Loss of phenotypic inheritance associated with mutation leads to increased frequency of small, slow persisters in .

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.