Coordination of antifungal azoles to rhenium di- and tricarbonyl complexes results in compounds with enhanced antimicrobial efficacy—up to 32-fold minimum inhibitory concentration improvement—against methicillin-sensitive and methicillin-resistant Staphylococcus aureus over parent azoles. Cationic fac-[Re(CO)₃]⁺ complexes are consistently more potent than cis-[Re(CO)₂]⁺ species, with a ketoconazole derivative acting by disrupting membrane integrity.

Herein, a library of rhenium di- and tricarbonyl complexes featuring various antimicrobial azoles as monodentate ligands is synthesized and characterized. Their antimicrobial activity is evaluated against both methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA), and selected compounds are also assessed for cytotoxicity, yielding promising therapeutic indices. Notably, the complexation of antifungal azoles to the rhenium core enhances antimicrobial efficacy, with a compound exhibiting up to a 32-fold improvement in minimum inhibitory concentration (MIC) values relative to the parent azole. Structure–activity relationships indicate that cationic fac-[Re(CO)₃]⁺ complexes consistently outperform their cis-[Re(CO)₂]⁺ counterparts, and mechanistic studies suggest that active complexes disrupt bacterial membrane integrity and interfere with the electron transport chain. Complementary small-angle X-ray scattering and in silico analysis corroborate these findings, offering insights into the mechanism of action of this family of complexes.