Malaria is a devastating disease, with 247 million cases and 619,000 deaths reported in 2021 alone. Malaria causes fever and a flu-like illness that occurs when people are infected with the parasite Plasmodium falciparum, which is spread by mosquitoes. Drugs to treat malaria symptoms and insecticides to kill malaria-spreading mosquitoes have improved in recent decades, but the parasite and the mosquitoes are evolving to become resistant to these strategies. Therefore, there is an urgent need for new antimalarial drugs, and a key goal is to prevent parasite spread by blocking their passage from human to mosquito, something that depends on the sexual phase of the parasite life cycle. The Baum laboratory along with colleagues at Imperial College London, UK, previously identified a new class of potent antimalarial compounds, belonging to a family of sulphonamides. These compounds kill the parasite only when it is in a specific sexual phase of its life cycle, rapidly stopping it from being able to infect a mosquito and, therefore, preventing any subsequent human infection. In their new Disease Models & Mechanisms article, Baum and colleagues explored exactly how these compounds work, which is an essential step before the compounds can be developed for testing in patients. The lead author of the work, Dr Sabrina Yahiya, commented that "targeting parasite transmission from human to mosquito and back again is pivotal if we hope to reach the goal of worldwide malaria elimination. If you only treat one symptomatic patient, you address their symptoms but neglect the issue of malaria spread. By limiting transmission, however, you can radically curtail the spread of malaria across a population".
The team began by growing human red blood cells infected with the malaria parasite in the lab, then manipulated the parasites to enter their sexual life stage. The scientists then treated these parasites with one of the sulphonamide compounds to find out which parasite proteins were being targeted by the transmission-blocking compounds. To do so, the scientists applied 'click chemistry', an approach that won the 2022 Nobel Prize in Chemistry to attach a chemical label to the sulphonamide compounds. This label would then tag any parasite proteins that came in contact with them. This technique identified a parasitic protein called Pfs16 as forming the strongest bond with drug. Interestingly, Pfs16 is important for sexual conversion of the malaria parasite. The team then performed additional experiments to confirm that the sulphonamides bind Pfs16 and, importantly, block its function.
The scientists then wanted to pin down the exact point in the parasites' sexual phase that was
being targeted by the sulphonamides. After malaria parasites commit to either male or female
forms in human blood, they can be transmitted to mosquitoes and once in the mosquito gut
develop to 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 newly reproduced
parasites undergo further maturation and are then transferred by the mosquito to infect more
humans. The process of sexual maturation, which normally occurs in the mosquito gut, can
be activated artificially in the lab and takes roughly 10-25 minutes in total. The authors found
that the sulphonamide compounds specifically targeted male parasites and uniquely inhibited
their sexual maturation if administered to the parasite within the first 6 minutes of the sexual
maturation process, which is the same time that the parasitic protein target, Pfs16, plays an
important role in blocking male parasite maturation. By identifying the compound's target and
window of activity, this work provides a more precise understanding of the parasites' life cycle
stage during which this class of sulphonamides are effective. It also highlights the unique
ability of these compounds to rapidly block sexual maturation, and by extension, malaria
parasite transmission, by targeting the important parasite protein, Pfs16.
Overall, Baum and colleagues have identified how this new class of antimalarials block the
parasite reaching sexual maturity, and therefore, their spread from human to human via a
mosquito bite. This is an important step in developing effective new drugs to reduce the
massive number of new malaria cases worldwide. Once thoroughly developed and tested,
these compounds could be given to patients with malaria alongside existing therapies for
treating their symptoms, to prevent the parasite being spread to more individuals. Professor
Baum also stated that, 'the unique ability of this class of sulphonamides to potently block
sexual maturation of the parasite with almost immediate impact makes the direct delivery of
the compounds to the mosquito a very appealing alternative administration strategy'. This
exciting alternative strategy could be achieved by coating mosquito nets or sugar baits with
the compounds. More research is underway to explore and refine the activity of this class of
sulphonamides for use either in humans or directly with mosquitoes, but nevertheless, this
study expands the breadth of strategies available to use in the fight against malaria.
