‘FAS’t inhibition of malaria

Abstract

Malaria, a tropical disease caused by Plasmodium sp., has been haunting mankind for ages. Unsuccessful attempts to develop a vaccine, the emergence of resistance against the existing drugs and the increasing mortality rate all call for immediate strategies to treat it. Intense attempts are underway to develop potent analogues of the current antimalarials, as well as a search for novel drug targets in the parasite. The indispensability of apicoplast (plastid) to the survival of the parasite has attracted a lot of attention in the recent past. The present review describes the origin and the essentiality of this relict organelle to the parasite. We also show that among the apicoplast specific pathways, the fatty acid biosynthesis system is an attractive target, because its inhibition decimates the parasite swiftly unlike the 'delayed death' phenotype exhibited by the inhibition of the other apicoplast processes. As the enzymes of the fatty acid biosynthesis system are present as discrete entities, unlike those of the host, they are amenable to inhibition without impairing the operation of the host-specific pathway. The present review describes the role of these enzymes, the status of their molecular characterization and the current advancements in the area of developing inhibitors against each of the enzymes of the pathway.

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

“…The apicoplast houses prokaryotic machinery, presumably to replicate its circular 35-kb genome and to transcribe and translate the genes that it possesses. Consequently, ciprofloxacin, earlier reported to inhibit the prokaryotic DNA gyrase, and chloramphenicol, clindamycin, and other lincosamide antibiotics, which are believed to inhibit transpeptidation of prokaryotic protein synthesis, abrogate Plasmodium growth (3,23,24,27). 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).…”

Herbicides and Protozoan Parasite Growth Control: Implications for New Drug Development

“…It was previously thought that apicomplexan parasites were incompetent for de novo fatty acid synthesis (Holz 1977;Matesanz et al 1999), but recent work showed the presence of nuclear-encoded apicomplast-targeted genes for all enzymes of the fatty acid biosynthesis pathway in several apicomplexa parasites and this finding provided strong arguments in favor of the presence of a de novo fatty acid biosynthesis in this organelle (Surolia et al 2004). The presence of highly conserved proteins known as Type II fatty acid synthase explains the susceptibility of T. gondii and P. falciparum to herbicides targeting plastidic Acetyl-CoA carboxylase, like the aryloxyphenoxypropionates.…”

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

“…This enzyme has already been known to be a potent drug target for the development of antimalarials and antibacterials (7,8). A structural characterization was performed for several classes of ENR inhibitors complexed with their target enzymes.…”