Effect of palladium(II) complexes on NorA efflux pump inhibition and resensitization of fluoroquinolone-resistant Staphylococcus aureus: in vitro and in silico approach

Abstract

Staphylococcus aureus leads to diverse infections, and their treatment relies on the use of antibiotics. Nevertheless, the rise of antibiotic resistance poses an escalating challenge and various mechanisms contribute to antibiotic resistance, including modifications to drug targets, enzymatic deactivation of drugs, and increased efflux of antibiotics. Hence, the quest for innovative antimicrobial solutions has intensified in the face of escalating antibiotic resistance and the looming threat of superbugs. The NorA protein of S. aureus, classified as an efflux pump within the major facilitator superfamily, when overexpressed, extrudes various substances, including fluoroquinolones (such as ciprofloxacin) and quaternary ammonium. Addressing this, the unexplored realm of inorganic and organometallic compounds in medicinal chemistry holds promise. Notably, the study focused on investigating two different series of palladium-based metal complexes consisting of QSL_PA and QSL_PB ligands to identify a potent NorA efflux pump inhibitor that can restore the susceptibility to fluoroquinolone antibiotics. QSL_Pd5A was identified as a potent efflux pump inhibitor from the real-time efflux assay. QSL_Pd5A also resensitized SA1199B to ciprofloxacin at a low concentration of 0.125 µg/mL without elucidating cytotoxicity on the NRK-62E cell line. The in vitro findings were substantiated by docking results, indicating favorable interactions between QSL_Pd5A and the NorA efflux pump.