hipB gene product is a small Cro-like protein with a helix-turn-helix DNA-binding domain. It functions as a repressor for the hipBA operon by binding to four operator sites on the promoter region of hipBA and inhibits HipA activity through covalently binding to the toxin (Black et al, 1991(Black et al, , 1994; (Rotem et al, 2010). Detailed knowledge of the crystal structure of HipA and the binding mechanism with HipB make this a very interesting target for the rational design of an anti-persistence therapy.…”

The evolutionary advantage of heritable phenotypic heterogeneity

“…Phenotypic variability is often caused by switches between different regulatory states that produce bi-or multi-stability, due to fluctuations in levels of methylation at CpG sites, for example in mRNA transcription, or protein translation 37 . Our focus here, however, is not on the specific mechanisms or bio-physical forces that govern these phenotypic state transitions 9,22,38,39 . Instead, we aim to elucidate the population-level consequences of increased phenotypic availability from a given genotype and how this non-genetic variability determines the long-term evolutionary outlook of a population 6,[40][41][42] .…”