ABSTRACT
The antibiotic feglymycin is a linear 13-mer peptide synthesized by the bacterium Streptomyces sp. DSM 11171. It mainly consists of the nonproteinogenic amino acids 4-hydroxyphenylglycine and 3,5-dihydroxyphenylglycine. An alanine scan of feglymycin was performed by solution-phase peptide synthesis in order to assess the significance of individual amino acid side chains for biological activity. Hence, 13 peptides were synthesized from di- and tripeptide building blocks, and subsequently tested for antibacterial activity against Staphylococcus aureus strains. Furthermore we tested the inhibition of peptidoglycan biosynthesis enzymes MurA and MurC, which are inhibited by feglymycin. Whereas the antibacterial activity is significantly based on the three amino acids D-Hpg1, L-Hpg5, and L-Phe12, the inhibitory activity against MurA and MurC depends mainly on L-Asp13. The difference in the position dependence for antibacterial activity and enzyme inhibition suggests multiple molecular targets in the modes of action of feglymycin.
Subject(s)
Alanine/chemistry , Anti-Infective Agents/chemistry , Proteins/chemistry , Alkyl and Aryl Transferases/antagonists & inhibitors , Alkyl and Aryl Transferases/metabolism , Anti-Infective Agents/chemical synthesis , Anti-Infective Agents/pharmacology , Microbial Sensitivity Tests , Peptides/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Proteins/chemical synthesis , Proteins/pharmacology , Staphylococcus aureus/drug effectsABSTRACT
In an antibiotic lead discovery program, the known strain Streptomyces armeniacus DSM19369 has been found to produce three new natural products when cultivated on a malt-containing medium. The challenging structural elucidation of the isolated compounds was achieved by using three independent methods, that is, chemical degradation followed by NMR spectroscopy, a computer-assisted structure prediction algorithm, and X-ray crystallography. The compounds, named armeniaspirolâ A-C (2-4), exhibit a compact, hitherto unprecedented chlorinated spiro[4.4]non-8-ene scaffold. Labeling experiments with [1-(13)C] acetate, [1,2-(13)C2] acetate, and [U-(13)C] proline suggest a biosynthesis through a rare two-chain mechanism. Armeniaspirols displayed moderate to high in vitro activities against gram-positive pathogens such as methicillin-resistant S. aureus (MRSA) or vancomycin resistant E. faecium (VRE). As analogue 2 was active in vivo in an MRSA sepsis model, and showed no development of resistance in a serial passaging experiment, it represents a new antibiotic lead structure.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Biological Products/chemistry , Biological Products/pharmacology , Gram-Positive Bacteria/chemistry , Gram-Positive Bacteria/drug effects , Pyrroles/chemistry , Pyrroles/pharmacology , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Staphylococcal Infections/drug therapy , Staphylococcus aureus/chemistry , Staphylococcus aureus/drug effects , Bacterial Structures , Crystallography, X-Ray , Drug DiscoveryABSTRACT
An adaptable approach: The first highly convergent stereoselective synthesis of feglymycin (see structure) and its enantiomer is based on the coupling of repeating peptide fragments. The use of weakly basic conditions throughout the synthesis suppressed the epimerization of sensitive aryl glycine units. Feglymycin has strong anti-HIV activity as well as potent (previously identified as weak) antibacterial activity against Staphylococcus aureus.
