?In 2023, malaria caused 597 000 deaths worldwide, according to the World Health Organization, with most occurring in Africa, where the deadliest malaria parasite, Plasmodium falciparum, is most prevalent. Once inside the body of an infected person, the parasite relies on a process called glycolysis—breaking down glucose (a sugar)—to produce energy and stay alive.
A new study at Stellenbosch 中国体育彩票 (SU) found that blocking the enzymes involved in this process could cut off the parasite's primary energy source and kill it. Some of these enzymes could also be good targets for new malaria drugs.
“Plasmodium falciparum relies heavily on free energy produced during glycolysis for its survival, growth and replication. It consumes vast amounts of glucose from the host's red blood cells to survive. If we can block the breaking down of sugar, it will be harder for the parasite to mutate or evade suppression without suffering severe consequences," says Dr Tagwin Frantz who recently obtained her PhD in biochemistry at SU.
As part of her study, Frantz tested three chemicals to determine how they affect the parasite's glucose metabolism, growth and use of available energy utilising experimental and modelling approaches to identify potential drug targets. Each chemical blocked a different enzyme (hexokinase, phosphofructokinase and glyceraldehyde-3-phosphate dehydrogenase) involved in breaking down sugar, securing a continuous energy supply, maintaining the parasite's redox balance (how it manages chemical reactions to produce energy and protect itself from harmful molecules) and helping it to survive.
Frantz says that two of these chemicals are known to inhibit the parasite's ability to extract nutrients from its host, converts them into energy, and adapts its biochemical processes for survival and reproduction. The chemicals—one being Spinosad, an insecticide derived from the bacteria Saccharopolyspora spinosa and used against pests like mosquitoes—have shown the ability to fight the parasite though the exact mechanism of action is unknown. These chemicals were tested on the isolated parasite, red blood cells (both infected and uninfected), and a type of bacteria used in biotechnology and medicine.
“Our results show that by inhibiting these enzymes, glucose cannot enter glycolysis, cutting off the parasite's primary energy source. Additionally, glycolysis could also be halted entirely, leading to a rapid energy crisis in the parasite, starving the parasite of energy, likely disrupting its redox balance and leading to its death.
“It is crucial to prevent glycolysis during the blood stage, i.e. the phase where the parasite, after entering the bloodstream from the liver, replicates within red blood cells, causing the clinical symptoms of malaria. Preventing glycolysis to kill the parasite is especially effective in infected individuals, where a fever that causes the body to work harder and use up more energy also makes the parasite more vulnerable. However, it can be challenging since both human cells and parasites undergo glycolysis.
“Beyond the blood stage, inhibiting glycolysis could also indirectly reduce the transmission of the parasite to the mosquito."
Targeting how the organism extracts nutrients from its host and converts them into energy metabolism (rather than traditional drug targets) offers a new way to kill resistant parasites, according to Frantz.
She points out that Spinosad directly inhibits the parasite's metabolism without damaging red blood cells.
“Since two of the three enzymes (hexokinase and phosphofructokinase) are essential and structurally distinct from human enzymes, selective inhibitors can be designed to minimise side effects. Combining either one of these enzyme inhibitors with current standard treatment for Plasmodium falciparum malaria (artemisinin-based therapies) could further reduce risks, making them valuable targets for new malaria drugs."
Frantz mentions that testing the effectiveness of chemicals against the parasite – and finding a dose that kills the parasite without harming red blood cells or other host tissues – was challenging. Another hurdle was ensuring that the parasite wouldn't quickly develop resistance to these compounds. To tackle these issues, she tested the long-term effects of the inhibitors over multiple parasite life cycles.
Frantz says that although her research is still in its early stages, it could be a building block for developing new malaria drugs.
“This study advances malaria research by pinpointing critical points where drugs can effectively target the parasite and predicting the most vulnerable parts of its energy-producing processes. These insights could help to develop next-generation malaria medicine that combat resistance, target multiple parasite lifecycles, and are safer for humans – supporting global efforts to eradicate the disease.
“With rising drug resistance, finding new drug targets is crucial to prevent treatment failure and protect millions at risk. Continuous innovation is key to eliminating malaria and staying ahead of the parasite's adaptation. Additionally, contributing to the broader understanding of how metabolic interventions (adjusting how the body uses energy and nutrients) can be leveraged to combat parasitic diseases.
“Future success will depend on the design of precision drugs, the use of combination therapies, and targeted delivery to kill the parasite while sparing human cells," adds Frantz. ?
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