盘尼西林结合蛋白 2a中初生细胞壁的变构位点：耐甲氧西林金黄色葡糖球菌的薄弱环节

Title:The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus

Volume: 22 Issue: 14

Author(s): Ivan Acebron, Mayland Chang, Shahriar Mobashery and Juan A. Hermoso

Affiliation:

关键词: 变构机制，抗生素耐药性，β-内酰胺抗生素，构象变化，耐甲氧西林金黄色葡萄球菌，盘尼西林结合蛋白，X-射线晶体结构。

摘要: The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to β-lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis. The recently published crystal structure of the complex of PBP2a with ceftaroline, a cephalosporin antibiotic that shows efficacy against MRSA, has revealed the allosteric site at 60-Å distance from the transpeptidase domain. Binding of ceftaroline to the allosteric site of PBP2a triggers conformational changes that lead to the opening of the active site from a closed conformation, where a second molecule of ceftaroline binds to give inhibition of the enzyme. The discovery of allostery in MRSA remains the only known example of such regulation of cellwall biosynthesis and represents a new paradigm in fighting MRSA. This review summarizes the present knowledge of the allosteric mechanism, the conformational changes allowing PBP2a catalysis and the means by which some clinical strains have acquired resistance to ceftaroline by disrupting the allosteric mechanism.

Cite this article as:

Ivan Acebron, Mayland Chang, Shahriar Mobashery and Juan A. Hermoso , The Allosteric Site for the Nascent Cell Wall in Penicillin-Binding Protein 2a: An Achilles’ Heel of Methicillin-Resistant Staphylococcus aureus, Current Medicinal Chemistry 2015; 22 (14) . https://dx.doi.org/10.2174/0929867322666150311150215