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Antimicrob. Agents Chemother. doi:10.1128/AAC.00808-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Inhibitors of Non-Housekeeping Functions of the Apicoplast Defy ‘Delayed Death’ in Plasmodium falciparum

Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, INDIA; Molecular Biology and Genetics Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore 560 064, INDIA; National Institute of Immunology, New Delhi 110067, INDIA

^* To whom correspondence should be addressed. Email: surolia{at}nii.res.in or surolia@mbu.iisc.ernet.in.

	Abstract

Targeting the apicoplast replication and protein synthesis in the apicomplexan, Toxoplasma gondii has been conventionally 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. However, interestingly, molecules like triclosan, cerulenin, fops and NAS-91, inhibitors of the recently discovered fatty acid synthesis pathway, and succinyl acetone, inhibitor of heme biosynthesis operating in the apicoplast of the parasite display a rapid and striking parasiticidal effect. 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 anti-malarial therapy.

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