Resistance Genes of Aminocoumarin Producers: Two Type II Topoisomerase Genes Confer Resistance against Coumermycin A1and Clorobiocin

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Abstract
The aminocoumarin resistance genes of the biosynthetic gene clusters of novobiocin, coumermycin A1, and clorobiocin were investigated. All three clusters contained agyrBRresistance gene, coding for a gyrase B subunit. Unexpectedly, the clorobiocin and the coumermycin A1clusters were found to contain an additional, similar gene, namedparYR. Its predicted gene product showed sequence similarity with the B subunit of type II topoisomerases. Expression ofgyrBRand likewise ofparYRinStreptomyces lividansTK24 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 ofStreptomyces coelicolorcontained two additional genes which hybridized with eithergyrBRorparYRand which may code for aminocoumarin-sensitive GyrB and ParY proteins. Two putative transporter genes,novAandcouR5, were found in the novobiocin and the coumermycin A1cluster, respectively. Expression of these genes inS. lividansTK24 resulted in moderate levels of resistance against novobiocin and coumermycin A1, suggesting that these genes may be involved in antibiotic transport.