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 the mosquitoes that spread malaria 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 the parasites from spreading by blocking their passage from humans to mosquitoes, which depends on the sexual phase of the parasite’s life cycle. The Baum lab together with colleagues at Imperial College London, UK, previously identified a new class of potent antimalarial compounds, belonging to a family of sulfonamides. These compounds only kill the parasite when it is in a specific sexual phase of its life cycle, rapidly preventing it from infecting a mosquito and, therefore, preventing any subsequent human infection. In their new Disease models and mechanisms article, Baum and colleagues explored exactly how these compounds work, which is an essential step before compounds can be developed for patient trials. Lead author of the paper, Dr. Sabrina Yahiya, commented that “targeting transmission of the parasite from humans to mosquitoes and vice versa is essential if we hope to achieve the goal of global malaria elimination. If you treat only a symptomatic patient, you address their symptoms but neglect the problem of the spread of malaria. By limiting transmission, however, it is possible to radically reduce the spread of malaria in a population“.
The team began by growing human red blood cells infected with the malaria parasite in the laboratory, then manipulated the parasites into their sexual life stage. The scientists then treated these parasites with one of the sulfonamide compounds to find out which parasite proteins had been targeted by the transmission-blocking compounds. To do so, the scientists applied ‘click chemistry’, an approach that won the 2022 Nobel Prize in Chemistry for attaching a chemical label to sulfonamide compounds. This tag would then tag any parasite proteins that came in contact with them. This technique identified a parasitic protein called Pfs16 as forming the strongest drug binding. Interestingly, Pfs16 is important for the sexual conversion of the malaria parasite. The team then performed further experiments to confirm that the sulfonamides bind Pfs16 and, importantly, block its function.
The scientists therefore wanted to pinpoint the exact point in the sexual phase of the parasites that was being targeted by sulfonamides. After the malaria parasites have committed to male or female forms in human blood, they can be passed on to mosquitoes and once in the mosquito’s gut they develop into a more mature sexual stage. These mature male and female parasites, similar to the human egg and sperm, 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 takes place in the intestines of mosquitoes, can be artificially triggered in the laboratory and takes around 10-25 minutes in total. The authors found that sulfonamide compounds specifically targeted male parasites and uniquely inhibited their sexual maturation when administered to the parasite within the first 6 minutes of the sexual maturation process, which is the same time the parasite protein target, Pfs16 , plays an important role in blocking the maturation of the male parasite. By identifying the compound’s target and window of activity, this work provides a more precise understanding of the phase of the parasite life cycle during which this class of sulfonamides is effective. It also highlights the unique ability of these compounds to rapidly block sexual maturation and, by extension, transmission of the malaria parasite by targeting the parasite’s important protein, Pfs16.
Collectively, Baum and colleagues identified how this new class of antimalarials prevents the parasite from reaching sexual maturity and, thus, its human-to-human spread through a mosquito bite. This is an important step in the development of new effective medicines to reduce the huge number of new malaria cases worldwide. Once developed and thoroughly tested, these compounds could be given to malaria patients alongside existing therapies to treat their symptoms, to prevent the parasite from spreading to more individuals. Professor Baum also said that ‘the unique ability of this class of sulfonamides to potently block sexual maturation of the parasite with near immediate impact makes direct administration of the compounds to the mosquito a very attractive alternative delivery 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 sulfonamides for use in humans or directly with mosquitoes, yet this study expands the breadth of strategies available for use in the fight against malaria .
The Society of Biologists
Yahiya, S. et al. (2023) A new class of sulfonamides potently blocks malaria transmission by targeting a Plasmodium vacuole membrane protein. Disease models and mechanisms. doi.org/10.1242/dmm.049950.