DataSheet_1_Effect of palladium(II) complexes on NorA efflux pump inhibition and resensitization of fluoroquinolone-resistant Staphylococcus aureus: in vitro and in silico approach.docx

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.

金黄色葡萄球菌（Staphylococcus aureus）可引发多种感染，其临床治疗依赖抗生素的使用。然而，抗生素耐药性的出现带来了日益严峻的挑战，且多种机制参与了抗生素耐药性的形成，包括药物靶点修饰、药物的酶促失活以及抗生素外排作用增强。鉴于抗生素耐药性问题不断加剧，且超级细菌的威胁迫在眉睫，针对新型抗菌解决方案的探索正不断加强。金黄色葡萄球菌的NorA蛋白属于主要易化子超家族（major facilitator superfamily）的外排泵（efflux pump），当其过表达时，可将包括氟喹诺酮类（fluoroquinolones，如环丙沙星ciprofloxacin）和季铵盐（quaternary ammonium）在内的多种物质泵出胞外。针对这一问题，药物化学领域中尚未被充分探索的无机及有机金属化合物展现出应用潜力。本研究聚焦于两类分别基于QSL_PA和QSL_PB配体的钯基金属配合物，旨在筛选可恢复细菌对氟喹诺酮类抗生素敏感性的强效NorA外排泵抑制剂。通过实时外排实验，研究人员筛选出强效外排泵抑制剂QSL_Pd5A。在0.125 µg/mL的低浓度下，QSL_Pd5A即可使SA1199B菌株对环丙沙星恢复敏感性，且未对NRK-62E细胞系产生细胞毒性。体外实验结果得到了分子对接（docking）结果的验证，表明QSL_Pd5A与NorA外排泵之间存在良好的相互作用。