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

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 (Hobby et al, 1942, Exp. Biol. Med. 50: 281-285; Bigger, 1944, The Lancet 244: 497-500). Despite its biomedical relevance, the origin of the phenomenon is still unknown and as a rare, phenotypically resistant sub-population, persisters are notoriously hard to study and define. Using computerised tracking we show that persisters are small at birth and slowly replicating. We also determine that the high persister mutant strain of E. coli, HipQ, is associated with the novel phenotype of reduced phenotypic inheritance (RPI). We identify the gene responsible for RPI, ydcI, which encodes a novel transcription factor, and propose a mechanism whereby loss of phenotypic inheritance causes increased frequency of persisters. These results provide a novel insight into the generation and maintenance of phenotypic variation and provide potential new targets for the development of novel therapeutic strategies that tackle persistence in bacterial infections.