Identification of a series of tricyclic natural products as potent broad-spectrum inhibitors of metallo-beta-lactamases.
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.
Payne
David J
DJ
Microbial, Musculoskeletal and Proliferative Diseases CEDD (UP1345), GlaxoSmithKline, Collegeville, Pennsylvania 19426-0989, USA. David_J_Payne@sbphrd.com
Hueso-Rodríguez
Juan Antonio
JA
Boyd
Helen
H
Concha
Néstor O
NO
Janson
Cheryl A
CA
Gilpin
Martin
M
Bateson
John H
JH
Cheever
Christy
C
Niconovich
Nancy L
NL
Pearson
Stewart
S
Rittenhouse
Stephen
S
Tew
David
D
Díez
Emilio
E
Pérez
Paloma
P
De La Fuente
Jesus
J
Rees
Michael
M
Rivera-Sagredo
Alfonso
A
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
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