Issue 16, 2003
From the journal:

Organic & Biomolecular Chemistry

Direct production of ivermectin-like drugs after domain exchange in the avermectinpolyketide synthase of Streptomyces avermitilis ATCC31272

Sabine Gaisser,a   Laurenz Kellenberger,be   Andrew L. Kaja,a   Alison J. Weston,a   Rachel E. Lill,a   Gabriele Wirtz,af   Steven G. Kendrew,a   Lindsey Low,a   Rose M. Sheridan,a   Barrie Wilkinson,a   Ian S. Galloway,ag   Kim Stutzman-Engwall,d   Hamish A. I. McArthur,d   James Stauntonbc  and  Peter F. Leadlay*ab  

* Corresponding authors

a Biotica Technology Limited, 181A Huntingdon Road, Cambridge, UK

b Cambridge Centre for Molecular Recognition and Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge, UK
E-mail: pfl10@mole.bio.cam.ac.uk

c Cambridge Centre for Molecular Recognition and Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK

d Bioprocess R & D, Pfizer Global Research & Development, Groton Labs., Eastern Point Road, Groton, CT 06340, USA

e BASILEA Pharmaceutica Ltd., Basel, Switzerland

f Bayer AG, 42096 Wuppertal, Germany

g Unilever Bestfoods UK, London Road, Purfleet, Essex, UK

Abstract

Ivermectin™, a mixture of 22,23-dihydroavermectin B1a 9 with minor amounts of 22,23-dihydroavermectin B1b 10, is one of the most successful veterinary antiparasitic drugs ever produced. In humans, ivermectin has been used for the treatment of African river blindness (onchocerciasis) resulting in an encouraging decrease in the prevalence of skin and eye diseases linked to this infection. The components of ivermectin are currently synthesized by chemical hydrogenation of a specific double bond at C22–C23 in the polyketide macrolides avermectins B1a 5 and B1b 6, broad-spectrum antiparasitic agents isolated from the soil bacterium Streptomyces avermitilis. We describe here the production of such compounds (22,23-dihydroavermectins B1a 9 and A1a 11) by direct fermentation of a recombinant strain of S. avermitilis containing an appropriately-engineered polyketide synthase (PKS). This suggests the feasibility of a direct biological route to this valuable drug.

Graphical abstract: Direct production of ivermectin-like drugs after domain exchange in the avermectin polyketide synthase of Streptomyces avermitilis ATCC31272

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Article information

DOI
https://doi.org/10.1039/B304022D
Article type
Paper
Submitted
14 Apr 2003
Accepted
16 Jun 2003
First published
09 Jul 2003

Org. Biomol. Chem., 2003,1, 2840-2847

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Direct production of ivermectin-like drugs after domain exchange in the avermectin polyketide synthase of Streptomyces avermitilis ATCC31272

S. Gaisser, L. Kellenberger, A. L. Kaja, A. J. Weston, R. E. Lill, G. Wirtz, S. G. Kendrew, L. Low, R. M. Sheridan, B. Wilkinson, I. S. Galloway, K. Stutzman-Engwall, H. A. I. McArthur, J. Staunton and P. F. Leadlay, Org. Biomol. Chem., 2003, 1, 2840 DOI: 10.1039/B304022D

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