Boosting Antibiotic Efficacy of Azole Drugs against Methicillin‐Resistant Staphylococcus Aureus by Coordination to Rhenium Carbonyl Complexes

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.