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Antimicrobial Agents and Chemotherapy, November 2004, p. 4120-4129, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4120-4129.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Chemical Diversity of Polyene Macrolides Produced by Streptomyces noursei ATCC 11455 and Recombinant Strain ERD44 with Genetically Altered Polyketide Synthase NysC

Per Bruheim,1 Sven E.F. Borgos,1 Pascale Tsan,2 Håvard Sletta,3 Trond E. Ellingsen,3 Jean-Marc Lancelin,2 and Sergey B. Zotchev1*

Department of Biotechnology, Norwegian University of Science and Technology,1 Department of Industrial Biotechnology, SINTEF Materials and Chemistry, SINTEF, Trondheim, Norway,3 RMN Biomoléculaire, Unité Mixte de Recherche, Université Claude Bernard-Lyon 1, CNRS Sciences Analytiques, ESCPE-Lyon, Villeurbanne, France2

Received 28 January 2004/ Returned for modification 29 March 2004/ Accepted 11 July 2004

The gram-positive bacterium Streptomyces noursei ATCC 11455 produces a complex mixture of polyene macrolides generally termed nystatins. Although the structures for nystatins A1 and A3 have been reported, the identities of other components of the nystatin complex remain obscure. Analyses of the culture extract from the S. noursei wild type revealed the presence of several nystatin-related compounds for which chemical structures could be suggested on the basis of their molecular weights, their UV spectra, and knowledge of the nystatin biosynthetic pathway. Nuclear magnetic resonance (NMR) studies with one of these polyene macrolides identified it as a nystatin analogue containing a mycarose moiety at C-35. A similar investigation was performed with the culture extract of the ERD44 mutant, which has a genetically altered polyketide synthase (PKS) NysC and which was previously shown to produce a heptaene nystatin analogue. The latter compound, tentatively named S44HP, and its derivative, which contains two deoxysugar moieties, were purified; and their structures were confirmed by NMR analysis. Nystatin analogues with an expanded macrolactone ring were also observed in the extract of the ERD44 mutant, suggesting that the altered PKS can "stutter" during the polyketide chain assembly. These data provide new insights into the biosynthesis of polyene macrolide antibiotics and the functionalities of PKSs and post-PKS modification enzymes.

* Corresponding author. Mailing address: Department of Biotechnology, Norwegian University of Science and Technology, N-7491 Trondheim, Norway. Phone: 47 73 59 86 79. Fax: 47 73 59 12 83. E-mail: sergey.zotchev{at}biotech.ntnu.no.

Antimicrobial Agents and Chemotherapy, November 2004, p. 4120-4129, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4120-4129.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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