  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.
