Sandbox 123

From Proteopedia

Revision as of 19:17, 23 July 2013

Introduction

, also known as penicillin-binding proteins (PBP), catalyze the cross-linking of peptidoglycan polymers during bacterial cell wall synthesis. The natural transpeptidase substrate is the D-Ala-D-Ala peptidoglycan side chain terminus. Beta-lactam (β-lactam) antibiotics, which include penicillins, cephalosporins and carbapenems, bind and irreversibly inhibit transpeptidases by mimicking the D-Ala-D-Ala substrate, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of β-lactams has led to the generation of methicillin-resistant Staphylococcus aureus (MRSA) isolates that have acquired an alternative transpeptidase, PBP2a, which is neither bound nor inhibited by β-lactams. MRSA isolates are resistant to all β-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Furthermore, they are often only susceptible to “last resort antibiotics”, such as vancomycin. Recently, two cephalosporins - ceftobiprole and ceftaroline - that bind and inhibit PBP2a have been developed. The Hostos-Lincoln Academy Students Modeling A Research Topic (SMART) Team generated a model of the PBP2a/ceftobiprole complex (PDB 4DKI) using 3D printing technology to illustrate the mechanism of action of ceftobiprole. Supported by a grant from the Camille and Henry Dreyfus Foundation.

Background Information

β-lactam antibiotics, which include penicillins, cephalosporins and carbapenems,have been used to treat Staphylococcus aureus infections. The overuse and misuse of β-lactam antibiotics has led to strains of Staphylococcus aureus that are resistant to all β-lactams; so called MRSA strains. MRSA can be hospital- or community-acquired and are often the cause of significant morbidity and mortality.

β-Lactam antibiotics stop the production of the cell wall by targeting bacterial PBPs. The cell wall, which is composed of peptidoglycan and surrounds the cell membrane, is crucial for maintaining the structural integrity of the bacterium.

The cell wall is composed of rows of peptidoglycan cross-linked together with pentaglycine chains. Peptidoglycan consists of N-acetylmuramic Acid (NAM) and N-acetylglucosamine (NAG) polymers. The NAM residues have a five amino acid side chain that terminates with two D-Alanine (D-Ala) residues.

The Mechanism of PBP2a

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 which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links.