A Genome-Scale Modeling Approach to Investigate the Antibiotics-Triggered Perturbation in the Metabolism of Pseudomonas aeruginosa

Recent studies indicate that pretreating microorganisms with ribosome-targeting antibiotics may promote a transition in the microbial phenotype, such as the formation of persister cells; i.e., those cells that survive antibiotic treatment by becoming metabolically dormant. In this letter, we developed the first genome-scale modeling approach to systematically investigate the influence of ribosome-targeting antibiotics on the metabolism of Pseudomonas aeruginosa. An approach for integrating gene expression data with metabolic networks was first developed to identify the metabolic reactions whose fluxes were positively correlated with gene activation levels. The fluxes of these reactions were further constrained via a flux balance analysis to mimic the inhibition of antibiotics on microbial metabolism. It was found that some of metabolic reactions with large flux change, including metabolic reactions for homoserine metabolism, the production of 2-heptyl-4-quinolone, and isocitrate lyase, were confirmed by existing experimental data for their important role in promoting persister cell formation. Metabolites with large exchange-rate change, such as acetate, agmatine, and oxoglutarate, were found important for persister cell formation in previous experiments. The predicted results on the flux change triggered by ribosome-targeting antibiotics can be used to generate hypotheses for future experimental design to combat antibiotic-resistant pathogens.