Glutamate Potentiates Meropenem Killing of Carbapenem-Resistant Pseudomonas aeruginosa by Increasing Outer Membrane Permeability to Increase Uptake.

Carbapenem-resistant Pseudomonas aeruginosa (CR-PA) has been designated a "priority" pathogen by the World Health Organization, calling for the development of new control strategies. However, no such new drugs are currently available. In this study, we restored bacterial sensitivity to meropenem through a metabolic state-reprogramming approach. Glutamate was identified as the key reprogramming metabolite that converts an antibiotic-resistant metabolic state to an antibiotic-sensitive state in both lab-evolved and clinically isolated CR-PA. This reprogramming leads to increased meropenem uptake, which overcomes drug efflux and enzymatic hydrolysis, elevates intracellular drug concentrations, and restores meropenem killing efficacy in vitro and in vivo. Mechanistically, glutamate metabolic flux enters fatty acid biosynthesis via the pyruvate cycle, elevating lauric acid levels. Increased lauric acid enhances outer membrane permeability, thereby raising intracellular meropenem accumulation. Glutamate is a nutritional amino acid, and the dose used in this study is lower than that in routine clinical use. Collectively, these findings provide an effective, convenient, and economical approach to restore meropenem killing efficacy against CR-PA.