ISOLATION AND STRUCTURE DETERMINATION OF 2 NOVEL PHENAZINES FROM A STREPTOMYCES WITH INHIBITORY ACTIVITY AGAINST METALLO-ENZYMES, INCLUDING METALLO-BETA-LACTAMASE

Two novel metabolites, SE 212021 and SE 212305, have been isolated from a Streptomyces and shown to have molecular formulae of C15H10N2O5 and C20H17N3O8S, respectively. The structures were deduced by a combination of NMR techniques and mass spectral fragmentation patterns and shown to be novel members of the phenazine group of antibiotics. In the absence of added zinc, both compounds had IC50's of 1 similar to 75 mu M for the Bacteroides fragilis 262 CfiA and Xanthomonas maltophilia L-l metallo-beta-lactamases. The compounds also inhibited ACE with IC50's of 55 and 68 mu M, respectively. Mode of action studies illustrate that the compounds inihibit some metalloenzymes by chelation of the active site metal ion. They exhibit poor antibacterial activity.