Synergistic antibacterial activity and mechanism of arginine combined with florfenicol against Escherichia coli

The persistent escalation of antibiotic resistance poses a severe threat to global public health. As a common opportunistic pathogen, the rapid development of resistance in Escherichia coli (E. coli) poses severe challenges to clinical anti-infective therapy. Against this backdrop, the combined use of amino acids and antibiotics is considered an effective strategy against multidrug-resistant bacterial infections. This study investigated the antibacterial efficacy and mechanism of action of the combination of arginine (Arg) and florfenicol (FFC) against resistant E. coli. Results indicate that Arg significantly enhances the bactericidal activity of FFC against resistant E. coli both in vivo and in vitro, successfully reversing the resistance phenotype. Mechanistic studies reveal that Arg disrupts fatty acid β-oxidation by inhibiting the arginine succinyl-transferase (AST) pathway, leading to excessive free fatty acid (FFA) accumulation. This triggers membrane structural damage, energy metabolism disorders, and oxidative stress. Concurrently, Arg inhibits the expression and function of multidrug efflux pumps, such as AcrAB-TolC and EmrAB-TolC, reducing FFC efflux and increasing its intracellular concentration. This study systematically reveals a novel pathway whereby Arg synergistically enhances the antibacterial activity of FFC through dual mechanisms of metabolic reprogramming and efflux pump inhibition, providing theoretical support for the development and application of amino acid compounds as antibiotic adjuvants.