Sandbox 126: Difference between revisions

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==='''Introduction'''===

Transpeptidase (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 moiety, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of beta-lactams has led to the generation of methicillin-resistant ''Staphylococcus aureus'' ([http://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureus MRSA]) isolates that have acquired an alternative transpeptidase, PBP2a, which is compromised in its ability to react with beta-lactams. MRSA isolates are resistant to all beta-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Futhermore, they are often only susceptible to so-called "last resort antibiotics", such as vancomycin. Recently, two broad range cephalosporins, ceftobiprole and ceftaroline, that bind and inhibit PBP2a have been developed.

==='''Background Information'''===

Transpeptidase (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 moiety, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of beta-lactams has led to the generation of methicillin-resistant ''Staphylococcus aureus'' (MRSA) isolates that have acquired an alternative transpeptidase, PBP2a, which is compromised in its ability to react with beta-lactams. MRSA isolates are resistant to all beta-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Futhermore, they are often only susceptible to so-called "last resort antibiotics", such as vancomycin. Recently, two broad range cephalosporins, ceftobiprole and ceftaroline, that bind and inhibit PBP2a have been developed.

~~==='''Introduction'''===~~

The bacterial cell wall is composed of sheets of peptidoglycan cross-linked together to form a highly polymeric "mesh" that helps maintain the structural strength of the cell (Figure 1). A peptidoglycan sheet consists of alternating residues of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) linked together by β-(1,4)- glycosidic bonds. In ''Staphylococcus aureus'' (S. aureus), the NAM residues are coupled to a (D-Ala) residues. The sheets of peptidoglycan are cross-linked together with pentaglycine chains. The cross-linking of adjacent peptidoglycan sheets is catalyzed by transpeptidases (TP). Beta-Lactam antibiotics, such as penicillin and the anti-MRSA cephlosporins, ceftobiprole and ceftaroline, stop the production of the cell wall, and so kill bacteria, by irreversibly inhibiting TPs. Therefore, TPs are also called penicillin-binding proteins.

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==='''Mechanism of action of Beta-Lactam Antibiotics'''===

The beta-lactam antibiotics irreversibly bind to and inhibit TPs. This results in the disruption of peptidoglycan synthesis and ultimately cell growth. Specifically, beta-lactams, such as penicillin and the anti-MRSA cephlasporins, ceftobiprole and ceftaroline, are molecular mimics of the peptidoglycan D-Ala-D-Ala moiety; the normal TP substrate (Figure 3; Tipper and Strominger, 1965). Therefore, they "trick" the TP active site serine residue to react with them, resulting in the irreversible inhibition of TP activity and of cell wall synthesis.

The beta-lactam antibiotics irreversibly bind to and inhibit TPs. This results in the disruption of peptidoglycan synthesis and ultimately cell growth. Specifically, beta-lactams, such as penicillin and the anti-MRSA cephlasporins, ceftobiprole and ceftaroline, are molecular mimics of the peptidoglycan D-Ala-D-Ala moiety; the normal TP substrate (Figure 2; Tipper and Strominger, 1965). Therefore, they "trick" the TP active site serine residue to react with them, resulting in the irreversible inhibition of TP activity and of cell wall synthesis.

==='''MRSA, PBP2a, and anti-MRSA Cephalosporins'''===

MRSA becomes resistant to beta-lactams by acquiring an alternative TP, PBP2a, that is encoded by the ''mecA'' gene (Matsuhashi ''et al.'', 1986). PBP2a is compromised in its ability to react with beta-lactam; therefore, MRSA strains are resistant to beta-lactams and are able to make their cell wall in the presence of high concentrations of beta-lactams.

Recently, two broad range cephalosporins: ceftaroline and ceftaroline (~~FIgure~~), that have anti-MRSA activity because they bind and inhibit PBP2a have been developed.

Recently, two broad range cephalosporins: ceftaroline and ceftaroline (Figure), that have anti-MRSA activity because they bind and inhibit PBP2a have been developed.

