Abstract
ABSTRACTDecades of research into bacterial persistence has been unable to fully characterize this antibiotic-tolerant phenotype, thereby hampering the development of therapies effective against chronic infections. Although some active persister mechanisms have been identified, the prevailing view is that cells become persistent because they enter a dormant state. We therefore characterized starvation-induced dormancy in Escherichia coli. Our findings indicate that dormancy develops gradually; persistence strongly increases during stationary phase and decreases again as persisters enter the viable but nonculturable (VBNC) state. Importantly, we show that dormancy development is tightly associated with progressive protein aggregation, which occurs concomitantly with ATP depletion during starvation. Persisters contain protein aggregates in an early developmental stage, while VBNC cells carry more mature aggregates. Finally, we show that at least one persister protein, ObgE, works by triggering aggregation, even at endogenous levels, and thereby changing the dynamics of persistence and dormancy development. These findings provide evidence for a genetically controlled, gradual development of persisters and VBNC cells through protein aggregation.
Highlights
IMPORTANCE While persistence and the viable but nonculturable (VBNC) state are currently investigated in isolation, our results strongly indicate that these phenotypes represent different stages of the same dormancy program and that they should be studied within the same conceptual framework
Other states of bacterial dormancy have been described. Among these is the viable but nonculturable (VBNC) state, a phenotype in which cells have lost the ability to grow on conventional media that otherwise support their proliferation, even though they remain viable. These VBNC cells cannot readily resume growth when provided with fresh nutrients but instead require specific conditions to resuscitate [17,18,19]
To gain more insight into bacterial dormancy, we studied the behavior of E. coli in stationary phase, the growth phase where dormancy sets in [22]
Summary
IMPORTANCE While persistence and the viable but nonculturable (VBNC) state are currently investigated in isolation, our results strongly indicate that these phenotypes represent different stages of the same dormancy program and that they should be studied within the same conceptual framework. Other states of bacterial dormancy have been described Among these is the viable but nonculturable (VBNC) state, a phenotype in which cells have lost the ability to grow on conventional media that otherwise support their proliferation, even though they remain viable. Important similarities between persisters and VBNC cells exist; both are dormant bacterial phenotypes and both are tolerant to high antibiotic concentrations [1, 17, 18, 20] Because of these similarities, the hypothesis that persisters and VBNC cells are conceptually similar is gaining momentum [14, 17, 18, 21]. Detailed experimental evidence of the dynamic nature of persister formation and VBNC transition as well as genetic and molecular mechanisms to support this hypothesis are currently lacking
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