Malaria, iron and antimalarial drugs - new research brings us one step closer

Dr Timothy J Egan, Department of Chemistry,  University of Cape Town

Malaria is one of the most significant infectious diseases in the world. It is endemic through the entire tropical region of the Earth, except for high mountain areas, deserts and a few islands. Nonetheless, the problem is by far the most significant in Africa, where it accounts for about 90% of infections and deaths. Exact figures for the number of infections and deaths are not available, but it is generally considered that about one third of the Earth's population is at risk, and that there are 100 - 200 million infections and 1 - 3 million deaths annually. Most of the deaths occur in children under the age of five years. Malaria is the fifth largest killer out of all the infectious diseases world-wide, and is a leading killer in Africa. It places a huge burden on the continent's economy and social fabric.

There are several reasons why malaria is such a serious problem in Africa. Firstly, a species of mosquito called Anopheles gambiae, which exists only in Africa, specialises in feeding exclusively on humans. This mosquito lives inside people's houses and is thus very efficient at transmitting malaria from infected individuals to uninfected people. The presence of this mosquito in Africa is probably a result of mankind's origin on this continent. A second factor is the very high incidence of malaria in Africa, which makes it more difficult to control than in areas where the incidence is lower. This already difficult situation has been made worse by three additional factors. Poverty and civil wars have weakened malaria control measures, changes in agricultural practices (such as introduction of irrigation) have brought people into closer contact with mosquitoes and finally population movements have caused an influx of infected individuals into areas where malaria may previously have been less prevalent. There are concerns that climate change may also worsen the problem. Superimposed on all of these is the occurrence of drug resistant malaria, especially chloroquine resistant malaria. This makes it far more difficult to reduce malaria infection in the population, further increasing its incidence.

The disease is caused by four species of single-celled parasites of the genus Plasmodium. Most infections are caused by Plasmodium falciparum and Plasmodium vivax. Deaths are caused almost exclusively by the former, while the latter causes a form of malaria that is recurrent in the infected patient (causing bouts of disease long after the original infection). These parasites have a complicated life cycle, being transmitted from one individual to the next by mosquitoes. The life cycle thus consists of a mosquito stage, where it develops inside the mosquito. It also has two main stages in the human, first in the liver and then in the blood. The liver stage, which has no symptoms, lasts for about a week to ten days after the bite of the infected mosquito. Thereafter the parasites emerge into the blood, with the onset of symptoms. Malaria treatment is therefore directed at the blood stage.

Blood stage malaria parasites live inside human red blood cells. This helps them to conceal themselves from the immune system and is one of the reasons why the development of a vaccine has been so elusive. Nonetheless, a red blood cell is a harsh environment. Almost the only source of nourishment available inside the red cell is haemoglobin, a protein responsible for transporting oxygen in humans and other vertebrates. This protein has attached to it an iron containing substance called haem. It is actually this iron that bonds to oxygen. The parasite uses the protein part of haemoglobin as food, but haem is a waste product from its point of view and it is faced with the problem of ridding itself of this haem. 

For almost a century it has been known that at least a part of the haem is incorporated into an insoluble crystalline substance called malaria pigment. This pigment acts as a sink for removal of haem because it is very insoluble. However, until now it was not known whether all of the haem was removed in this way, or whether other, possibly dominant pathways exist for its removal.

This question is of considerable importance. There is accumulating evidence produced over the last decade that certain antimalarial drugs such as chloroquine act by blocking the removal of haem from the parasite, thus causing it to be poisoned by its own waste. Chloroquine resistance appears to result from the ability of the parasite to exclude the drug from the site where haem processing occurs and not from any fundamental change in the way in which the haem is processed. This means that if we understand how this haem is dealt with in the parasite, we should be able to design successor drugs to chloroquine which retain activity against the parasite based on the same, very successful mechanism of action.

The actual process was recently investigated as a large multidisciplinary team. The team was made up of pharmacologists Jill Combrinck, Joanne Egan, Pete Smith, Dale Taylor, Donelly van Schalkwyk and Jason Walden, an electron microscopist, Trevor Sewell (all at the University of Cape Town), physicists Giovanni Hearne and Skhumbuzo Ntenteni (University of the Witwatersrand) and chemists Helder Marques (University of the Witwatersrand) and Tim Egan. 

The team showed unequivocally that virtually all of the haem is indeed incorporated into malaria pigment in Plasmodium falciparum. The results have been published as an accelerated communication in the Biochemical Journal (UK). This process should thus be of primary interest in the design of new drugs that have a similar mode of action to chloroquine. As the structure of malaria pigment was finally reported in 2000 by Scott Bohle and co-workers in America the basic information for design of new drugs is now available. Of course, it is still a long road from this basic knowledge to new drugs, a road made even more difficult by the need to ensure eventual affordability of any new antimalarial drug.

 

August 2002