Michael Delves and colleagues compare the activity of 50 current and experimental antimalarials against liver, sexual blood, and mosquito stages of selected human and nonhuman parasite species, including Plasmodium falciparum, Plasmodium berghei, and Plasmodium yoelii.
Malaria remains a disease of devastating global impact, killing more than 800,000 people every year—the vast majority being children under the age of 5. While effective therapies are available, if malaria is to be eradicated a broader range of small molecule therapeutics that are able to target the liver and the transmissible sexual stages are required. These new medicines are needed both to meet the challenge of malaria eradication and to circumvent resistance.
Methods and Findings
Little is known about the wider stage-specific activities of current antimalarials that were primarily designed to alleviate symptoms of malaria in the blood stage. To overcome this critical gap, we developed assays to measure activity of antimalarials against all life stages of malaria parasites, using a diverse set of human and nonhuman parasite species, including male gamete production (exflagellation) in Plasmodium falciparum, ookinete development in P. berghei, oocyst development in P. berghei and P. falciparum, and the liver stage of P. yoelii. We then compared 50 current and experimental antimalarials in these assays. We show that endoperoxides such as OZ439, a stable synthetic molecule currently in clinical phase IIa trials, are strong inhibitors of gametocyte maturation/gamete formation and impact sporogony; lumefantrine impairs development in the vector; and NPC-1161B, a new 8-aminoquinoline, inhibits sporogony.
These data enable objective comparisons of the strengths and weaknesses of each chemical class at targeting each stage of the lifecycle. Noting that the activities of many compounds lie within achievable blood concentrations, these results offer an invaluable guide to decisions regarding which drugs to combine in the next-generation of antimalarial drugs. This study might reveal the potential of life-cycle–wide analyses of drugs for other pathogens with complex life cycles.
Please see later in the article for the Editors' Summary
Malaria is a life-threatening disease caused by the Plasmodium parasite, which is transmitted to people through the bites of infected mosquitoes. According to latest global estimates, about 250 million people are infected with malaria every year with roughly 800,000 deaths—most occurring among young children living in Africa. Malaria also causes severe morbidity in children, such as anemia, low birth weight, and neurological problems, which compromise the health and development of millions of children living in malaria endemic areas. In addition to strategies that scale up and roll out the prevention of malaria, such as country-wide programs to provide insecticide-treating bednets, in the goal to eradicate malaria, the global health community has refocused efforts on the treatment of malaria, including finding new compounds that target different stages of the parasite life cycle as it passes from vector to host and back.
The interruption of malaria transmission worldwide is one of the greatest challenges for the global health community. In January 2011, this journal published a series on The Malaria Eradication Research Agenda (malERA), which described a set of research and development priorities, identified key knowledge gaps and the necessary tools needed, and introduced a draft research and development agenda for the worldwide eradication of malaria.
Why Was This Study Done?
Most currently available antimalarial drugs primarily target the disease-causing parasites' stages in the human blood system. But to eradicate malaria, new drugs that block transmission of the parasite between the human host and the mosquito vector, and eliminate the various stages of the parasite during its cycle in the human body, are needed. In this laboratory study, the researchers compared the profiles of all available and experimental antimalarials and analyzed each drug for activity against each specific stage in the malaria parasite's life cycle to provide a reference set of methods and data, that might serve as a benchmark to help guide the malaria research community in assessing the potential of newly discovered antimalarials. Furthermore, this analysis could provide insights into which chemical drug classes might provide transmission-blocking capabilities—an essential component of malaria eradication.
What Did the Researchers Do and Find?
The researchers used novel laboratory techniques under standardized conditions to develop a series of novel assays to analyze the activities of 50 antimalarial compounds (current drugs and those under development) against three Plasmodium species encompassing every major cellular strategy of the malarial life cycle including drug resistant parasite strains. In their comparative analysis, the researchers undertook a chemical profiling approach to identify the drugs that block transmission from the host to the mosquito vector and additionally suppress transmission from the mosquito to the human host.
The researchers highlighted some encouraging results; for example, the potencies of some antimalarials against the asexual blood stage of cultivated P. falciparum and P. vivax isolates show a very good correlation, suggesting that most of the pathways inhibited by antimalarials in P. falciparum may also be valid targets in P. vivax. The researchers also have shown that approved drugs, such as pyronaridine and atovaquone, can target liver and sexual stages in addition to asexual blood stages. Furthermore, the researchers found promising results for new compounds currently in clinical trials, such as the endoperoxide OZ439, a stable synthetic molecule currently being studied in a phase IIa clinical trial, which seemed to be a strong inhibitor of gametocyte maturation and gamete formation. The new 8-aminoquinoline, NPC-1161B, also inhibited sporogony.
What Do These Findings Mean?
The results of this analysis provide a valuable guide to help researchers decide which drugs and compounds show most promise as potential future antimalarial drugs for blocking the transmission of malaria. This study could also help researchers make decisions about which molecules could be best combined to provide the next generation of drugs that will succeed artemisinin compound therapy and support the eradication of malaria. Furthermore, this comprehensive approach to drug discovery could be applied to test drugs against other pathogens with complex life cycles.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001169.
The malERA a research agenda for malaria eradication sponsored collection, published by PLoS in January 2011, comprises 12 Review articles that discuss agendas in malaria research and development