Restoration of ampicillin susceptibility in drug-resistant enterococcus faecalis via synergistic therapy with co-functionalized gold nanoparticles

Enterococcus faecalis (E. faecalis), a leading pathogen associated with severe nosocomial infections, poses a major control challenge owing to its widespread multidrug resistance. Current first-line therapies for E. faecalis infections combine ampicillin (Amp) with gentamicin or ceftriaxone, yet this approach is plagued by inherent toxicity and a tendency to promote drug-resistant strain colonization. To explore novel strategies against E. faecalis infections, we devised a combined treatment regimen consisting of methimazole (MMI) -melamine (Mel) co-functionalized gold nanoparticles (Au NPs, Mel-MMI@Au NPs) and Amp. Experiments demonstrated that Mel-MMI@Au NPs outperformed their single-ligand counterparts (Mel@Au NPs or MMI@Au NPs) in both stability and antibacterial activity. By disrupting bacterial cell membranes, Mel-MMI@Au NPs enhance Amp penetration across bacterial barriers for targeted inhibition, reducing Amp's minimum inhibitory concentration (MIC) by eightfold. The fractional inhibitory concentration index (FICI) of the combination was determined to be 0.375 (below the synergism threshold of 0.5), confirming a robust synergistic antibacterial effect. This dual-modified Au NPs-antibiotic strategy achieves low-dose synergistic bactericidal activity, delays resistance evolution, and ensures favorable biosafety, thereby overcoming the limitations of single antibiotics and representing a promising approach against multidrug-resistant E. faecalis.