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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

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 gyrB^R 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 parY^R. Its predicted gene product showed sequence similarity with the B subunit of type II topoisomerases. Expression of gyrB^R and likewise of parY^R 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 gyrB^R or parY^R 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.

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