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Antimicrobial Agents and Chemotherapy, January 2003, p. 297-301, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.297-301.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

A Type II Pathway for Fatty Acid Biosynthesis Presents Drug Targets in Plasmodium falciparum

Ross F. Waller,1* Stuart A. Ralph,2 Michael B. Reed,3 Vanessa Su,2 James D. Douglas,4 David E. Minnikin,4 Alan F. Cowman,3 Gurdyal S. Besra,5 and Geoffrey I. McFadden2

School of Biochemistry and Molecular Biology,1 Plant Cell Biology Research Centre, School of Botany, University of Melbourne, Melbourne, Victoria 3010,2 Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia,3 Department of Chemistry,4 Department of Microbiology and Immunology, The Medical School, The University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom5

Received 3 May 2002/ Returned for modification 15 September 2002/ Accepted 23 October 2002

It has long been held that the malaria parasite, Plasmodium sp., is incapable of de novo fatty acid synthesis. This view has recently been overturned with the emergence of data for the presence of a fatty acid biosynthetic pathway in the relict plastid of P. falciparum (known as the apicoplast). This pathway represents the type II pathway common to plant chloroplasts and bacteria but distinct from the type I pathway of animals including humans. Specific inhibitors of the type II pathway, thiolactomycin and triclosan, have been reported to target this Plasmodium pathway. Here we report further inhibitors of the plastid-based pathway that inhibit Plasmodium parasites. These include several analogues of thiolactomycin, two with sixfold-greater efficacy than thiolactomycin. We also report that parasites respond very rapidly to such inhibitors and that the greatest sensitivity is seen in ring-stage parasites. This study substantiates the importance of fatty acid synthesis for blood-stage parasite survival and shows that this pathway provides scope for the development of novel antimalarial drugs.

* Corresponding author. Mailing address: School of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia. Phone: 61 3 8344 0293. Fax: 61 3 9347 7730. E-mail: rossfw{at}unimelb.edu.au.

Antimicrobial Agents and Chemotherapy, January 2003, p. 297-301, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.297-301.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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