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

Two novel metabolites, SE 212021 and SE 212305, have been isolated fro m a Streptomyces and shown to have molecular formulae of C15H10N2O5 an d C20H17N3O8S, respectively. The structures were deduced by a combinat ion of NMR techniques and mass spectral fragmentation patterns and sho wn to be novel members of the phenazine group of antibiotics. In the a bsence 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 t hat the compounds inihibit some metalloenzymes by chelation of the act ive site metal ion. They exhibit poor antibacterial activity.