Plasmodium falciparum, a human-infecting malaria parasite, is shown emerging from human red blood cells (red) and their replicating DNA is shown in this photo. Credit: Dr. Sabrina Yahiya and Professor Jake Baum
Malaria is a serious illness, with 247 million cases reported and 6199,000 fatalities in 2021. This disease, caused by the mosquito Plasmodium falciparum, is transmitted by mosquitoes, and has developed over time, becoming resistant to treatment.
Therefore, the development of novel antimalarial medications is a pressing concern. One crucial goal is to stop the spread of the parasite from humans to mosquitoes, which is dependent on the sexual phase of its life cycle.
Baum and colleagues describe how these compounds work, and why do they need to be tested in patients.
Dr. Sabrina Yahiya, the principal author of the study, said that "targeting parasite transmission from human to mosquito and back again is vital if we wish to eradicate global malaria." If you only treat one symptomatic patient, you minimize the likelihood of malaria spreading. However, by limiting transmission, you can significantly reduce malaria spread across a population."
The scientists first grew human red blood cells infected with the malaria parasite in the lab and then manipulated the parasites to enter their sexual life stage. They then used 'click chemistry,' a 2022 Nobel Prize in Chemistry technique to mark the sulphonamide compounds.
Any parasite proteins that came in contact with this would be labeled with this label. Pfs16 is interesting because it is required for the malaria parasite's sexual conversion. The researchers then performed additional experiments to verify that the sulphonamides work.
The scientists wanted to know at what point in the parasites' sexual phase were aiming for the sulphonamides. Once malaria parasites commit to male or female forms in human blood, they can be transmitted to mosquitoes and once in the mosquito gut develop into a more mature sexual phase. These mature male and female parasites – similar to the human egg and sperm – then fuse to enable sexual reproduction.
The process of sexual maturation, which normally takes place in the mosquito gut, can be activated artificially in the lab in just 10-25 minutes, and it takes approximately 10-25 minutes to complete. If administered to a parasite within the first 6 minutes of the sexual maturation process, the parasitic protein target, Pfs16, plays an important role in preventing male parasite maturation.
This research provides a more detailed understanding of the life cycle stage during which this class of sulphonamides is efficient. It also highlights the unique ability of these compounds to accelerate malaria parasite transmission by targeting the important parasite protein, Pfs16.
Baum and colleagues have identified how this new class of antimalarials prevents the parasite from maturing, and hence, its transfer from human to human via a mosquito bite. This is an essential step in the development of powerful new medicines to reduce the large amount of new malaria cases worldwide. Once fully developed and tested, these compounds may be given to patients with malaria in conjunction with existing medications to prevent the parasite from becoming larger.
Professor Baum added that the unique capability of this class of sulphonamides to completely inhibit sexual maturation of the parasite with very little impact makes direct administration of the compounds to the mosquito a very attractive alternative administration strategy. Nonetheless, this study broadens the scope of options available in the fight against malaria.
Sabrina Yahiya, Charlie N. Saunders, Ursula Straschil, Ainoa Rueda-Zubiaurre, Mifuliat Toyin Famodimu, Sarah Jordan, Michael J. Delves, Anna Barnard, Matthew J. Fuchter, and Jake Baum, 30 January 2023, Disease Models & Mechanisms. DOI: 10.1242/dmm.049950 Sabrina Yahiya, Charlie N. Saunders, Ursula Straschil, Ainoa Rueda-Zubiaurre, Mufuliat Toyin Famodimu, Sarah Jordan, Michael J. Delves, Anna Barnard, Matthew J. Fuchter, and Jake Baum, 30 January 2023, Disease Models & Mechanisms. DOI: 10.1242/dmm.049950
The Engineering and Physical Sciences Research Council, the Bill and Melinda Gates Foundation, the Wellcome Trust, Medicines for Malaria Venture, and the Royal Society all provided funding for the research.
