Sandbox 126

Introduction

β-lactam antibiotics, including penicillins, cephalosporins and carbapenems, traditionally have been used to treat Staphylococcus aureus infections. It has been the overuse and misuse of these antibiotics that has led to strains of resistant Staphylococcus aureus, including ones that are resistant to multiple β-lactams. Methicillin-resistant Staphylococcus aureus (MRSA) can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality.

Antibiotics stop the production of the cell wall by targeting the enzyme penicillin-binding protein(PBP), also known as transpeptidase(TP). The cell wall, surrounding the cell membrane, is crucial for maintaining the structural integrity of the bacterium preventing cell lysis.

Background

PBP2a is composed of two domains: a non-penicillin binding (NPB) domain and a TP domain. The NBP domain of PBP2a is anchored in the cell membrane, while the TP domain “sits” 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.

How does PBP2a work