MOF nanozyme mediated bacterial metabolic regulation to intervene MRSA antibiotic tolerance for enhanced antimicrobial efficacy

Abstract

The rising prevalence of multidrug-resistant pathogens poses a significant threat to human health, with methicillin-resistant Staphylococcus aureus (MRSA) being particularly concerning. Although vancomycin has long been the standard treatment for MRSA, its repeated use can lead to antibiotic tolerance and resistance. The accumulation of bacterial metabolites contributes to this tolerance, suggesting that modulation of bacterial metabolic pathways may provide a novel solution. Herein, we developed Ga/Cu-MOF nanomyze, characterized by a high specific surface area, which could be capable of loading antibiotics and serve as a dual-metal ion reservoir for the sustained release of gallium ions (Ga³⁺) and copper ions (Cu²⁺). These ions independently inhibited nitric oxide (NO) production and promoted the decomposition of S-nitrosothiols (RSNO), significantly reducing MRSA's tolerance to vancomycin. Moreover, Ga/Cu-MOF induced programmed cell death in MRSA, specifically targeting ferroptosis and cuproptosis. Antibiotic-loaded nanomyze exhibited robust synergistic antibacterial properties, including the inhibition of biofilm formation and the clearance of intracellular bacteria in macrophages. In preclinical models of skin defect infections in mice and osteomyelitis in rats, Ga/Cu-MOF showed the ability to regulate the host inflammatory response, facilitating faster recovery. Our goal is to reduce bacterial tolerance by modulating metabolic pathways and enhance antibacterial efficacy through bacterial cell death, thereby presenting a potential novel therapeutic strategy for the clinical management of multidrug-resistant bacteria.