Proteome Remodeling of a Carbapenem-Resistant Escherichia coli Strain upon Meropenem Exposure

Carbapenem-resistant Escherichia coli poses a serious threat to global health, with limited treatment options and potentially fatal outcomes. Beyond horizontally acquired resistance genes, other cellular pathways are remodeled in the resistant phenotype, but these systemic responses remain poorly understood. Here, tandem mass tag-based quantitative proteomics was used to characterize the response of E. coli strain CCUG 70745 to Meropenem. Two inhibitory concentrations (128 and 192 μg/mL), anchored to the MIC of the isolate (128 μg/mL), were compared with an antibiotic-free control after 15 min. The analysis quantified 60% of the theoretical proteome, identifying 172 and 813 differentially expressed proteins at 128 and 192 μg/mL, respectively. Canonical resistance determinants, including β-lactamases and efflux pumps, were altered, as well as proteins involved in cell-wall formation, membrane transport, and signal transduction. Gene set enrichment analysis highlighted oxidative phosphorylation, ABC transporters, two-component systems, and cofactor metabolism. Increased abundances of two-component-system and membrane-integrity proteins were consistent with a coordinated, dose-dependent stress response, and interaction networks linked a cell-division module to efflux and metabolic adaptation. These results suggest that Meropenem engages both primary and auxiliary resistance-associated processes, providing a proteomic framework that may guide therapies targeting bacterial metabolism and membrane functions.