Sandbox Reserved 988: Difference between revisions

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== Background ==

[[Image:Beta-lactam.jpg|200px|thumb|right|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections. This class ~~of antibiotics~~ targets [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase ~~transpeptidases~~]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer of the bacterial cell wall. <ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref> This cross-linking process strengthens the cell wall and enables the bacteria to resist osmotic pressure from its external environment.

[[Image:Beta-lactam.jpg|200px|thumb|right|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections. This antibiotic class targets [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), which are also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidase enzymes]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer of the bacterial cell wall. <ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref> This cross-linking process strengthens the cell wall and enables the bacteria to resist osmotic pressure from its external environment.

[[Image:Peptidoglycan_cross_linking.png|400px|thumb|center|Peptidoglycan with PBP Cross-linking Mechanism]]

β-lactam antibiotics covalently ~~bind~~ to PBPs, [http://en.m.wikipedia.org/wiki/Enzyme_inhibitor inhibiting] them from ~~executing their role in properly~~ cross-linking the peptidoglycan layer of the cell wall. The catalytic serine in the active site of a PBP performs a nucleophilic attack on the carbonyl carbon of a β-lactam ring. The β-lactam cannot be removed and thus permanently renders the PBP incapable of its catalytic function. Ultimately, this results in death of bacterial cells from osmotic instability or [http://en.m.wikipedia.org/wiki/Autolysis_(biology) autolysis].<ref name="MSUDP 2014">

β-lactam antibiotics covalently link to PBPs, [http://en.m.wikipedia.org/wiki/Enzyme_inhibitor inhibiting] them from cross-linking the peptidoglycan layer of the cell wall. The catalytic serine in the active site of a PBP performs a nucleophilic attack on the carbonyl carbon of a β-lactam ring. The β-lactam cannot be removed and thus permanently renders the PBP incapable of its catalytic function. Ultimately, this results in death of bacterial cells from osmotic instability or [http://en.m.wikipedia.org/wiki/Autolysis_(biology) autolysis].<ref name="MSUDP 2014">

Beta Lactam Antibiotics, 2011. Antimicrobial Resistance Learning Site. Michigan State University Department of Pharmacology. 16 Sept, 2014.

</ref>

One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam antibiotics is caused by β-~~lactamases~~. Chemically, β-lactamases and PBPs bind to β-lactam antibiotics in similar mechanisms, nucleophilic attack ~~of the enzyme's catalytic serine~~ on to the ~~antibiotics~~ carbonyl group. However, β-lactamases are then able to ~~deactivate the antimicrobial activity of~~ the β-~~lactams by cleaving~~ the β-lactam ~~bound in the <scene name='69/691534/Class_c_beta-lactamase_as/2'>active site</scene>~~<ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> ~~through a molecular process called [http://en.m.wikipedia.org/wiki/Acetylation deacylation], rendering it~~ incapable of inhibiting ~~the~~ PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation.

One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam antibiotics is caused by β-lactamase enzymes. Chemically, β-lactamases and PBPs bind to β-lactam antibiotics in similar mechanisms. The catalytic serine of both enzymes performs a nucleophilic attack on to the carbonyl group in the β-lactam functional group of the antibiotic. However, β-lactamases are then able to undergo [http://en.m.wikipedia.org/wiki/Acetylation deacylation]. This process cleaves the β-lactam ring, ridding the β-lactam antibiotic of its antimicrobial activity. <ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> The cleaved β-lactam antibiotic is rendered incapable of inhibiting PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation.

