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Antimicrobial Agents and Chemotherapy, January 2007, p. 307-316, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00808-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibitors of Nonhousekeeping Functions of the Apicoplast Defy Delayed Death in Plasmodium falciparum{triangledown}

T. N. C. Ramya,1 Satyendra Mishra,1,{dagger} Krishanpal Karmodiya,2,{dagger} Namita Surolia,2* and Avadhesha Surolia1,3*

Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India,1 Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560064, India,2 National Institute of Immunology, New Delhi 110067, India3

Received 4 July 2006/ Returned for modification 6 August 2006/ Accepted 25 September 2006

Targeting of apicoplast replication and protein synthesis in the apicomplexan Toxoplasma gondii has conventionally been associated with the typical "delayed death" phenotype, characterized by the death of parasites only in the generation following drug intervention. We demonstrate that antibiotics like clindamycin, chloramphenicol, and tetracycline, inhibitors of prokaryotic protein synthesis, invoke the delayed death phenotype in Plasmodium falciparum, too, as evident from a specific reduction of apicoplast genome copy number. Interestingly, however, molecules like triclosan, cerulenin, fops, and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, an inhibitor of heme biosynthesis that operates in the apicoplast of the parasite, display rapid and striking parasiticidal effects. Our results draw a clear distinction between apicoplast functions per se and the apicoplast as the site of metabolic pathways, which are required for parasite survival, and thus subserve the development of novel antimalarial therapy.

* Corresponding author. Mailing address for Avadhesha Surolia: National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110067, India. Phone: 91-11-26717102. Fax: 91-11-26717104. E-mail: surolia{at}nii.res.in. Mailing address for Namita Surolia: Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bangalore 560064, India. Phone: 91-80-22082821. Fax: 91-80-22082766. E-mail: surolia{at}jncasr.ac.in.

{triangledown} Published ahead of print on 23 October 2006.

{dagger} These authors contributed equally to the manuscript.

Antimicrobial Agents and Chemotherapy, January 2007, p. 307-316, Vol. 51, No. 1
0066-4804/07/$08.00+0     doi:10.1128/AAC.00808-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gratraud, P., Surolia, N., Besra, G. S., Surolia, A., Kremer, L. (2008). Antimycobacterial Activity and Mechanism of Action of NAS-91. Antimicrob. Agents Chemother. 52: 1162-1166 [Abstract] [Full Text]  
  • Barthel, D., Schlitzer, M., Pradel, G. (2008). Telithromycin and Quinupristin-Dalfopristin Induce Delayed Death in Plasmodium falciparum. Antimicrob. Agents Chemother. 52: 774-777 [Abstract] [Full Text]  
  • Dahl, E. L., Rosenthal, P. J. (2007). Multiple Antibiotics Exert Delayed Effects against the Plasmodium falciparum Apicoplast. Antimicrob. Agents Chemother. 51: 3485-3490 [Abstract] [Full Text]  
  • Ramya, T. N. C., Karmodiya, K., Surolia, A., Surolia, N. (2007). 15-Deoxyspergualin Primarily Targets the Trafficking of Apicoplast Proteins in Plasmodium falciparum. J. Biol. Chem. 282: 6388-6397 [Abstract] [Full Text]  


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