Antibiotics GE23077, novel inhibitors of bacterial RNA polymerase. Part 3: Chemical derivatization

GE23077 is a novel RNA polymerase inhibitor that is isolated from the fermentation broth of an Actinomadura sp. It is a cyclic heptapeptide complex made up of four factors, differing in the structure of acyl group connected to the side chain of an α,β-diaminopropanoic acid moiety and in the configuration of the stereocenter of an α-amino-malonic acid residue. Although GE23077 shows strong inhibitory activity on both Rifampicin-sensitive and -resistant polymerases, it exhibits poor antimicrobial activity. The most reasonable explanation for this property has been based on the lack of penetration of the molecule across the bacterial membrane, owing to its strong hydrophilic character. To improve penetration, several parts of the molecule were accordingly modified with the aim of altering the physico-chemical properties of GE23077. The current SAR study has identified moieties important for RNA polymerase activity.

Chemical derivatization of a novel inhibitor of bacterial RNA polymerase GE23077 (IC50 = 0.02 mg/l) is reported.Figure optionsDownload as PowerPoint slide