Bacterial persistence and the hip genes of E.coli

Bacterial persistence is a poorly understood phenomenon by which a small fraction of bacteria in a population survive prolonged exposure to lethal concentrations of antibiotics. An important distinction between persistence and resistance to antibiotics is that persistence occurs in only a very small number of cells in a population whereas resistance is a characteristic of the entire population. Furthermore, persistent survivors of antibiotic exposure produce offspring that are equally susceptible to antibiotic as the parent cells and give rise to new persister cells at the same low frequency as the parental cells. In contrast, resistant cells pass the trait on to all offspring and produce a genetically uniform culture in which all cells survive subsequent exposure to antibiotic.

Mutations in the hip locus of E. coli, which includes hipA and hipB, confer a high frequency of persistence. Whereas wild type cells survive at a frequency of one cell in a million following antibiotic exposure, hipA7 mutants survive at a frequency of one cell per hundred. The hip genes are expressed coordinately from a toxin-antitoxin module located in the chromosomal terminus. HipA is a toxin that inhibits cell growth when expressed in excess of HipB. HipB is a Cro-like repressor protein that autoregulates the hip operon and also binds directly to HipA to inactivate its toxic effects. The mechanism by which cells express the high persistence phenotype is unknown, as is the normal physiological role and biochemical activities of HipA and HipB. It is not known what component in the cell acts as the target of HipA, how mutations in hipA convert a toxic protein to one that is capable of saving the cell, or how HipB prevents the toxic effects of HipA. Our goals are to elucidate the mechanism of high persistence and attempt to understand how the hip genes confer this survival response in E. coli.