BACKGROUND AND AIM: The global rise in antimicrobial resistance (AMR) has rendered many conventional antibiotics less effective, particularly against nosocomial pathogens such as , , , and . This study investigated the antimicrobial and synergistic effects of postbiotics derived from , , , and , administered alone or in combination with either linezolid (for ) or amikacin (for Gram-negative strains). MATERIALS AND METHODS: Postbiotics were obtained through anaerobic fermentation, followed by centrifugation and filtration. Cytotoxicity was assessed via MTT assays on Vero cell lines. Infection models involving pathogen-specific adhesion and invasion assays were used, with CFU/mL quantification and statistical evaluation by one-way ANOVA and Tukey's test. RESULTS: The postbiotics exhibited potent antimicrobial activity across all tested pathogens. Combined with linezolid, the dual and triple postbiotic formulations significantly enhanced antibacterial effects against from the early hours of incubation. Similarly, combinations with amikacin produced potent synergistic effects against , , and , particularly in triple combinations involving and . Postbiotics sometimes outperformed antibiotics, such as ST+LC postbiotics against . These findings suggest that postbiotics can enhance antibiotic efficacy-possibly by modulating membrane permeability, disrupting biofilms, or altering bacterial communication systems. Their low cytotoxicity and pathogen-specific responses indicate that postbiotics are safe and may be tailored for targeted use. CONCLUSIONS: In conclusion, postbiotic-antibiotic combinations, especially with linezolid and amikacin, present promising low-toxicity, synergistic therapeutic strategies. These results lay a strong foundation for advancing microbiome-based adjunct therapies to combat AMR in clinical settings.