1kr3

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spinqualitylabelsall models 1kr3, resolution 2.50Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Crystal Structure of the Metallo beta-Lactamase from Bacteroides fragilis (CfiA) in Complex with the Tricyclic Inhibitor SB-236050.

Overview

This work describes the discovery and characterization of a novel series, of tricyclic natural product-derived metallo-beta-lactamase inhibitors., Natural product screening of the Bacillus cereus II enzyme identified an, extract from a strain of Chaetomium funicola with inhibitory activity, against metallo-beta-lactamases. SB236050, SB238569, and SB236049 were, successfully extracted and purified from this extract. The most active of, these compounds was SB238569, which possessed K(i) values of 79, 17, and, 3.4 microM for the Bacillus cereus II, Pseudomonas aeruginosa IMP-1, and, Bacteroides fragilis CfiA metallo-beta-lactamases, respectively, yet none, of the compounds exhibited any inhibitory activity against the, Stenotrophomonas maltophilia L-1 metallo-beta-lactamase (50% inhibitory, concentration > 1,000 microM). The lack of activity against, angiotensin-converting enzyme and serine beta-lactamases demonstrated the, selective nature of these compounds. The crystal structure of SB236050, complexed in the active site of CfiA has been obtained to a resolution of, 2.5 A. SB236050 exhibits key polar interactions with Lys184, Asn193, and, His162 and a stacking interaction with the indole ring of Trp49 in the, flap, which is in the closed conformation over the active site groove., SB236050 and SB238569 also demonstrate good antibacterial synergy with, meropenem. Eight micrograms of SB236050 per ml gave rise to an eightfold, drop in the MIC of meropenem for two clinical isolates of B. fragilis, producing CfiA, making these strains sensitive to meropenem (MIC < or = 4, microg/ml). Consequently, this series of metallo-beta-lactamase inhibitors, exhibit the most promising antibacterial synergy activity so far observed, against organisms producing metallo-beta-lactamases.

About this Structure

1KR3 is a Single protein structure of sequence from Bacteroides fragilis with ZN, NA and 113 as ligands. Active as Beta-lactamase, with EC number 3.5.2.6 Full crystallographic information is available from OCA.

Reference

Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases., Payne DJ, Hueso-Rodriguez JA, Boyd H, Concha NO, Janson CA, Gilpin M, Bateson JH, Cheever C, Niconovich NL, Pearson S, Rittenhouse S, Tew D, Diez E, Perez P, De La Fuente J, Rees M, Rivera-Sagredo A, Antimicrob Agents Chemother. 2002 Jun;46(6):1880-6. PMID:12019104

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