Strain-specific synergy: an oxo-rhenium(V) complex potentiates antibiotic efficacy in Staphylococcus aureus strains

In this study, a library of oxo-rhenium(V) complexes of general formula [Cl₃ReO(NN)] bearing diimine ligands was synthesized and fully characterized. The complexes were evaluated for antibacterial activity against Gram-positive and Gram-negative bacteria (MSSA, MRSA, E. coli, and P. aeruginosa). Increasing the lipophilicity of the diimine ligand led to an enhancement in biological activity. The most active compound, bearing NN = bathocuproine (complex 9), exhibited potent activity against S. aureus strains (MIC = 2 µM). Its toxicity profile was assessed in vitro and in vivo: cytotoxicity toward L929 fibroblasts afforded a therapeutic index (TI) of 4.9, while evaluation in the invertebrate model Artemia salina showed only 12.9% lethality at 4× MIC after 24 h, indicating a favorable preliminary safety profile. Mechanistic investigations in MSSA and MRSA revealed strain-specific synergistic interactions of 9 with chloramphenicol and tetracycline in MSSA, and with ampicillin in MRSA, increasing the therapeutic index up to 19.5. Notably, co-administration of sub-inhibitory concentrations of ampicillin and 9 suppressed MRSA growth for more than 72 h. Computational studies suggest that complex 9 may interfere with the β-lactam resistance pathway in MRSA.