Copper Single-Atoms Loaded on Molybdenum Disulphide Drive Bacterial Cuproptosis-Like Death and Interrupt Drug-Resistance Compensation Pathways

Abstract The development of highly efficient and multifunctional nanozymes holds promise for addressing the challenges posed by drug-resistant bacteria. Here, copper single-atom-loaded MoS 2 nanozymes (Cu SAs/MoS 2 ) were developed to effectively combat drug-resistant bacteria by synergistically integrating the triple strategies of oxidative damage, cuproptosis-like death and disruption of cell wall synthesis. Density functional theory revealed that each Cu center coordinated with three sulfur ligands, enhancing the adsorption of H 2 O 2 , which reduced the activation energy of the key step by 17%, thereby improving peroxidase-like (POD-like) activity. The generation of reactive oxygen species in combination with Cu SAs/MoS 2 glutathione peroxidase-like (GSH-Px-like) for glutathione scavenging resulted in an imbalance in redox homeostasis within bacteria. Cu SAs/MoS 2 , which act as nanopioneers, drive oxidative stress to initiate the process of cuproptosis-like death, leading to abnormal aggregation of lipoylated proteins and inactivation of iron‒sulfur cluster proteins. Moreover, Cu SAs/MoS 2 inhibited the biosynthesis of the peptidoglycan synthesis precursors d -glutamate and m-diaminopimelic acid and disrupted the peptidoglycan cross-linking process mediated by penicillin-binding proteins, effectively blocking the compensatory cell wall remodeling pathway of β-lactam-resistant bacteria. Overall, Cu SAs/MoS 2 with multiple functions can not only efficiently kill bacteria but also decelerate the development of bacterial resistance to combat drug-resistant bacterial infections.