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Applied and Environmental Microbiology, July 2007, p. 4162-4170, Vol. 73, No. 13
0099-2240/07/$08.00+0     doi:10.1128/AEM.00485-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Identification of the Biosynthetic Gene Cluster and an Additional Gene for Resistance to the Antituberculosis Drug Capreomycin{triangledown} ,{dagger}

Elizabeth A. Felnagle,1,2 Michelle R. Rondon,1 Andrew D. Berti,1,2 Heidi A. Crosby,1,2 and Michael G. Thomas1,2*

Department of Bacteriology,1 Microbiology Doctoral Training Program, University of Wisconsin—Madison, Madison, Wisconsin 537062

Received 2 March 2007/ Accepted 5 May 2007

Capreomycin (CMN) belongs to the tuberactinomycin family of nonribosomal peptide antibiotics that are essential components of the drug arsenal for the treatment of multidrug-resistant tuberculosis. Members of this antibiotic family target the ribosomes of sensitive bacteria and disrupt the function of both subunits of the ribosome. Resistance to these antibiotics in Mycobacterium species arises due to mutations in the genes coding for the 16S or 23S rRNA but can also arise due to mutations in a gene coding for an rRNA-modifying enzyme, TlyA. While Mycobacterium species develop resistance due to alterations in the drug target, it has been proposed that the CMN-producing bacterium, Saccharothrix mutabilis subsp. capreolus, uses CMN modification as a mechanism for resistance rather than ribosome modification. To better understand CMN biosynthesis and resistance in S. mutabilis subsp. capreolus, we focused on the identification of the CMN biosynthetic gene cluster in this bacterium. Here, we describe the cloning and sequence analysis of the CMN biosynthetic gene cluster from S. mutabilis subsp. capreolus ATCC 23892. We provide evidence for the heterologous production of CMN in the genetically tractable bacterium Streptomyces lividans 1326. Finally, we present data supporting the existence of an additional CMN resistance gene. Initial work suggests that this resistance gene codes for an rRNA-modifying enzyme that results in the formation of CMN-resistant ribosomes that are also resistant to the aminoglycoside antibiotic kanamycin. Thus, S. mutabilis subsp. capreolus may also use ribosome modification as a mechanism for CMN resistance.

* Corresponding author. Mailing address: Department of Bacteriology, University of Wisconsin—Madison, 150 Biochemistry, 420 Henry Mall, Madison, WI 53706. Phone: (608) 263-9075. Fax: (608) 262-9865. E-mail: thomas{at}bact.wisc.edu

{triangledown} Published ahead of print on 11 May 2007.

{dagger} Supplemental material for this article may be found at http://aem.asm.org/.

Applied and Environmental Microbiology, July 2007, p. 4162-4170, Vol. 73, No. 13
0099-2240/07/$08.00+0     doi:10.1128/AEM.00485-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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