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A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum

Lookup NU author(s): Professor David Minnikin, Professor Del Besra

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Abstract

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.


Publication metadata

Author(s): Waller RF, Ralph SA, Reed MB, Su V, Douglas JD, Minnikin DE, Cowman AF, Besra GS, McFadden GI

Publication type: Article

Publication status: Published

Journal: Antimicrobial Agents and Chemotherapy

Year: 2003

Volume: 47

Issue: 1

Pages: 297-301

ISSN (print): 0066-4804

ISSN (electronic): 1098-6596

Publisher: American Society for Microbiology

URL: http://dx.doi.org/10.1128/AAC.47.1.297-301.2003

DOI: 10.1128/AAC.47.1.297-301.2003

PubMed id: 12499205


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