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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.
