2i72: Difference between revisions

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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.

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==

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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]

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: Escherichia coli]]

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[[Category: Cancian, L.]]

[[Category: Cannazza, G.]]

[[Category: Costi, M.P.]]

[[Category: Costi, M P.]]

[[Category: Morandi, F.]]

[[Category: Prati, F.]]

[[Category: Segatore, B.]]

[[Category: Shoichet, B.K.]]

[[Category: Shoichet, B K.]]

[[Category: Tondi, D.]]

[[Category: Venturelli, A.]]

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[[Category: serine hydrolase]]

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@@ Line 4: / Line 4: @@
 ==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.
+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==
@@ Line 10: / Line 10: @@
 ==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]
+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: Escherichia coli]]
@@ Line 17: / Line 17: @@
 [[Category: Cancian, L.]]
 [[Category: Cannazza, G.]]
-[[Category: Costi, M.P.]]
+[[Category: Costi, M P.]]
 [[Category: Morandi, F.]]
 [[Category: Prati, F.]]
 [[Category: Segatore, B.]]
-[[Category: Shoichet, B.K.]]
+[[Category: Shoichet, B K.]]
 [[Category: Tondi, D.]]
 [[Category: Venturelli, A.]]
@@ Line 30: / Line 30: @@
 [[Category: serine hydrolase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 11:56:38 2008''
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:49:47 2008''