Department of Microbial and Cellular Sciences, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, United Kingdom.
Advanced Technology Institute, Department of Electronic Engineering, University of Surrey, Guildford GU2 7XH, United Kingdom.
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4152-4157. doi: 10.1073/pnas.1914741117. Epub 2020 Feb 6.
Whenever a genetically homogenous population of bacterial cells is exposed to antibiotics, a tiny fraction of cells survives the treatment, the phenomenon known as bacterial persistence [G.L. Hobby , 50, 281-285 (1942); J. Bigger, 244, 497-500 (1944)]. Despite its biomedical relevance, the origin of the phenomenon is still unknown, and as a rare, phenotypically resistant subpopulation, persisters are notoriously hard to study and define. Using computerized tracking we show that persisters are small at birth and slowly replicating. We also determine that the high-persister mutant strain of , , is associated with the phenotype of reduced phenotypic inheritance (RPI). We identify the gene responsible for RPI, , which encodes a transcription factor, and propose a mechanism whereby loss of phenotypic inheritance causes increased frequency of persisters. These results provide insight into the generation and maintenance of phenotypic variation and provide potential targets for the development of therapeutic strategies that tackle persistence in bacterial infections.
当一个遗传同质的细菌细胞群体暴露于抗生素时，一小部分细胞能在治疗中存活下来，这种现象被称为细菌持续存在[G.L.霍比，50，281-285（1942）；J.比格，244，497-500（1944）]。尽管其具有重要的生物医学意义，但该现象的起源仍不清楚，而且由于持久存在的细胞是罕见的、表型上具有抗性的亚群，因此很难对其进行研究和定义。我们使用计算机化追踪技术表明，持久存在的细胞在出生时很小并且复制缓慢。我们还确定了，，的高持久存在突变株与表型遗传减少（RPI）的表型相关。我们鉴定了负责 RPI 的基因，，它编码一个转录因子，并提出了一种机制，其中表型遗传的丧失导致持久存在的细胞的频率增加。这些结果为表型变异的产生和维持提供了深入的了解，并为开发治疗策略提供了潜在的靶点，以解决细菌感染中的持续存在问题。
