Is there a clear relationship between hipA and the phenotypic shift of persisters?

The number of persisters increases during late exponential and stationary phases. Also, the overexpression of HipA produces a high frequency of persisters (Falla and Chopra 1998). Similarly, mutation in hipA also produces a high frequency of persisters (Moyed and Bertrand 1983). Based on these findings, it was proposed that persister formation is governed by both deterministic mechanisms and by stochastic fluctuations in the expression of HipA. However, researchers have not provided any evidence to demonstrate such stochastic fluctuations in the levels of HipA following antibiotic treatment. Moreover, overexpression of a number of proteins can generate a high frequency of persisters, as indicated  previously.

hipA mutants can not be easily isolated even though persisters are present in any bacterial cultures. After plating approximately 10¹⁰ bacteria on agar plates containing different concentrations of ciprofloxacin for 96 h, Marcusson et al. (2005) found that some bacteria could survive the lethal action of the antibiotic. However, the survival of this subpopulation was not associated with any mutation in the hipA or hipB genes, indicating that the persistence of bacteria in the presence of antibiotics may not be due to hipA or hipB mutations.

Moreover, hip locus is restricted to relatively few bacterial species, (not even all strains of E. coli), and hence the antibiotic tolerance due to hip mutations may not be clinically significant (Falla and Chopra 1998). Similarly, persistence in many species of bacteria may not be related to hip (Falla and Chopra 1998).

Thus the role of hipA in the phenotypic shift of persisters is vague and obscure.

Falla, T. J., and Chopra, I. (1998). Joint tolerance to beta-lactam and fluoroquinolone antibiotics in Escherichia coli results from overexpression of hipA. Antimicrob Agents Chemother 42(12), 3282-4.

Moyed, H. S., and Bertrand, K. P. (1983). hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 155(2), 768-75.

Marcusson et al. (2005). Mutant prevention concentration of ciprofloxacin for urinary tract infection isolates of Escherichia coli. J Antimicrob Chemother 55(6): 938-43.