1fsw
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AMPC BETA-LACTAMASE FROM E. COLI COMPLEXED WITH INHIBITOR CEPHALOTHINBORONIC ACID
OverviewOverview
BACKGROUND: Penicillins and cephalosporins are among the most widely used, and successful antibiotics. The emergence of resistance to these, beta-lactams, most often through bacterial expression of beta-lactamases, threatens public health. To understand how beta-lactamases recognize their, substrates, it would be helpful to know their binding energies., Unfortunately, these have been difficult to measure because beta-lactams, form covalent adducts with beta-lactamases. This has complicated, functional analyses and inhibitor design. RESULTS: To investigate the, contribution to interaction energy of the key amide (R1) side chain of, beta-lactam antibiotics, eight acylglycineboronic acids that bear the side, chains of characteristic penicillins and cephalosporins, as well as four, other analogs, were synthesized. These transition-state analogs form, reversible adducts with serine beta-lactamases. Therefore, binding, energies can be calculated directly from K(i) values. The K(i) values, measured span four orders of magnitude against the Group I beta-lactamase, AmpC and three orders of magnitude against the Group II beta-lactamase, TEM-1. The acylglycineboronic acids have K(i) values as low as 20 nM, against AmpC and as low as 390 nM against TEM-1. The inhibitors showed, little activity against serine proteases, such as chymotrypsin. R1 side, chains characteristic of beta-lactam inhibitors did not have better, affinity for AmpC than did side chains characteristic of beta-lactam, substrates. Two of the inhibitors reversed the resistance of pathogenic, bacteria to beta-lactams in cell culture. Structures of two inhibitors in, their complexes with AmpC were determined by X-ray crystallography to 1.90, A and 1.75 A resolution; these structures suggest interactions that are, important to the affinity of the inhibitors. CONCLUSIONS:, Acylglycineboronic acids allow us to begin to dissect interaction energies, between beta-lactam side chains and beta-lactamases. Surprisingly, there, is little correlation between the affinity contributed by R1 side chains, and their occurrence in beta-lactam inhibitors or beta-lactam substrates, of serine beta-lactamases. Nevertheless, presented in acylglycineboronic, acids, these side chains can lead to inhibitors with high affinities and, specificities. The structures of their complexes with AmpC give a, molecular context to their affinities and may guide the design of, anti-resistance compounds in this series.
About this StructureAbout this Structure
1FSW is a Single protein structure of sequence from Escherichia coli with PO4 and CTB as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.
ReferenceReference
Energetic, structural, and antimicrobial analyses of beta-lactam side chain recognition by beta-lactamases., Caselli E, Powers RA, Blasczcak LC, Wu CY, Prati F, Shoichet BK, Chem Biol. 2001 Jan;8(1):17-31. PMID:11182316
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