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@@ Line 6: / Line 6: @@
 == Background ==
-[[Image:Beta-lactam.jpg|200px|thumb|right|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections.  This class of antibiotics targets [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidases]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer of the bacterial cell wall. <ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref> This cross-linking process strengthens the cell wall and enables the bacteria to resist osmotic pressure from its external environment.
+[[Image:Beta-lactam.jpg|200px|thumb|right|A [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotic] ([http://en.m.wikipedia.org/wiki/Penicillin Penicillin])]]Clinically, [http://en.m.wikipedia.org/wiki/Beta-lactam_antibiotic β-lactam antibiotics], characterized by their central chemical structure, are utilized to combat bacterial infections.  This antibiotic class targets [http://proteopedia.org/wiki/index.php/Penicillin-binding_protein penicillin-binding proteins] (PBPs), which are also known as [http://en.m.wikipedia.org/wiki/DD-transpeptidase transpeptidase enzymes]. PBPs are enzymes that are located in the cell membrane of bacteria and function in [http://en.wikipedia.org/wiki/Cross-link cross-linking] to form the [http://en.m.wikipedia.org/wiki/Peptidoglycan peptidoglycan] layer of the bacterial cell wall. <ref>"Peptidoglycan cell wall." The University of Warwick. n.d. Web. 25 Jan 15</ref> This cross-linking process strengthens the cell wall and enables the bacteria to resist osmotic pressure from its external environment.
 [[Image:Peptidoglycan_cross_linking.png|400px|thumb|center|Peptidoglycan with PBP Cross-linking Mechanism]]
-β-lactam antibiotics covalently bind to PBPs, [http://en.m.wikipedia.org/wiki/Enzyme_inhibitor inhibiting] them from executing their role in properly cross-linking the peptidoglycan layer of the cell wall.  The catalytic serine in the active site of a PBP performs a nucleophilic attack on the carbonyl carbon of a β-lactam ring. The β-lactam cannot be removed and thus permanently renders the PBP incapable of its catalytic function. Ultimately, this results in death of bacterial cells from osmotic instability or [http://en.m.wikipedia.org/wiki/Autolysis_(biology) autolysis].<ref name="MSUDP 2014">
+β-lactam antibiotics covalently link to PBPs, [http://en.m.wikipedia.org/wiki/Enzyme_inhibitor inhibiting] them from cross-linking the peptidoglycan layer of the cell wall.  The catalytic serine in the active site of a PBP performs a nucleophilic attack on the carbonyl carbon of a β-lactam ring. The β-lactam cannot be removed and thus permanently renders the PBP incapable of its catalytic function. Ultimately, this results in death of bacterial cells from osmotic instability or [http://en.m.wikipedia.org/wiki/Autolysis_(biology) autolysis].<ref name="MSUDP 2014">
 Beta Lactam Antibiotics, 2011. Antimicrobial Resistance Learning Site. Michigan State University Department of Pharmacology. 16 Sept, 2014.
 </ref>
-One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam antibiotics is caused by β-lactamases. Chemically, β-lactamases and PBPs bind to β-lactam antibiotics in similar mechanisms, nucleophilic attack of the enzyme's catalytic serine on to the antibiotics carbonyl group. However, β-lactamases are then able to deactivate the antimicrobial activity of the β-lactams by cleaving the β-lactam bound in the <scene name='69/691534/Class_c_beta-lactamase_as/2'>active site</scene><ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> through a molecular process called [http://en.m.wikipedia.org/wiki/Acetylation deacylation], rendering it incapable of inhibiting the PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation.
+One of the main causes of [http://en.wikipedia.org/wiki/Antimicrobial_resistance resistance] to β-lactam antibiotics is caused by β-lactamase enzymes. Chemically, β-lactamases and PBPs bind to β-lactam antibiotics in similar mechanisms. The catalytic serine of both enzymes performs a nucleophilic attack on to the carbonyl group in the β-lactam functional group of the antibiotic. However, β-lactamases are then able to undergo [http://en.m.wikipedia.org/wiki/Acetylation deacylation].  This process cleaves the β-lactam ring, ridding the β-lactam antibiotic of its antimicrobial activity. <ref>Powers, Rachel, Hollister C. Swanson, Magdalena A. Taracila, Nicholas W. Florek, Chiara Romagnoli, Emilia Caselli, Fabio Prati, Robert A. Bonomo, and Bradley J. Wallar. Biochemical and Structural Analysis of Inhibitors Targeting the ADC-7 Cephalosporinase of Acinetobacter baumannii. Biochemistry, 2014, 53 (48), 7670-7679.</ref> The cleaved β-lactam antibiotic is rendered incapable of inhibiting PBPs and ultimately, allowing cross-linking to occur for adequate cell wall formation.