Theragnostic Dual-Action Platform: Ruthenium p-Cymene-Derived Metalloantibiotics With NIR-II Photoacoustic Spectral Signal

This study initiates the development of Ru1, a metalloantibiotic derived from p-cymene, which delivers dual functionality. Our approach begins with the design and synthesis of half-sandwich ruthenium complexes, Ru1-Ru11. By varying the structure of the ancillary ligand, the biological activities of eleven ruthenium complexes against five bacterial strains were explored. Most active, Ru1 (4 µg mL⁻¹) and Ru 11 (1 µg mL−1) was solicited for further study. To assess the safety of these compounds, hemolytic activity and cytotoxicity were evaluated against human red blood cells (RBCs) and the HEK cell line, respectively. Based on these results, Ru1 was selected for further investigation. Ru1 exhibited significant efficacy against MRSA (methicillin-resistant S. aureus) and VRSA (vancomycin-resistant S. aureus). Additionally, Ru1 exhibited strong DNA-binding affinity (K_b = 1.73*10⁵ M⁻¹ and 1.6 *10⁵ M⁻¹). Molecular docking studies further highlighted Ru1's potent interaction with the active sites of key bacterial proteins, including S. aureus MurB, topoisomerase II DNA gyrase, and 1BNA, with binding energies of −12.05 kcal/mol, −6.30 kcal/mol and −7.77 kcal/mol, respectively. Furthermore, Ru1 showed high photoacoustic signal intensity at 902 nm in MSOT imaging, underscoring its potential as a dual-function therapeutic and diagnostic (theragnostic) agent.