Analysis of CRP-Mediated Persister Cell Metabolism in Bacteria

Antibiotic resistance is regarded as a global public health crisis and is much worse in many developing countries. Bacterial persistence contributes to this problem because persisters are thought to facilitate the recurrence of chronic and biofilm related infections (e.g., tuberculosis, cystic fibrosis lung infection, chronic wound infections, and urinary tract infections) and serve as a reservoir for the emergence of drug resistant mutants. Persisters enter a non-growing state before antibiotic treatments, survive lethal concentrations of antibiotics, and become resuscitated after the conclusion of the antibiotic treatments. Upon the removal of antibiotic treatment, persisters can regain the ability to initiate cell growth and produce daughter cells that are sensitive to the same antibiotic treatment. The Orman lab found that persisters survive antibiotic treatment by getting their energy from self-digestion. This causes self-inflicted damage that gives persister cells its non-growing characteristic. They also found that reducing stationary phase metabolic activity decreases persister levels since they cannot undergo self-digestion and get their energy to survive the antibiotic treatment. Since most metabolism related genes are regulated by CRP/cAMP, targeting any key component related to CRP will reduce bacterial persistence. During my SURF project, I identified persistence related genes mediated by CRP/cAMP and analyzed measured metabolites in wild-type and knockout E. coli strains to identify differences in the metabolic profile. By understanding the genes and metabolites involved in persister formation, certain drugs can be identified to target specific metabolic pathways that eliminate persisters and substantially improve drug efficacy.