HMR-3004

The escalating threat of Methicillin-resistant Staphylococcus aureus (MRSA) infections seriously endangers human health, so facing the immense threat of drug-resistant bacteria, discovering new and potent antibacterial drugs less prone to inducing resistance is urgently needed. In this study, four amphiphilic ruthenium polypyridyl complexes were synthesized, namely [Ru(II)(bpy)₂(DIPPB)] (PF₆)₃ (Ru-1), [Ru(II)(dmb)₂(DIPPB)] (PF₆)₃ (Ru-2), [Ru(II)(dmob)₂(DIPPB)] (PF₆)₃ (Ru-3) and [Ru(II)(bpy)₂(DIPPB)] (PF₆)₃ (Ru-4). Among these complexes, complex Ru-4 incorporates N-methylimidazole and quaternary ammonium cations, in vitro experiments have demonstrated the presence of potent antibacterial activity against Staphylococcus aureus and MRSA, accompanied by low hemolytic activity and a diminished tendency to induce drug resistance. It acts by disrupting bacterial membranes via interaction with phosphatidylglycerol and phosphatidylethanolamine, increasing permeability, elevating ROS levels, and causing content leakage. Transcriptomics confirmed its impact on membrane-related genes. Notably, in vivo experimental results demonstrated that Ru-4 exhibits superior efficacy compared to vancomycin, thereby identifying it as a promising therapeutic candidate for MRSA infection treatment.

Metal-based chemoimmunotherapy has recently attracted considerable interest for its ability to stimulate tumor-specific immunity beyond direct cytotoxic effects. These immunostimulatory outcomes are commonly mediated through immunogenic cell death (ICD). However, metal complex scaffolds capable of eliciting antitumor immune responses through mechanisms other than ICD remain relatively unexplored. In this study, we designed and synthesized six novel half-sandwich Ru(II) complexes featuring an isoquinoline alkaloid-derived C^N ligand, p-cymene, and various 4-pyridyl ancillary ligands. Among these, Ru-4 demonstrated superior cytotoxicity. Mechanistic studies indicated that Ru-4-induced ROS accumulation plays a key role in reducing β-catenin levels, upregulating MHC-I expression, and promoting CCL4 secretion, critical factors for T-cell infiltration and activation. Moreover, its combination with anti-PD1 therapy resulted in synergistic antitumor efficacy. This work represents the first report of a half-sandwich metal-based complex that targets the Wnt/β-catenin pathway to sensitize tumors to immune checkpoint blockade (ICB), offering a novel approach for designing metal-based chemoimmunotherapeutic agents.