2i72
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Benzo[b]thiophene-2-ylboronic acid, 1, is a 27 nM inhibitor of the class C | + | 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== | ||
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==Reference== | ==Reference== | ||
| - | Optimizing | + | 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):5644-54. 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: Cancian, L.]] | [[Category: Cancian, L.]] | ||
[[Category: Cannazza, G.]] | [[Category: Cannazza, G.]] | ||
| - | [[Category: Costi, M | + | [[Category: Costi, M P.]] |
[[Category: Morandi, F.]] | [[Category: Morandi, F.]] | ||
[[Category: Prati, F.]] | [[Category: Prati, F.]] | ||
[[Category: Segatore, B.]] | [[Category: Segatore, B.]] | ||
| - | [[Category: Shoichet, B | + | [[Category: Shoichet, B K.]] |
[[Category: Tondi, D.]] | [[Category: Tondi, D.]] | ||
[[Category: Venturelli, A.]] | [[Category: Venturelli, A.]] | ||
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[[Category: serine hydrolase]] | [[Category: serine hydrolase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:49:47 2008'' |
Revision as of 15:49, 21 February 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):5644-54. Epub 2007 Oct 23. PMID:17956081
Page seeded by OCA on Thu Feb 21 17:49:47 2008
