Boosting Antibiotic Efficacy of Azole Drugs against Methicillin‐Resistant <i>Staphylococcus Aureus</i> 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.