title: A type II pathway for fatty acid biosynthesis presents drug targets in Plasmodium falciparum.
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.
authors.affiliation: School of Biochemistry and Molecular Biology, University of Melbourne, Melbourne, Victoria 3010, Australia. rossfw@unimelb.edu.au
authors.forename: Ross F
authors.initials: RF
authors.lastname: Waller
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Ralph
authors.forename: Michael B
authors.initials: MB
authors.lastname: Reed
authors.forename: Vanessa
authors.initials: V
authors.lastname: Su
authors.forename: James D
authors.initials: JD
authors.lastname: Douglas
authors.forename: David E
authors.initials: DE
authors.lastname: Minnikin
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Geoffrey I
authors.initials: GI
authors.lastname: McFadden
mesh_terms: D000818:Animals; D005227:Fatty Acids / Q000096:biosynthesis*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D005227:Fatty Acids; D013876:Thiophenes; C035068:thiolactomycin