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

TL;DR

This paper investigates the optimal bacterial lag time strategies under antibiotic stress, revealing phase transitions and the advantage of diverse phenotypes for survival and growth.

Contribution

It introduces a theoretical framework for determining optimal lag time distributions, highlighting discontinuous and continuous transitions and the benefit of multiple phenotypes.

Findings

Optimal lag time exhibits a discontinuous transition with increased antibiotic severity.

Presence of multiple phenotypes with different lag times can be advantageous.

Optimal lag time distributions often have multiple peaks, even with monotonically decreasing antibiotic application durations.

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 exhibits a discontinuous transition when the severeness of the antibiotic 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.