Copper Single-Atoms Loaded on Molybdenum Disulphide Drive Bacterial Cuproptosis-Like Death and Interrupt Drug-Resistance Compensation Pathways
Wenqi Wang, Xiaolong Wei, Bolong Xu, Hengshuo Gui, Yan Yan, Huiyu Liu, Xianwen Wang
Abstract
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.