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Antimicrobial Agents and Chemotherapy, March 2003, p. 869-877, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.869-877.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Resistance Genes of Aminocoumarin Producers: Two Type II Topoisomerase Genes Confer Resistance against Coumermycin A1 and Clorobiocin

Elisabeth Schmutz, Agnes Mühlenweg, Shu-Ming Li, and Lutz Heide*

Pharmazeutische Biologie, Eberhard-Karls-Universität Tübingen, D-72076 Tübingen, Germany

Received 26 September 2002/ Returned for modification 29 October 2002/ Accepted 4 December 2002

The aminocoumarin resistance genes of the biosynthetic gene clusters of novobiocin, coumermycin A1, and clorobiocin were investigated. All three clusters contained a gyrBR resistance gene, coding for a gyrase B subunit. Unexpectedly, the clorobiocin and the coumermycin A1 clusters were found to contain an additional, similar gene, named parYR. Its predicted gene product showed sequence similarity with the B subunit of type II topoisomerases. Expression of gyrBR and likewise of parYR in Streptomyces lividans TK24 resulted in resistance against novobiocin and coumermycin A1, suggesting that both gene products are able to function as aminocoumarin-resistant B subunits of gyrase. Southern hybridization experiments showed that the genome of all three antibiotic producers and of Streptomyces coelicolor contained two additional genes which hybridized with either gyrBR or parYR and which may code for aminocoumarin-sensitive GyrB and ParY proteins. Two putative transporter genes, novA and couR5, were found in the novobiocin and the coumermycin A1 cluster, respectively. Expression of these genes in S. lividans TK24 resulted in moderate levels of resistance against novobiocin and coumermycin A1, suggesting that these genes may be involved in antibiotic transport.

* Corresponding author. Mailing address: Eberhard-Karls-Universität Tübingen, Pharmazeutische Biologie, Auf der Morgenstelle 8, D-72076 Tübingen, Germany. Phone: 49 7071 2978789. Fax: 49 7071 295250. E-mail: heide{at}uni-tuebingen.de.

Antimicrobial Agents and Chemotherapy, March 2003, p. 869-877, Vol. 47, No. 3
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.3.869-877.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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