title: Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.
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.
authors.affiliation: Microbial, Musculoskeletal and Proliferative Diseases CEDD (UP1345), GlaxoSmithKline, Collegeville, Pennsylvania 19426-0989, USA. David_J_Payne@sbphrd.com
authors.forename: David J
authors.initials: DJ
authors.lastname: Payne
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Hueso-Rodríguez
authors.forename: Helen
authors.initials: H
authors.lastname: Boyd
authors.forename: Néstor O
authors.initials: NO
authors.lastname: Concha
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Janson
authors.forename: Martin
authors.initials: M
authors.lastname: Gilpin
authors.forename: John H
authors.initials: JH
authors.lastname: Bateson
authors.forename: Christy
authors.initials: C
authors.lastname: Cheever
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Niconovich
authors.forename: Stewart
authors.initials: S
authors.lastname: Pearson
authors.forename: Stephen
authors.initials: S
authors.lastname: Rittenhouse
authors.forename: David
authors.initials: D
authors.lastname: Tew
authors.forename: Emilio
authors.initials: E
authors.lastname: Díez
authors.forename: Paloma
authors.initials: P
authors.lastname: Pérez
authors.forename: Jesus
authors.initials: J
authors.lastname: De La Fuente
authors.forename: Michael
authors.initials: M
authors.lastname: Rees
authors.forename: Alfonso
authors.initials: A
authors.lastname: Rivera-Sagredo
mesh_terms: D001407:Bacillus / Q000187:drug effects; D001409:Bacillus cereus / Q000187:drug effects / Q000201:enzymology; D001665:Binding Sites; D002597:Chaetomium / Q000737:chemistry* / Q000378:metabolism; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005285:Fermentation; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology*; D007700:Kinetics; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D013845:Thienamycins / Q000494:pharmacology; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; C466664:SB 236049; C466665:SB 236050; C466666:SB 238569; D013845:Thienamycins; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases; D000077731:Meropenem