Compound amino acid synergizes ceftazidime-avibactam to eradicate extracellular and facultative intracellular MDR pathogens.

With the rise in antibiotic-resistant infections, enhancing the efficacy of currently available antibiotics is crucial to address this crisis. In this study, we demonstrate that the clinically approved amino acid formulation 18AA (18 amino acids) synergistically enhances ceftazidime-avibactam (CZA) efficacy against extracellular and intracellular multidrug-resistant (MDR) pathogens, including carbapenem-resistant (CR) strains. The CZA+18AA combination eliminated CR Escherichia coli (CR-ECO) and MDR Edwardsiella tarda. Synergy was consistently demonstrated across all 10 tested clinical isolates, including CR-ECO, MDR-ECO, MDR E. tarda, and other CR pathogens, and validated in animal infection models. Mechanistically, 18AA promotes inosine biosynthesis, activating CusS/CusR-CusC regulatory pathways to increase antibiotic influx. This enhanced drug uptake overcomes resistance mechanisms mediated by efflux pumps and β-lactamases. Notably, these inosine-activated pathways were identified as previously unknown resistant mechanisms in antibiotic-sensitive bacterial mutants. Our findings establish nutritional adjuvants as clinically translatable tools to potentiate existing antibiotics against intractable MDR/CR infections through targeted metabolic modulation.