Sandbox 123
From Proteopedia
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== The Mechanism of PBP2a == | == The Mechanism of PBP2a == | ||
| - | PBP2a is composed of two domains: a <font color='orange'><b>non-penicillin binding (NPB) domain </b></font> and a <font color='dodgerblue'><b>TP domain </b></font>. 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 <scene name='36/365380/Ser403/15'>a serine residue at position 403 (ser403)</scene> which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. | + | PBP2a is composed of two domains: a <font color='orange'><b>non-penicillin binding <scene name='36/365380/4dki_cartoon/10'>(NPB) </scene> domain </b>(NPB)</font> and a <font color='dodgerblue'><b><scene name='36/365380/4dki_cartoon/11'>TP</scene> domain </b></font>. 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 <scene name='36/365380/Ser403/15'>a serine residue at position 403 (ser403)</scene> which catalyzes the cross-linking of the peptidoglycan rows with pentaglycine cross-links. |
== Ceftobiprole == | == Ceftobiprole == | ||
MRSA becomes resistant to β-lactams by acquiring an alternative PBP, PBP2a, that is neither bound nor inhibited by β-lactams. Ceftobiprole is able to inhibit PBP2a because additional chemical groups at the position of the the <scene name='36/365380/Ceftobiprole/2'>R2</scene> position of the cephalosporin backbone are able to interact with additional amino acid residues in PBP2a; specifically <scene name='36/365380/Ceftobiprole/3'>Tyr446 and Met641</scene>. 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. | MRSA becomes resistant to β-lactams by acquiring an alternative PBP, PBP2a, that is neither bound nor inhibited by β-lactams. Ceftobiprole is able to inhibit PBP2a because additional chemical groups at the position of the the <scene name='36/365380/Ceftobiprole/2'>R2</scene> position of the cephalosporin backbone are able to interact with additional amino acid residues in PBP2a; specifically <scene name='36/365380/Ceftobiprole/3'>Tyr446 and Met641</scene>. 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. | ||
Revision as of 17:52, 30 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. 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. Furthermore, they are often only susceptible to “last resort antibiotics”, such as vancomycin. Recently, two cephalosporins - and ceftaroline - that bind and inhibit PBP2a have been developed. and ceftaroline - that bind and inhibit PBP2a have been developed.
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.
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