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==='''Structure of PBP2a, a B-Lactam Resistant Transpeptidase'''=== | ==='''Structure of PBP2a, a B-Lactam Resistant Transpeptidase'''=== | ||
Isolates of methicillin-resistant S. aureus (MRSA) are resistant to almost all currently available B-lactams because they have acquired an alternative PBP, PBP2A (encoded by the mecA gene) that is neither bound nor inhibited by B-lactams. PBP2a is composed of two domains: a non-penicillin binding domain (NPB) and a TP-binding domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain residues in the periplasm with its active site facing the inner surface of the cell wall. The active site contains a serine residue at position 403( Ser403), which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | Isolates of methicillin-resistant S. aureus (MRSA) are resistant to almost all currently available B-lactams because they have acquired an alternative PBP, PBP2A (encoded by the mecA gene) that is neither bound nor inhibited by B-lactams. PBP2a is composed of two domains: a non-penicillin binding domain <scene name='37/372728/Npb_domain/1'>(NPB)</scene> and a TP-binding domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain residues in the periplasm with its active site facing the inner surface of the cell wall. The active site contains a serine residue at position 403( Ser403), which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | ||
==='''B-Lactams that Inhibit PBP2a'''=== | ==='''B-Lactams that Inhibit PBP2a'''=== | ||
MRSA becomes resistant to almost all B-Lactams by acquiring an alternative TP, PBP2a, that is neither bound nor inhibited by B-Lactams. Recently, two cephlosporins- ceftobiprole and ceftaroline- that have anti-MRSA activity have been developed. Ceftobiprole is able to inhibit PBP2a because additional chemical groups at the R2 position of ceftobiprole are able to interact with additional amino acid residues in PBP2a; specifically Tyr446 and Met641, and increase the association of ceftobiprole with PBP2a. As such, ceftobiprole is (shown as colors of the atom types [CPK]) is able to more efficiently react with Ser403 and therefore inhibit the activity of PBP2a. | MRSA becomes resistant to almost all B-Lactams by acquiring an alternative TP, PBP2a, that is neither bound nor inhibited by B-Lactams. Recently, two cephlosporins- ceftobiprole and ceftaroline- that have anti-MRSA activity have been developed. Ceftobiprole is able to inhibit PBP2a because additional chemical groups at the R2 position of ceftobiprole are able to interact with additional amino acid residues in PBP2a; specifically Tyr446 and Met641, and increase the association of ceftobiprole with PBP2a. As such, ceftobiprole is (shown as colors of the atom types [CPK]) is able to more efficiently react with Ser403 and therefore inhibit the activity of PBP2a. | ||