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.

Functional characterization of a fatty acyl-CoA-binding protein (ACBP) from the apicomplexan Cryptosporidium parvum

“…Fatty acids are essential to all organisms. Recently, fatty acid metabolism has been considered as a promising target for drug development against cryptosporidiosis and other important pathogenic apicomplexans (Gornicki, 2003;Kuo et al, 2003;Ralph et al, 2001;Roberts et al, 2003;Waller et al, 2003;Zhu, 2004). Because ACBP plays a critical role in fatty acid metabolism, it is reasonable to speculate that CpACBP1 and other apicomplexan ACBPs may be explored as new drug targets for the control of cryptosporidiosis or other apicomplexan-based diseases.…”

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

“…More importantly, the apicoplast is predicted to provide the microenvironment required for fatty acid synthesis, non-mevalonate isopentenyl diphosphate synthesis, and some of the reactions of the heme biosynthesis pathway, and given the cyanobacterial heritage of the apicoplast, many of the nucleusencoded and apicoplast-targeted enzymes involved in these pathways are fundamentally different from those in their mammalian host counterparts, thereby making them potent drug targets (9,28,29). Inhibitors of these apicoplast resident metabolic pathways-triclosan (7), cerulenin (32), aryloxyphenoxypropionate herbicides (20), NAS-91 (25), succinyl acetone (15), and fosmidomycin (14)-have been demonstrated to kill Plasmodium (8,14,25,28,29,32,33).…”

The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites

“…Thiolactomycin is one such drug that inhibits type II FAS in plants and bacteria and by enzyme kinetics and crystal structure studies is known to bind specifically to β-ketoacyl-ACP synthases (most strongly to synthases I and II). Thiolactomycin kills parasites in vitro (Table 1) and several analogues show up to five-fold greater efficacy (Waller et al, 2003). Triclosan is another drug selective for the prokaryote pathway that shows even greater efficacy against parasites and is also effective as an anti-malarial in mouse models (McLeod et al, 2001;Surolia and Surolia, 2001;Perozzo et al, 2002).…”

“…This drug has a long record of safety for human use (as an anti-microbial in toothpastes and other products) and triclosan analogues are being explored for anti-malarial use (Perozzo et al, 2002). Both thiolactomycin and triclosan show rapid inhibition of Plasmodium falciparum with greatest parasite sensitivity seen in ring-stage parasites (Waller et al, 2003). Cerulenin also targets β-ketoacyl-ACP synthases I and II (although type I FAS is also sensitive) and inhibits P. falciparum (Table 1) (Waller et al, 2003).…”