Deciphering the Antibacterial Mechanism of Hollow Sphere Metal–Organic Frameworks against <i>Staphylococcus aureus</i> and Its Application in Wound Healing

Staphylococcus aureus infection and antimicrobial resistance (AMR) to antibiotics are two significant factors that pose escalating threats to public health, potentially leading to persistent pain or even death. Consequently, there is an urgent need for the development of alternative antibacterial materials. In this study, we have successfully developed a biocompatible nanosystem based on hollow spherical zeolitic imidazolate framework-67 (ZIF-67 HS), which exhibits remarkable bactericidal efficacy against Gram-positive S. aureus both in vitro and in vivo. Importantly, our findings demonstrate that prolonged exposure of S. aureus to subminimum inhibitory concentrations of ZIF-67 HS does not induce secondary resistance as observed with conventional antibiotics; instead, it maintains sustained susceptibility toward antibiotic-resistant strains. Multiomics analyses (including transcriptomics, metabolomics, and metalomics) have indicated that ZIF-67 HS regulates 95 genes, 261 metabolites, and 2 metal elements in S. aureus. Through bioinformatics analysis in combination with bioassays, we demonstrated that ZIF-67 HS disrupted multiple essential pathways in the pathogen, including amino acid metabolism, iron metabolism, membrane transport, reactive oxygen species (ROS), and S. aureus infection pathways. Our findings suggest that ZIF-67 HS induces bacterial death through multiple mechanisms rather than a single target and highlight its long-lasting antibacterial properties. This study presents valuable insights into the potential of nanobiomedicine for eradicating bacteria and elucidates the related molecular mechanism.