Interdisciplinary Program of Genetics, Bioinformatics, and Computational Biology, Virginia Polytechnic Institute and State University, Blacksburg, VA 24060, USA.
Phys Biol. 2010 Feb 10;7(1):16013. doi: 10.1088/1478-3975/7/1/016013.
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.
一个细菌菌落可能会产生一小部分细胞,这些细胞在遗传上与其他正常生长的细菌相同,但表型上不同。这些所谓的持久细胞使自己处于休眠状态,因此对抗生素治疗不敏感,导致严重的耐药问题。在本文中,我们提出了一种通过触发它们以快速和同步的方式切换到对抗生素敏感的正常生长细胞来“杀死”持久细胞的新策略。该策略基于共振激活(RA),这是物理学中一个研究得很好的现象,其中系统的内部噪声可以建设性地促进快速和同步的势垒穿越。通过带有通用切换开关模型的随机 Gillespie 模拟,我们证明了 RA 存在于单个细菌的表型转换中。此外,通过耦合单细胞水平和群体水平的模拟,我们表明,通过 RA,可以大大减少杀死细菌群体所需的抗生素的时间和总量。我们认为共振激活是表型转变中的一种普遍现象,并可以在癌症治疗等其他领域找到应用。