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Impacts of global transcriptional regulators on persister metabolism

Wendy W K Mok1, Mehmet A Orman1, Mark P Brynildsen2

  • 1Department of Chemical and Biological Engineering, Princeton University, Princeton, New Jersey, USA.

Antimicrobial Agents and Chemotherapy
|February 26, 2015
PubMed

Insights

Bacterial persisters are rare cells that tolerate antibiotics. Targeting cyclic AMP/cyclic AMP receptor protein (cAMP/CRP) significantly impairs persister metabolism, making them susceptible to antibiotics.

Area of Science:

  • Microbiology
  • Molecular Biology
  • Drug Discovery

Background:

  • Bacterial persisters are phenotypic variants exhibiting high antibiotic tolerance, contributing to chronic and relapsing infections.
  • Targeting persister metabolism is a promising therapeutic strategy, but knowledge is limited due to isolation challenges.
  • Persister catabolic activity can be measured by their ability to enable aminoglycoside (AG) killing.

Purpose of the Study:

  • To investigate the role of seven global transcriptional regulators (ArcA, Cra, cAMP receptor protein [CRP], DksA, FNR, Lrp, and RpoS) in bacterial persister metabolism.
  • To understand how these regulators influence the metabolic activity of persisters and their susceptibility to antibiotics.

Main Methods:

  • Utilized a novel assay measuring persister catabolic activity based on aminoglycoside (AG) potentiation.
  • Systematically evaluated the impact of deleting key transcriptional regulators on persister metabolism.
  • Quantified the effect of regulator deletion on the ability of AGs to kill persisters.

Main Results:

  • The absence of cyclic AMP receptor protein (CRP) abolished AG potentiation across all tested metabolites.
  • Perturbation of CRP significantly diminished persister metabolic capabilities.
  • Deletion of CRP eliminated the efficacy of AGs in eradicating persisters.

Conclusions:

  • Cyclic AMP/cyclic AMP receptor protein (cAMP/CRP) plays a crucial role in bacterial persister metabolism.
  • Targeting the cAMP/CRP pathway offers a potential strategy to enhance antibiotic efficacy against persister cells.
  • Understanding persister metabolism is key to developing new treatments for persistent bacterial infections.

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