Recent highlights in antimalarial drug resistance and chemotherapy research

Abstract

This review summarizes recent investigations into antimalarial drug resistance and chemotherapy, including reports of some of the many exciting talks and posters on this topic that were presented at the third Molecular Approaches to Malaria meeting held in Lorne, Australia, in February 2008 (MAM 2008). After surveying this area of research, we focus on two important questions: what is the molecular contribution of pfcrt to chloroquine resistance, and what is the mechanism of action of artemisinin? We conclude with thoughts about the current state of antimalarial chemotherapy and priorities moving forward.

Polymorphism in PfMRP1 ( Plasmodium falciparum Multidrug Resistance Protein 1) Amino Acid 1466 Associated with Resistance to Sulfadoxine-Pyrimethamine Treatment

“…These observations are applied in vitro to modify protocols for the determination of parasite sensitivity to SP (25). Further studies have shown that probenecid can reverse P. falciparum resistance to several antifolates, including sulfadoxine and pyrimethamine, due to the reduction of folate influx into both red blood cells and parasites (8,16,18). In mammalian cells, MRPs have a role in folate homeostasis and have been shown to transport folate out of the cell (3,27).…”

“…falciparum has an endogenous folate biosynthesis pathway, but most strains can also use exogenous folate through the folate salvage pathway (17,23). The influx of exogenous folate (23) and the proteins responsible for this process (8,16,18), as well as efflux systems able to pump antifolate drugs out of the parasite intracellular space (16), have been proposed to further influence antifolate resistance.…”

Anti-malaria drug development targeting the M1 alanyl and M17 leucyl aminopeptidases

“…59 While a promising vaccine for malaria is currently in phase III trials, its efficacy appears to be in the order of 50%, 60 and thus malaria drugs are still critical to control and elimination programs. Artemisinin (ART) derivatives in combination with one or more longer acting antimalarial drug(s) of a distinct chemical class, for example lumefantrine, mefloquine or amodiaquine [2][3][4][5] (referred to as ART-based combination therapies, ACTs) are recommended for the treatment of uncomplicated P. falciparum malaria in most malaria-endemic areas and are arguably our last line of defense against this devastating disease.…”

Staurosporine-induced programmed cell death in Blastocystis occurs independently of caspases and cathepsins and is augmented by calpain inhibition

“…In parasitic organisms, PCD has been described in the kinetoplastid trypanosomes (Ameisen et al, 1995;Welburn et al, 1996) and Leishmania (Arnoult et al, 2002;Bera et al, 2003;Zangger et al, 2002), the apicomplexan parasite Plasmodium Unicellular protozoan parasites cause a wide variety of human diseases. The current treatment of these infections is being challenged by an increasing incidence of drug resistance and a lack of effective vaccines (Croft et al, 2006;Fidock et al, 2008). The investigation of PCD pathways in these organisms might lead to the discovery of novel parasite control strategies (Alvarez et al, 2008;Deponte & Becker, 2004).…”

“…The current treatment of these infections is being challenged by an increasing incidence of drug resistance and a lack of effective vaccines (Croft et al, 2006;Fidock et al, 2008). The investigation of PCD pathways in these organisms might lead to the discovery of novel parasite control strategies (Alvarez et al, 2008;Deponte & Becker, 2004).…”