Resonant activation: a strategy against bacterial persistence

TL;DR

This paper introduces a novel resonant activation strategy to induce phenotypic switching in bacterial persister cells, making them susceptible to antibiotics more efficiently, with potential applications in combating drug resistance.

Contribution

It demonstrates that resonant activation can be used to synchronize bacterial phenotypic switching, reducing antibiotic treatment time and dosage needed for sterilization.

Findings

Resonant activation exists in bacterial phenotypic switching.

RA can significantly reduce antibiotic treatment duration.

Coupled simulations show improved bacterial eradication efficiency.

Abstract

A bacterial colony may develop a small number of cells genetically identical to, but phenotypically different from other normally growing bacteria. These so-called persister cells keep themselves in a dormant state and thus are insensitive to antibiotic treatment, resulting in serious problems of drug resistance. In this paper, we proposed a novel strategy to "kill" persister cells by triggering them to switch, in a fast and synchronized way, into normally growing cells that are susceptible to antibiotics. The strategy is based on resonant activation (RA), a well-studied phenomenon in physics where the internal noise of a system can constructively facilitate fast and synchronized barrier crossings. Through stochastic Gilliespie simulation with a generic toggle switch model, we demonstrated that RA exists in the phenotypic switching of a single bacterium. Further, by coupling single cell level and population level simulations, we showed that with RA, one can greatly reduce the time and total amount of antibiotics needed to sterilize a bacterial population. We suggest that resonant activation is a general phenomenon in phenotypic transition, and can find other applications such as cancer therapy.