Understanding the Biosynthesis of the 2,4-Dimethylindolic Acid Moiety in the Thiopeptide Antibiotic Nosiheptide

Project: Research project

Description

Abstract The thiopeptide antibiotics are an emerging class of natural products that exhibit formidable activity against drug resistant, Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus, penicillin- resistant Streptococcus pneumoniae, and vancomycin-resistant enterococci. These natural products are highly modified, sulfur-rich, cyclic peptides that feature a central nitrogen-containing six-membered ring of differing degrees of saturation that is tri- or tetra-substituted. Additional modifications include multiple thiazole or oxazole rings, and dehydro-amino acids. These antibiotics are generated from a precursor peptide that is synthesized ribosomally and then modified by a number of tailoring enzymes. One of these enzymes, NosN, a Class C RS methylase involved in the biosynthesis of nosiheptide, catalyzes the methylation of a carbon atom of a 3-methylindolic acid (MIA) molecule that becomes attached to the thiopeptide framework. The mechanism by which this reaction takes place is unknown, and is the focus of much of the proposed work. Additionally, the timing of attachment of the MIA moiety to the thiopeptide framework is unknown and will be similarly addressed by recapitulating the biosynthesis of the thiopeptide in vitro.
StatusFinished
Effective start/end date5/18/174/30/19

Funding

  • National Institutes of Health: $189,000.00
  • National Institutes of Health: $157,500.00

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Biosynthesis
Biological Products
Oxazoles
Anti-Bacterial Agents
Thiazoles
Cyclic Peptides
Methicillin
Acids
Methylation
Pathogens
Enzymes
Vancomycin
Sulfur
Penicillins
Nitrogen
Carbon
Amino Acids
Atoms
Peptides
Molecules