identification of a series of tricyclic natural products as potent broadspectrum inhibitors of metallobetalactamases this work describes the discovery and characterization of a novel series of tricyclic natural productderived metallobetalactamase inhibitors natural product screening of the bacillus cereus ii enzyme identified an extract from a strain of chaetomium funicola with inhibitory activity against metallobetalactamases sb236050 sb238569 and sb236049 were successfully extracted and purified from this extract the most active of these compounds was sb238569 which possessed ki values of 79 17 and 34 microm for the bacillus cereus ii pseudomonas aeruginosa imp1 and bacteroides fragilis cfia metallobetalactamases respectively yet none of the compounds exhibited any inhibitory activity against the stenotrophomonas maltophilia l1 metallobetalactamase 50 inhibitory concentration 1000 microm the lack of activity against angiotensinconverting enzyme and serine betalactamases 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 25 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 microgml consequently this series of metallobetalactamase inhibitors exhibit the most promising antibacterial synergy activity so far observed against organisms producing metallobetalactamases