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0 reviewsMethicillin-resistant Staphylococcus aureus (MRSA) has become one of the deadliest bacteria globally due to antibiotic resistance. In this study, we crosslinked antigen-binding fragments of monoclonal antibodies against the wall-teichoic acid of S. aureus with polysialic acid to form an antibody‒PSA conjugate, which can efectively target and induce calcifcation on the surface of MRSA. This process eliminates bacteria by hindering the energy metabolism and multiple essential metabolic pathways of MRSA. We found that bacterial calcifcation leads to increased expression of calprotectin, S100A8/S100A9, in macrophages and monocytes in vivo and can stimulate the activation of macrophages to an infammatory state, thereby promoting bacterial eradication as an immunomodulator. Systemic administration of the antibody‒PSA conjugate demonstrates high efcacy and safety for treating chronic lung infections and chronic osteomyelitis caused by MRSA in mice. This study ofers a promising therapy for treating drug-resistant bacteria and related refractory pathogenic infections.