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Antimicrobial Agents and Chemotherapy, September 2006, p. 3124-3131, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00394-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Tetracyclines Specifically Target the Apicoplast of the Malaria Parasite Plasmodium falciparum

Erica L. Dahl,1 Jennifer L. Shock,2 Bhaskar R. Shenai,1,{dagger} Jiri Gut,1 Joseph L. DeRisi,2 and Philip J. Rosenthal1*

Department of Medicine, Box 0811,1 Department of Biochemistry and Biophysics, Box 2240, University of California—San Francisco, San Francisco, California 941432

Received 30 March 2006/ Returned for modification 2 June 2006/ Accepted 13 June 2006

Tetracyclines are effective but slow-acting antimalarial drugs whose mechanism of action remains uncertain. To characterize the antimalarial mechanism of tetracyclines, we evaluated their stage-specific activities, impacts on parasite transcription, and effects on two predicted organelle targets, the apicoplast and the mitochondrion, in cultured Plasmodium falciparum. Antimalarial effects were much greater after two 48-h life cycles than after one cycle, even if the drugs were removed at the end of the first cycle. Doxycycline-treated parasites appeared morphologically normal until late in the second cycle of treatment but failed to develop into merozoites. Doxycycline specifically impaired the expression of apicoplast genes. Apicoplast morphology initially appeared normal in the presence of doxycycline. However, apicoplasts were abnormal in the progeny of doxycycline-treated parasites, as evidenced by a block in apicoplast genome replication, a lack of processing of an apicoplast-targeted protein, and failure to elongate and segregate during schizogeny. Replication of the nuclear and mitochondrial genomes and mitochondrial morphology appeared normal. Our results demonstrate that tetracyclines specifically block expression of the apicoplast genome, resulting in the distribution of nonfunctional apicoplasts into daughter merozoites. The loss of apicoplast function in the progeny of treated parasites leads to a slow but potent antimalarial effect.

* Corresponding author. Mailing address: Box 0811, Department of Medicine, University of California, San Francisco, CA 94143-0811. Phone: (415) 206-8845. Fax: (415) 648-8425. E-mail: rosnthl{at}itsa.ucsf.edu.

{dagger} Present address: Metagenics, Inc., 9770 44th Ave. NW, Suite 100, Gig Harbor, WA 98332.

Antimicrobial Agents and Chemotherapy, September 2006, p. 3124-3131, Vol. 50, No. 9
0066-4804/06/$08.00+0     doi:10.1128/AAC.00394-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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