New drugs in the fight against malaria

Malaria is one of the world’s deadliest infectious diseases. Around 600,000 people die from it every year. The disease is caused by single-celled parasites and transmitted by the Anopheles mosquito. The problem with treating malaria is that the pathogen keeps becoming resistant to the available drugs, meaning that new therapies and treatment strategies continually have to be found. X-ray microscopes such as PETRA III are an ideal way of searching for new, more effective substances. And DESY’s project PETRA IV could speed up the search considerably in the future. The more efficient these machines are, the faster the search for drugs can be carried out.

Plasmodium, the parasite that causes malaria, is a particularly tricky adversary. It changes shape several times as it moves rapidly through its host’s body, with different proteins active in each phase of its life. The parasite is transmitted by the Anopheles mosquito, which is widespread in tropical regions of the world. During an acute infection, the parasite multiplies rapidly in the body of the host and also has high mutation rates. This is why the parasite is able to quickly develop resistance to available drugs. According to the World Health Organisation (WHO), around 600,000 people die of malaria every year.

For this reason, researchers are constantly looking for new antimalarial drugs and vaccines. They would like their drugs to disrupt the life cycle of the parasite, which extends over a number of stages in mosquitoes and in humans. The planned X-ray microscope PETRA IV will significantly improve the possibilities for discovering new drugs.

A 3D atlas of malaria

Researchers are already using X-ray sources to study mosquitoes, the pathogen and the progression of the disease, with the aim of creating a kind of multimodal 3D atlas of malaria. They want to produce a comprehensive spatial and functional model of the parasite throughout all stages of its life cycle, and identify targets for new treatments from the microscopic details. At the start of the cycle, the mosquito ingests the reproductive cells of the parasite, known as female and male gametocytes, along with the blood of the human host. In the mosquito’s gut, these develop into microgametes and macrogametes. The microgametes then fertilise the macrogametes to produce a zygote. Next, this fertilised egg lodges in the intestinal wall and develops into an oocyst, producing infectious sporozoites through repeated division. These migrate into the saliva of the mosquito and are injected into the blood of a human host. At PETRA III, a team led by Elizabeth Duke and Jonas Albers from the European Molecular Biology Laboratory (EMBL) in Hamburg has succeeded in producing an X-ray scan of the midgut of an infected Anopheles mosquito. On examining the resulting images, they identified the areas relevant to the progression of the disease and studied these in even greater detail using electron microscopy.

The researchers were surprised to discover that, contrary to what had been assumed, the parasites in the infected mosquito do not all develop at the same time, but co-exist in different stages. This provides an important starting point for fighting the malaria pathogen while it is still inside the mosquito.

Blocking the parasite’s self-defences

Another way of containing the disease is to stop the parasite in the blood of the human host before it can multiply rapidly. The parasite penetrates red blood cells and feeds on their haemoglobin. This protein is responsible for transporting oxygen in the blood. When the parasite digests the haemoglobin, it produces haem, which contains iron and which is toxic to the parasite. However, the parasite uses a special protein to convert this into an insoluble crystalline form called haemozoin. In this form, it poses no threat to the parasite.

Drugs such as chloroquine block this conversion so that the malaria pathogen is killed by the haem. However, the pathogen is becoming increasingly resistant to such antimalarials. Medical research is therefore testing alternatives such as ferroquine, which – as the name suggests – is iron-based rather than chlorine-based. Ferroquine is difficult to distinguish from haem using synchrotron radiation, however, because it too is iron-based. Scientists have therefore replaced the iron in ferroquine with rubidium, an alkali metal that shows up well in X-ray fluorescence and provides good contrast. Modern synchrotrons are used to study the effectiveness such new drugs and the mechanisms by which they work. Even today, these processes can be resolved and monitored down to the sub-micrometre range. “But thanks to its smaller, high-intensity X-ray beam, PETRA IV will allow researchers to take an even closer look,” says Selina Storm. “The higher spatial resolution and greater sensitivity means that local drug concentrations can be precisely mapped, for example. Above all, though, the series of measurements can be performed substantially faster. The throughput increases, improving the statistics for identifying promising new drugs as quickly as possible. That brings down development costs.”

PETRA IV will speed up the search for a vaccine

Another way of fighting malaria is to administer vaccinations. Different proteins are active in each phase of the parasite’s life cycle – offering many potential targets for the body’s natural immune system. If the immune system produces defence cells early on, thanks to a suitable vaccine, an outbreak of the disease can be prevented. PETRA IV could be used to determine what a particularly effective vaccine ought to look like much more quickly than before.

The physicist Selina Storm says that medical-pharmaceutical research could benefit greatly from the expansion of the synchrotron: “When you consider its many advantages – especially the fact that the new facility will be embedded in a huge existing and rapidly growing ecosystem for research and development – then this is simply a fantastic opportunity.”

Blocking the parasite’s self-defences

Another way of containing the disease is to stop the parasite in the blood of the human host before it can multiply rapidly. The parasite penetrates red blood cells and feeds on their haemoglobin. This protein is responsible for transporting oxygen in the blood. When the parasite digests the haemoglobin, it produces haem, which contains iron and which is toxic to the parasite. However, the parasite uses a special protein to convert this into an insoluble crystalline form called haemozoin. In this form, it poses no threat to the parasite.

Drugs such as chloroquine block this conversion so that the malaria pathogen is killed by the haem. However, the pathogen is becoming increasingly resistant to such antimalarials. Medical research is therefore testing alternatives such as ferroquine, which – as the name suggests – is iron-based rather than chlorine-based. Ferroquine is difficult to distinguish from haem using synchrotron radiation, however, because it too is iron-based. Scientists have therefore replaced the iron in ferroquine with rubidium, an alkali metal that shows up well in X-ray fluorescence and provides good contrast. Modern synchrotrons are used to study the effectiveness such new drugs and the mechanisms by which they work. Even today, these processes can be resolved and monitored down to the sub-micrometre range. “But thanks to its smaller, high-intensity X-ray beam, PETRA IV will allow researchers to take an even closer look,” says Selina Storm. “The higher spatial resolution and greater sensitivity means that local drug concentrations can be precisely mapped, for example. Above all, though, the series of measurements can be performed substantially faster. The throughput increases, improving the statistics for identifying promising new drugs as quickly as possible. That brings down development costs.”

PETRA IV will speed up the search for a vaccine

Another way of fighting malaria is to administer vaccinations. Different proteins are active in each phase of the parasite’s life cycle – offering many potential targets for the body’s natural immune system. If the immune system produces defence cells early on, thanks to a suitable vaccine, an outbreak of the disease can be prevented. PETRA IV could be used to determine what a particularly effective vaccine ought to look like much more quickly than before.

The physicist Selina Storm says that medical-pharmaceutical research could benefit greatly from the expansion of the synchrotron: “When you consider its many advantages – especially the fact that the new facility will be embedded in a huge existing and rapidly growing ecosystem for research and development – then this is simply a fantastic opportunity.”