Abstract: OBJECTIVE Methicillin-resistant Staphylococcus aureus (MRSA) is a significant pathogen responsible for various local and systemic critical infections such as pneumonia and sepsis, and its drug resistance poses a severe challenge to clinical treatment. This review focuses on the resistance mechanisms mediated by the modification of chromosome-encoded penicillin-binding proteins (PBPs), particularly how PBP2a encoded by the mecA gene reduces bacterial sensitivity to penicillin and other β-Lactam antibiotics. By systematically elucidating the structural and functional characteristics of PBP2a, this article aims to provide a theoretical basis for the design of novel antimicrobial agents, thereby restoring and enhancing the therapeutic efficacy of β-Lactam antibiotics against MRSA infections.