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@@ Line 1: / Line 1: @@
+==='''Introduction'''===
+Transpeptidase (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 moiety, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of beta-lactams has led to the generation of methicillin-resistant ''Staphylococcus aureus'' ([http://en.wikipedia.org/wiki/Methicillin-resistant_Staphylococcus_aureus MRSA]) isolates that have acquired an alternative transpeptidase, PBP2a, which is compromised in its ability to react with beta-lactams. MRSA isolates are resistant to all beta-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Futhermore, they are often only susceptible to so-called "last resort antibiotics", such as vancomycin. Recently, two broad range cephalosporins, ceftobiprole and ceftaroline, that bind and inhibit PBP2a have been developed.
 ==='''Background Information'''===
-Transpeptidase (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 moiety, resulting in the inhibition of cell wall synthesis and ultimately bacterial cell growth. Overuse and misuse of beta-lactams has led to the generation of methicillin-resistant ''Staphylococcus aureus'' (MRSA) isolates that have acquired an alternative transpeptidase, PBP2a, which is compromised in its ability to react with beta-lactams. MRSA isolates are resistant to all beta-lactams, can be hospital- or community-acquired, and are often the cause of significant morbidity and mortality. Futhermore, they are often only susceptible to so-called "last resort antibiotics", such as vancomycin. Recently, two broad range cephalosporins, ceftobiprole and ceftaroline, that bind and inhibit PBP2a have been developed.
-==='''Introduction'''===
 The bacterial cell wall is composed of sheets of peptidoglycan cross-linked together to form a highly polymeric "mesh" that helps maintain the structural strength of the cell (Figure 1). A peptidoglycan sheet consists of alternating residues of N-acetylmuramic acid (NAM) and N-acetylglucosamine (NAG) linked together by β-(1,4)- glycosidic bonds. In ''Staphylococcus aureus'' (S. aureus), the NAM residues are coupled to a (D-Ala) residues. The sheets of peptidoglycan are cross-linked together with pentaglycine chains. The cross-linking of adjacent peptidoglycan sheets is catalyzed by transpeptidases (TP). Beta-Lactam antibiotics, such as penicillin and the anti-MRSA cephlosporins, ceftobiprole and ceftaroline, stop the production of the cell wall, and so kill bacteria, by irreversibly inhibiting TPs. Therefore, TPs are also called penicillin-binding proteins.
@@ Line 8: / Line 8: @@
 ==='''Mechanism of action of Beta-Lactam Antibiotics'''===
-The beta-lactam antibiotics irreversibly bind to and inhibit TPs. This results in the disruption of peptidoglycan synthesis and ultimately cell growth. Specifically, beta-lactams, such as penicillin and the anti-MRSA cephlasporins, ceftobiprole and ceftaroline, are molecular mimics of the peptidoglycan D-Ala-D-Ala moiety; the normal TP substrate (Figure 3; Tipper and Strominger, 1965). Therefore, they "trick" the TP active site serine residue to react with them, resulting in the irreversible inhibition of TP activity and of cell wall synthesis.
+The beta-lactam antibiotics irreversibly bind to and inhibit TPs. This results in the disruption of peptidoglycan synthesis and ultimately cell growth. Specifically, beta-lactams, such as penicillin and the anti-MRSA cephlasporins, ceftobiprole and ceftaroline, are molecular mimics of the peptidoglycan D-Ala-D-Ala moiety; the normal TP substrate (Figure 2; Tipper and Strominger, 1965). Therefore, they "trick" the TP active site serine residue to react with them, resulting in the irreversible inhibition of TP activity and of cell wall synthesis.
 ==='''MRSA, PBP2a, and anti-MRSA Cephalosporins'''===
 MRSA becomes resistant to beta-lactams by acquiring an alternative TP, PBP2a, that is encoded by the ''mecA'' gene (Matsuhashi ''et al.'', 1986). PBP2a is compromised in its ability to react with beta-lactam; therefore, MRSA strains are resistant to beta-lactams and are able to make their cell wall in the presence of high concentrations of beta-lactams.
-Recently, two broad range cephalosporins: ceftaroline and ceftaroline (FIgure), that have anti-MRSA activity because they bind and inhibit PBP2a have been developed.
+Recently, two broad range cephalosporins: ceftaroline and ceftaroline (Figure), that have anti-MRSA activity because they bind and inhibit PBP2a have been developed.