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Journal of Bacteriology, April 1999, p. 2507-2512, Vol. 181, No. 8
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Mitomycin Resistance in Streptomyces lavendulae Includes a Novel Drug-Binding-Protein-Dependent Export System

Paul J. Sheldon,dagger Yingqing Mao, Min He, and David H. Sherman*

Department of Microbiology and Biological Process Technology Institute, University of Minnesota, Minneapolis, Minnesota 55455

Received 16 November 1998/Accepted 5 February 1999

Sequence analysis of Streptomyces lavendulae NRRL 2564 chromosomal DNA adjacent to the mitomycin resistance locus mrd (encoding a previously described mitomycin-binding protein [P. Sheldon, D. A. Johnson, P. R. August, H.-W. Liu, and D. H. Sherman, J. Bacteriol. 179:1796-1804, 1997]) revealed a putative mitomycin C (MC) transport gene (mct) encoding a hydrophobic polypeptide that has significant amino acid sequence similarity with several actinomycete antibiotic export proteins. Disruption of mct by insertional inactivation resulted in an S. lavendulae mutant strain that was considerably more sensitive to MC. Expression of mct in Escherichia coli conferred a fivefold increase in cellular resistance to MC, led to the synthesis of a membrane-associated protein, and correlated with reduced intracellular accumulation of the drug. Coexpression of mct and mrd in E. coli resulted in a 150-fold increase in resistance, as well as reduced intracellular accumulation of MC. Taken together, these data provide evidence that MRD and Mct function as components of a novel drug export system specific to the mitomycins.

* Corresponding author. Mailing address: Department of Microbiology, University of Minnesota, Box 196, 1460 Mayo Memorial Building, 420 Delaware St. S.E., Minneapolis, MN 55455-0312. Phone: (612) 626-0199. Fax: (612) 624-6641. E-mail: david-s{at}biosci.cbs.umn.edu.

dagger Present address: School of Pharmacy, University of Wisconsin, Madison, WI 53706.

Journal of Bacteriology, April 1999, p. 2507-2512, Vol. 181, No. 8
0021-9193/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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