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

Chemical derivatization of a novel inhibitor of bacterial RNA polymerase GE23077 (IC 50 = 0.02 mg/l) is reported. 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...

Full description

Saved in:
Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2005-08, Vol.15 (16), p.3748-3752
Main Authors: Mariani, Riccardo, Granata, Giorgio, Maffioli, Sonia I., Serina, Stefania, Brunati, Cristina, Sosio, Margherita, Marazzi, Alessandra, Vannini, Alfredo, Patel, Dinesh, White, Richard, Ciabatti, Romeo
Format: Article
Language:English
Subjects:
Actinomycetales - drug effects
Actinomycetales - enzymology
Anti-Bacterial Agents - chemical synthesis
Anti-Bacterial Agents - chemistry
Anti-Bacterial Agents - pharmacology
DNA-Directed RNA Polymerases - antagonists & inhibitors
Enzyme Inhibitors - chemical synthesis
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Molecular Structure
Peptides, Cyclic - chemical synthesis
Peptides, Cyclic - chemistry
Peptides, Cyclic - pharmacology
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Chemical derivatization of a novel inhibitor of bacterial RNA polymerase GE23077 (IC 50 = 0.02 mg/l) is reported. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.05.060