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

Transpeptidases (TP), 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, and 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.

How does PBP2a work