A New Weak Spot Found in the Malaria Parasite

A study by ISGlobal, a centre supported by “la Caixa” Foundation, has identified a crucial weakness in Plasmodium falciparum, the parasite that causes most malaria deaths. The findings, published in PLOS Pathogens, pave the way for developing new antimalarial treatments that target the parasite without being toxic to human cells.

Malaria remains one of the leading causes of illness and death worldwide, especially in sub-Saharan Africa. With resistance to current antimalarial treatments on the rise, finding new and more effective ways to fight the parasite is urgent.

“The challenge is that malaria-causing Plasmodium parasites are eukaryotic organisms, just like us (i.e. they share many core metabolic pathways with our own cells), which means it’s hard to find drugs that are lethal to them but safe for humans,” explains ISGlobal researcher Luis Izquierdo, senior author of the study.

In this study, Izquierdo and his team focused on a metabolic pathway the parasite relies on, known as the hexosamine biosynthetic pathway. This metabolic route plays a key role in the synthesis of essential molecules known as glycosylphosphatidylinositols (GPIs), which anchor critical proteins to the parasite surface and help maintain its structure.

A parasite-specific metabolic step

The team zoomed in on an enzyme called PfGNA1, which is essential for this pathway and structurally very different from its equivalent in humans. Disrupting the PfGNA1 gene in the parasite led to a dramatic loss of these anchor proteins and to the improper localisation of the merozoite surface protein 1 (MSP1), which plays a vital role in the parasite’s invasion of red blood cells. Parasite development was arrested at the final stage of their cycle (the schizont stage) preventing their escape from red blood cells and effectively blocking further invasion.

“Our results confirm the central role of this metabolic pathway for parasite survival, and highlight this enzymatic step as a critical point of vulnerability” says first author Maria Pia Alberione. “The great advantage,” adds Izquierdo, “is that this enzyme looks very different in humans – it has evolved independently in parasites like P. falciparum, giving us a chance to design drugs that hit the parasite without affecting human cells.”

Previous research by Izquierdo’s group found that the same metabolic pathway and enzyme are also critical in another disease-causing parasite, Toxoplasma gondii. This reinforces the idea that these pathogens share a common metabolic “Achilles’ heel” – a weakness that can be exploited for developing new and safer drugs.

Reference

Alberione MP, Avalos-Padilla Y, Rangel GW et al. Hexosamine Biosynthesis Disruption Impairs GPI Production and Arrests Plasmodium falciparum Growth at Schizont Stages. Plos Pathogens. Doi: 10.1371/journal.ppat.1012832