Project

Back to overview

The Biosynthesis of the Glycopeptide Antibiotic Vancomycin

English title The Biosynthesis of the Glycopeptide Antibiotic Vancomycin
Applicant Robinson John A.
Number 111678
Funding scheme Project funding
Research institution Organisch-chemisches Institut Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Organic Chemistry
Start/End 01.06.2006 - 31.05.2009
Approved amount 262'050.00
Show all

All Disciplines (2)

Discipline
Organic Chemistry
Biochemistry

Keywords (8)

vancomycin; antibiotic; biosynthesis; enzyme; glycopeptide; natural product; secondary metabolism; cytochrome P450

Lay Summary (English)

Lead
Lay summary
Glycopeptide antibiotics such as vancomycin are complex natural products biosynthesized in several soil-borne bacteria. They inhibit bacterial growth by interfering with cell wall biosynthesis, and are clinically used as last resort antibiotics against infections with multi-resistant Gram positive pathogens. There is now great interest in discovering modified forms of the glycopeptides to ovecome the emergence of resistance to these antibiotics. For this reason, considerable interest has arisen in exploiting knowledge about the biosynthesis of these metabolites, as a means to structural manipulation of the glycopeptides. Basically, the enzymes responsible for making these antibiotics might be used to create novel analogues with improved antibiotic properites. In addition, there is great fundamental interest in understanding how these very complex molecules are made in Nature. Glycopeptide antibiotics consist of a heptapeptide skeleton, which is highly modified through cross-linking of several aromatic moieties, as well as by chlorination, glycosylation, methylation, acylation and/or sulfation. The cross-linking steps are of special interest here, since these steps belong to the family of so-called oxidative phenol coupling reactions. The cross-linking steps are also essential for the antibiotic activity of these molecules. The aims of this project are to elucidate when and how during the biosynthesis, these cross-links are introduced. Already three enzymes have been identified, belonging to the cytochrome P450 family that catalyze the oxidative phenol coupling reactions during vancomycin biosynthesis. However, the substrates which are acted upon by these enzymes have until recently not been identified. In our recent work, we could show for the first time, that the first cross-linking step occurs upon peptidic precursors only when they are attached to the very large, multi-domain, peptide synthetase that assembles the peptide backbone (much like an assembly line). Other important goals of our work are to study how these enzymes work, what other substrates they might act upon, as well as to elucidate the timing of the second and third cross-linking steps in vancomycin biosynthesis.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
124490 The Biosynthesis of the Glycopeptide Antibiotics 01.06.2009 Project funding
103984 1. Protein Epitope Mimetics and Biomedical research and 2. The Biosynthesis of the Glycopeptide Antibiotic Vancomycin 01.06.2004 Project funding

-