Sandbox 124

From Proteopedia

Revision as of 17:21, 10 July 2013

Physical Model of the Staphylococcus aureus Transpeptidase PBP2a in Complex with an Anti-Methicillin-Resistant Staphylococcus aureus Cephalosporin

Fatima Assad1, Kavita Bhikhi1, Annie Briglall1, Diana Eusebio1, Edwin Flores1, Andrew Ramirez1, Hillary Ramirez1, Tashina Valentin1, Mohammed Zaman1, Joel L. Sussman2, Andrew L. Lovering3, Lars F. Westblade4, and Allison Granberry1 1Hostos-Lincoln Academy, 600 St. Ann’s Avenue, Bronx, NY 10455, USA; 2Department of Structural Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; 3School of Biosciences, University of Birmingham, Birmingham B15 2TT, UK; 4Department of Pathology and Laboratory Medicine, Hofstra North Shore-LIJ School of Medicine, Hempstead, NY 11549, USA

Introduction

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, 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.