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

Yusuke Himeoka,Namiko Mitarai,Lingchong You

doi:10.1371/journal.pcbi.1008655

Abstract

Prolonged lag time can be induced by starvation contributing to the antibiotic tolerance of bacteria. We analyze the optimal lag time to survive and grow the iterative and stochastic application of antibiotics. A simple model shows that the optimal lag time can exhibit a discontinuous transition when the severeness of the antibiotic application, such as the probability to be exposed the antibiotic, the death rate under the exposure, and the duration of the exposure, is increased. This suggests the possibility of reducing tolerant bacteria by controlled usage of antibiotics application. When the bacterial populations are able to have two phenotypes with different lag times, the fraction of the second phenotype that has different lag time shows a continuous transition. We then present a generic framework to investigate the optimal lag time distribution for total population fitness for a given distribution of the antibiotic application duration. The obtained optimal distributions have multiple peaks for a wide range of the antibiotic application duration distributions, including the case where the latter is monotonically decreasing. The analysis supports the advantage in evolving multiple, possibly discrete phenotypes in lag time for bacterial long-term fitness.

Highlights

When bacterial cells are transferred from a starving environment to a substrate-rich condition, it takes sometime before the cells start to grow exponentially
The optimal lag time exhibits a steep transition from immediate wake-up to over-sleep when the severeness of the antibiotics exceeds the threshold
We extend the model so that the population can be split into two subgroups with different average lag time, to show that there is a continuous transition from single-strategy to bet-hedging strategy when changing the antibiotics application probability and time

Summary

Introduction

When bacterial cells are transferred from a starving environment to a substrate-rich condition, it takes sometime before the cells start to grow exponentially This lag phase [1] is often considered as the delay during which the cells modify their gene expression pattern and intracellular composition of macromolecules to adapt to the new environment [2,3,4,5,6]. Having a subpopulation with long lag time can be beneficial under certain circumstances, for instance, when the nutrients are supplied together with antibiotics This is because antibiotics often target active cellular growth processes and dormant, non-growing cells are tolerant of the killing by antibiotics [10,11,12]. The lag phase can work as a shelter for the cells from lethal stress

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