2i72
From Proteopedia
(New page: 200px<br /><applet load="2i72" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i72, resolution 2.200Å" /> '''AmpC beta-lactamase...) |
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| - | [[Image:2i72.jpg|left|200px]]<br /><applet load="2i72" size=" | + | [[Image:2i72.jpg|left|200px]]<br /><applet load="2i72" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2i72, resolution 2.200Å" /> | caption="2i72, resolution 2.200Å" /> | ||
'''AmpC beta-lactamase in complex with 5-diformylaminomethyl-benzo[b]thiophen-2-boronic acid'''<br /> | '''AmpC beta-lactamase in complex with 5-diformylaminomethyl-benzo[b]thiophen-2-boronic acid'''<br /> | ||
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| + | ==Overview== | ||
| + | Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C, beta-lactamase AmpC and potentiates the activity of beta-lactam, antibiotics in bacteria that express this and related enzymes. As is often, true, the potency of compound 1 against the enzymes is much attenuated in, cell culture against Gram negative bacteria, where the minimum inhibitor, concentration of compound 1 is in the mid-micromolar range. Here, we, modulated the properties of this lead to enhance its ability to cross the, membrane, using a combination of X-ray crystallography, structure-based, design, and application of physical models of outer membrane crossing., This strategy led us to derivatives with substantially improved, permeability. Also, the greater solubility of these compounds allowed us, to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of, ceftazidime on resistant bacteria. | ||
==About this Structure== | ==About this Structure== | ||
| - | 2I72 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with VA1 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http:// | + | 2I72 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli] with <scene name='pdbligand=VA1:'>VA1</scene> as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2I72 OCA]. |
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| + | ==Reference== | ||
| + | Optimizing Cell Permeation of an Antibiotic Resistance Inhibitor for Improved Efficacy., Venturelli A, Tondi D, Cancian L, Morandi F, Cannazza G, Segatore B, Prati F, Amicosante G, Shoichet BK, Costi MP, J Med Chem. 2007 Nov 15;50(23):5644-5654. Epub 2007 Oct 23. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17956081 17956081] | ||
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Escherichia coli]] | [[Category: Escherichia coli]] | ||
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[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:56:38 2008'' |
Revision as of 09:56, 23 January 2008
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AmpC beta-lactamase in complex with 5-diformylaminomethyl-benzo[b]thiophen-2-boronic acid
Overview
Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C, beta-lactamase AmpC and potentiates the activity of beta-lactam, antibiotics in bacteria that express this and related enzymes. As is often, true, the potency of compound 1 against the enzymes is much attenuated in, cell culture against Gram negative bacteria, where the minimum inhibitor, concentration of compound 1 is in the mid-micromolar range. Here, we, modulated the properties of this lead to enhance its ability to cross the, membrane, using a combination of X-ray crystallography, structure-based, design, and application of physical models of outer membrane crossing., This strategy led us to derivatives with substantially improved, permeability. Also, the greater solubility of these compounds allowed us, to measure their efficacy at higher concentrations than with the lead 1, leading to higher maximum potentiation of the antibiotic effect of, ceftazidime on resistant bacteria.
About this Structure
2I72 is a Single protein structure of sequence from Escherichia coli with as ligand. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
Reference
Optimizing Cell Permeation of an Antibiotic Resistance Inhibitor for Improved Efficacy., Venturelli A, Tondi D, Cancian L, Morandi F, Cannazza G, Segatore B, Prati F, Amicosante G, Shoichet BK, Costi MP, J Med Chem. 2007 Nov 15;50(23):5644-5654. Epub 2007 Oct 23. PMID:17956081
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