Targeting MRSA penicillin-binding protein 2a: structural insights, allosteric mechanisms, and the potential of adjuvant inhibitors.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a critical global challenge requiring new therapeutic and management strategies. As a major cause of nosocomial infections, MRSA is associated with a high mortality rate owing to its resistance to multiple β-lactam antibiotics. Methicillin resistance is primarily attributed to acquisition of the mecA gene, which encodes penicillin-binding protein 2a (PBP2a). The MecA/PBP2a protein, which catalyzes critical cell wall synthesis steps, exhibits a markedly low affinity for β-lactams, allowing peptidoglycan formation to continue and enabling bacterial survival in the presence of these antibiotics. PBP2a undergoes conformational changes involving protective loops that surround its active site, adopting a closed conformation that is largely inaccessible to β-lactams. Notably, these conformational alterations are regulated by an allosteric site that is located distal to the active site. In light of this context, there exists an urgent need for the development of innovative strategies, particularly the formulation of adjuvant compounds, to enhance the efficacy of existing antibiotics and fight resistance in MRSA strains. This review elucidates the role of PBP2a in mediating resistance to β-lactam antibiotics, with a particular focus on the conformational changes that underpin this resistance and the allosteric mechanisms that mediate such alterations. Furthermore, interactions between PBP2a and various ligands that may critically influence protein inhibition are examined, emphasizing their potential modulation of protein conformational dynamics. Insights derived from this review will inform the design of novel adjuvants targeting the PBP2a allosteric site, with the objective of restoring and enhancing the effectiveness of β-lactam antibiotics against MRSA infections.