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Antimicrobial Agents and Chemotherapy, February 2004, p. 575-588, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.575-588.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Functional Angucycline-Like Antibiotic Gene Cluster in the Terminal Inverted Repeats of the Streptomyces ambofaciens Linear Chromosome

Xiuhua Pang,1,{dagger} Bertrand Aigle,1,{dagger}* Jean-Michel Girardet,2 Sophie Mangenot,3 Jean-Luc Pernodet,4 Bernard Decaris,1 and Pierre Leblond1

Laboratoire de Génétique et Microbiologie, UMR INRA-UHP 1128, IFR 110,1 Laboratoire des Biosciences de l'Aliment, UC885 INRA, Faculté des Sciences et Techniques, Université Henri Poincaré, Nancy 1, 54506 Vandoeuvre-lès-Nancy,2 Génoscope, CNS, 91057 Evry Cedex,3 Institut de Génétique et Microbiologie, UMR-CNRS 8621, Université Paris-Sud, Centre Universitaire d'Orsay, 91405 Orsay Cedex, France4

Received 17 July 2003/ Returned for modification 11 September 2003/ Accepted 29 October 2003

Streptomyces ambofaciens has an 8-Mb linear chromosome ending in 200-kb terminal inverted repeats. Analysis of the F6 cosmid overlapping the terminal inverted repeats revealed a locus similar to type II polyketide synthase (PKS) gene clusters. Sequence analysis identified 26 open reading frames, including genes encoding the ß-ketoacyl synthase (KS), chain length factor (CLF), and acyl carrier protein (ACP) that make up the minimal PKS. These KS, CLF, and ACP subunits are highly homologous to minimal PKS subunits involved in the biosynthesis of angucycline antibiotics. The genes encoding the KS and ACP subunits are transcribed constitutively but show a remarkable increase in expression after entering transition phase. Five genes, including those encoding the minimal PKS, were replaced by resistance markers to generate single and double mutants (replacement in one and both terminal inverted repeats). Double mutants were unable to produce either diffusible orange pigment or antibacterial activity against Bacillus subtilis. Single mutants showed an intermediate phenotype, suggesting that each copy of the cluster was functional. Transformation of double mutants with a conjugative and integrative form of F6 partially restored both phenotypes. The pigmented and antibacterial compounds were shown to be two distinct molecules produced from the same biosynthetic pathway. High-pressure liquid chromatography analysis of culture extracts from wild-type and double mutants revealed a peak with an associated bioactivity that was absent from the mutants. Two additional genes encoding KS and CLF were present in the cluster. However, disruption of the second KS gene had no effect on either pigment or antibiotic production.

* Corresponding author. Mailing address: Laboratoire de Génétique et Microbiologie, Faculté des Sciences et Techniques, Université Henri Poincaré, Nancy 1, Boulevard des Aiguillettes, BP239, 54506 Vandoeuvre-lès-Nancy, France. Phone: 33 3 83 68 42 05. Fax: 33 3 83 68 44 99. E-mail: Bertrand.Aigle{at}scbiol.uhp-nancy.fr.

{dagger} X.P. and B.A. contributed equally to this report.

Antimicrobial Agents and Chemotherapy, February 2004, p. 575-588, Vol. 48, No. 2
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.2.575-588.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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