evaluation of the efficacy of ceftaroline and ceftobiprole against pbp2a in methicillin-resistant staphylococcus aureus: new insights from molecular modeling

Penicillin-binding protein 2a (pbp2a) is the primary cause of bacterial resistance to beta-lactam antibiotics such as methicillin. pbp2a mutations produce structural alterations that reduce the antibiotic's efficacy. fifth-generation antibiotics, such as ceftaroline and ceftobizole, have a high affinity for binding to pbp2a, making them effective treatments for resistant staphylococcus aureus. the purpose of this study was to assess the influence of pbp2a mutations and the efficacy of ceftaroline fosamil and ceftobiprole when administered in combination as a novel therapeutic approach utilizing current molecular models. rcsb pdb data were utilized to select the wild-type strain 1vqq and the mutant 4cjn, as well as to examine their mutations (e246g, n146k, n204k) in three dimensions using pymol. the effect of the changes on binding energy was assessed using mcsm-ppi2 and mcsm-ab methods, and molecular docking simulations of ceftaroline and ceftobiprole were carried out using pyrx and autodockvina to determine binding energy and active sites. the findings revealed that the bulk of mutations, including e246g, e239k, and n146k, decreased protein affinity, whereas mutation n204k increased affinity. molecular research revealed that coadministration of ceftaroline and ceftobifole considerably reduced ceftaroline efficacy, while ceftobiprole efficacy was only slightly raised or unaffected in both wild-type and mutant strains. these findings point to an overlapping action between the two antagonists at the active and inactive locations. the combination of ceftaroline and ceftobiprol has adverse effects on antibiotic binding to pbp2a, confirming that they cannot be administered effectively together.