Sandbox Reserved 992: Difference between revisions
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== Background and β-lactam Antibiotics == | == Background and β-lactam Antibiotics == | ||
Since the discovery of penicillin in the late 1920s, β-lactam antibiotics, characterized by their central chemical structure, the β-lactam ring, have played an important role in human health. Unfortunately, extensive use, and often misuse, of such drugs has led to an increased resistance in many species of bacterium resulting in major clinical treatment dilemmas. Each year in the United States alone, a minimum of 2 million people are infected with drug-resistant bacteria and of those 2 million, at least 23,000 infections result in fatality.<ref>Antibiotic Resistant Threat Report in the United States, 2013. Centers for Disease Control and Prevention. 16 September, 2013. | Since the discovery of penicillin in the late 1920s, β-lactam antibiotics, characterized by their central chemical structure, the β-lactam ring, have played an important role in human health. Unfortunately, extensive use, and often misuse, of such drugs has led to an increased resistance in many species of bacterium resulting in major clinical treatment dilemmas. Each year in the United States alone, a minimum of 2 million people are infected with drug-resistant bacteria and of those 2 million, at least 23,000 infections result in fatality.<ref name = "CDC 2013">Antibiotic Resistant Threat Report in the United States, 2013. Centers for Disease Control and Prevention. 16 September, 2013. | ||
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[[Image:Beta-lactam.jpg|250px|thumb|left|A β-lactam antibiotic (Penicillin)]] | [[Image:Beta-lactam.jpg|250px|thumb|left|A β-lactam antibiotic (Penicillin)]] | ||
== Function and Mechanism == | == Function and Mechanism == | ||
Clinically, β-lactam antibiotics, characterized by their central chemical structure (Fig 1), are utilized to combat bacterial infections by targeting penicillin-binding proteins (PBPs), also known as transpeptidases. PBPs are enzymes that are located in the cell membrane and function in cross-linking to form the peptidoglycan layer. PBPs have a deprotonated serine which executes nucleophilic attack on the carbonyl carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref | Clinically, β-lactam antibiotics, characterized by their central chemical structure (Fig 1), are utilized to combat bacterial infections by targeting penicillin-binding proteins (PBPs), also known as transpeptidases. PBPs are enzymes that are located in the cell membrane and function in cross-linking to form the peptidoglycan layer. PBPs have a deprotonated serine which executes nucleophilic attack on the carbonyl carbon. The PBP is then covalently attached to one unit of peptidoglycan. The amino group of an alanine on a second unit of peptidoglycan then performs a second nucleophilic attack on the carbonyl carbon, resulting in two covalently cross-linked peptidoglycan units and the regeneration of the catalytic PBP.<ref name = "CDC 2013" /> | ||
[[Image:Peptidoglycan_cross_linking.png|500px|thumb|right|Peptidoglycan with PDB Cross-linking Mechanism]] | [[Image:Peptidoglycan_cross_linking.png|500px|thumb|right|Peptidoglycan with PDB Cross-linking Mechanism]] | ||
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== Class C Mechanism == | == Class C Mechanism == | ||
There are four main classes of β-lactamase enzymes, A, B, C, and D. While these main classes all disable the antimicrobial activity of β-lactams by breaking open the β-lactam ring at the amide bond, each class has individually conserved residues that allow the enzyme to maintain catalytic function. Classes A, C and D are most similar by functioning via catalytic serine, while class B functions via catalytic zinc.<ref> | There are four main classes of β-lactamase enzymes, A, B, C, and D. While these main classes all disable the antimicrobial activity of β-lactams by breaking open the β-lactam ring at the amide bond, each class has individually conserved residues that allow the enzyme to maintain catalytic function. Classes A, C and D are most similar by functioning via catalytic serine, while class B functions via catalytic zinc.<ref name = "Bush 2013"> | ||
Bush, Karen. The ABCD’s of β-lactamase nomenclature. J Infect chemother. (2013) 19, 549-559. | Bush, Karen. The ABCD’s of β-lactamase nomenclature. J Infect chemother. (2013) 19, 549-559. | ||
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Class C β-lactamases share a very similar mechanism as the Class A β-lactams, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref | Class C β-lactamases share a very similar mechanism as the Class A β-lactams, acylation followed by hydrolytic deacylation.4 Class C differs from A in that the hydrolytic water, activated by tyrosine 150, approaches the enzyme from the opposite side. This activated water is what allows β-lactamases to deacylation and maintain their catalytic function, while PBPs cannot.<ref name = "Bush 2013" /> | ||
Bush | |||
Class C β-lactamases, among many other enzyme types, also contain a structural component known as an oxyanion hole. This pocket of hydrophilic residues directly stabilizes the high-energy tetrahedral intermediate, lowering the activation energy and promoting a faster overall reaction.5 | Class C β-lactamases, among many other enzyme types, also contain a structural component known as an oxyanion hole. This pocket of hydrophilic residues directly stabilizes the high-energy tetrahedral intermediate, lowering the activation energy and promoting a faster overall reaction.5 | ||
