Sandbox 126

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. [[Image:Cell Wall 7 30 2013.jpg|thumb|alt= Alt text| Figure 1. A.Bacterial Cell Wall B.Peptidoglycan with D-Ala-D-Ala substrate |550px]] 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 - <scene name='37/372726/Ceftobiprole/2'>Ceftobiprole</scene> and ceftaroline - that bind and inhibit PBP2a have been developed.

<scene name='37/372726/Ceftobiprole/2'>Ceftobiprole</scene> is able to inhibit PBP2a because additional chemical groups at <scene name='37/372726/Ceftobiprole/4'>the R2 position of the cephalosporin backbone</scene> are able to interact with additional amino acid residues in PBP2a; specifically <scene name='37/372726/Tyr446_residue/1'>Tyr446</scene> and Met641. As a result of its tighter binding to PBP2a, ceftobiprole is able to more efficiently react with the serine active site residue and therefore inhibit the activity of PBP2a.