PDBsum entry: 1kr3

Hydrolase

PDB id: 1kr3

Contents

Protein chains

227 a.a. *

Ligands

113 ×2

Metals

_ZN ×4

_NA ×2

Waters ×40

* Residue conservation analysis

PDB id:

1kr3

Name:

Hydrolase

Title:

Crystal structure of the metallo beta-lactamase from bacteroides fragilis (cfia) in complex with the tricyclic inhibitor sb-236050.

Structure:

Beta-lactamase, type ii. Chain: a, b. Engineered: yes

Source:

Bacteroides fragilis. Organism_taxid: 817. Gene: cfia. Expressed in: escherichia coli. Expression_system_taxid: 562.

Resolution:

2.50Å R-factor: 0.152 R-free: 0.222

Authors:

D.J.Payne,J.A.Hueso-Rodrguez,H.Boyd,N.O.Concha,C.A.Janson, M.Gilpin,J.H.Bateson,C.Cheever,N.L.Niconovich,S.Pearson, S.Rittenhouse,D.Tew,E.Dez,P.Prez,J.De La Fuente,M.Rees, A.Rivera-Sagredo

Key ref:

D.J.Payne et al. (2002). Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases. Antimicrob Agents Chemother, 46, 1880-1886. PubMed id: 12019104 DOI: 10.1128/AAC.46.6.1880-1886.2002

Date:

08-Jan-02 Release date: 08-Jan-03

Protein chains

P25910  (BLAB_BACFR) -  Beta-lactamase type II

Seq: 249 a.a.

Struc: 227 a.a.

Enzyme reactions

• Enzyme class: E.C.3.5.2.6 - Beta-lactamase.
• Pathway: Penicillin Biosynthesis and Metabolism
• Reaction: A beta-lactam + H₂O = a substituted beta-amino acid
• Cofactor: Zinc

 Gene Ontology (GO) functional annotation 

• Biological process: response to antibiotic (2 terms)
• Biochemical function: hydrolase activity (4 terms)

DOI no: 10.1128/AAC.46.6.1880-1886.2002

Antimicrob Agents Chemother 46:1880-1886 (2002)

PubMed id: 12019104

Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.

D.J.Payne, J.A.Hueso-Rodríguez, H.Boyd, N.O.Concha, C.A.Janson, M.Gilpin, J.H.Bateson, C.Cheever, N.L.Niconovich, S.Pearson, S.Rittenhouse, D.Tew, E.Díez, P.Pérez, J.De La Fuente, M.Rees, A.Rivera-Sagredo.

ABSTRACT

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.