When to wake up? The optimal waking-up strategies for starvation-induced persistence

Abstract

Dormancy of bacteria can be induced by starvation stress as prolonged lag time, and often contributes to the antibiotic tolerance of bacteria. We analyze the optimal lag time for wake-up from the starvation to survive the iterative and stochastic application of antibiotics. By using a population dynamics model, we show that the optimal lag time exhibits a discontinuous transition from zero lag time to a finite lag time when the severeness of the application of the antibiotic is increased. When the bacterial populations are able to split into subpopulations to have two phenotypes with different average lag time, the fraction of the finite lag time population shows continuous transition when changing the severeness of antibiotics application. The result suggests the possibility of reducing tolerant bacteria by controlled usage of antibiotics application.

Phenotypic-dependent variability and the emergence of tolerance in bacterial populations

“…How do the statistical features of the environmental variability translate into the emerging lag-time distributions? [22,27,28,82,122,123].…”

“…In the last section we discuss recent alternatives to Markovian processes, i.e. including some form of "memory", which can give rise to non-exponential residence times, to describe this type of waking-up phenomena [81,82].…”

Emergence of growth and dormancy from a kinetic model of theEscherichia colicentral carbon metabolism

“…In rough terms, it checks if the distribution needs at least two Gaussian functions with distant peaks (see SI Text section.2 for the details). Note that in the following analysis, the computation of the expansion ratio and PCA were performed for the trajectories converted to the logarithmic scale so that the dynamic behaviours of the chemicals with low concentrations are also reflected in the analysis 5 .…”

“…R becomes smaller than 1 if there is any point on x which is closer to y(0) than x(0). This argument is symmetric for the swap of the indices 5. As a side effect of the logarithm-conversion, the behaviours of the chemicals with quite low concentrations may be too much highlighted.…”

Emergence of growth and dormancy from a kinetic model of the Escherichia coli central carbon metabolism

“…This dormancy is a beneficial strategy for surviving the nutrient-poor conditions as it can lower the cell's nutrient requirements [4]. Also, the dormancy is known as the main cause of bacterial persistence that has a high tolerance to antibiotics, and thus, has been gathering attention from a wide range of fields from microbiology to therapeutic studies [2,3,5,6].Notable changes in the timescale of cellular physiology are happening in the dormant cells. It has been implied that the dormant cells have a sort of memory capacities: The lag time was shown to depend on the length of time that the cells are starved [7,8] and the death rates of the starved cells differ depending on the previous culture conditions even though the starvation condition is identical [9].…”