New drugs to squash the spread of malaria

Abstract

The human-infecting malaria parasite, Plasmodium falciparum (green), is depicted erupting from human red blood cells (red). Eight sexually mature parasites (male gametes, green) emerge from the human cell (red), with their replicating DNA shown in blue. This image is courtesy of Dr Sabrina Yahiya and Prof. Jake Baum. For permission to reuse, contact Jake Baum at jake.baum@unsw.edu.au.Malaria is a devastating disease, with 247 million cases and 619,000 deaths reported in 2021 alone. Drugs to treat malaria symptoms and insecticides to kill the mosquito vector have improved in recent decades, but the parasite – Plasmodium falciparum - and the mosquitoes are evolving to become resistant to these strategies. Therefore, there is an urgent need for new antimalarial drugs with new modes of action. An attractive target is to prevent P. falciparum transmission to the mosquito vector, a process that depends on sexual maturation of male and female parasites from their dormant gametocyte form into gametes, known as gametogenesis.With this aim, the Baum laboratory have been investigating the mode of action of a new class of antimalarial sulphonamides – known as N-[(4-hydroxychroman-4-yl)methyl]-sulphonamide (N-4HCS) compounds – which have previously been shown to potently block male gametogenesis. The authors cultured gametocytes in human erythrocytes and treated them with one of the N-4HCS compounds to identify potential targets. Using photo-affinity labelling and mass spectrometry, the authors identified the gametocyte-specific parasitophorous vacuole membrane (PVM) protein Pfs16 as having the most significant interaction with this N-4HCS compound. The team then used complementary techniques to confirm that this N-4HCS compound binds and blocks Pfs16 function, which is known to be indispensable for male gametogenesis.The authors proceeded to explore the activity window of this N-4HCS compound in male gametocytes. They activated the process of gametogenesis, and then treated the male gametocytes with the N-4HCS compound at staggered time points up to 25 minutes, which is the point of male gamete maturation. Impressively, the N-4HCS compound was able to traverse the erythrocyte membrane and act within zero to six minutes of male gametogenesis initiation to prevent completion of the process. Probing further, the team used immunofluorescence imaging to show that the N-4HCS compound blocked P. falciparum cytoskeleton rearrangements and prevented Pfs16-dependent breakdown of the PVM, both of which are essential for male gametogenesis.Overall, Baum and colleagues have identified how this new class of antimalarials block male gamete formation and, therefore, malaria transmission. Once thoroughly developed and tested, there is potential for N-4HCS compounds to be given to malaria patients alongside existing symptomatic therapies, or even delivered directly to mosquitoes by coating nets or sugar baits – both of which could diminish subsequent infection of humans. More research is under way to explore and refine the activity of this class of sulphonamides, but, nevertheless, this study expands the breadth of strategies available to be used in the fight against malaria.