Malaria is one of the leading causes of diseases and deaths across the globe particularly in the Sub-Saharan Africa. According to the World Malaria report released in November last year, “there were 229 million cases of malaria in 2019 compared to 228 million cases in 2018. The estimated number of malaria deaths stood at 409 000 in 2019, compared with 411 000 deaths in 2018”,
But this problem could be eliminated if the University of Pretoria (UP) succeeds in its latest research discovery of “new potent chemical compounds that show potential as candidates for both the treatment and elimination of malaria”.
Professor Lyn-Marie Birkholtz, Professor in Biochemistry and South African Research Chair in Sustainable Malaria Control (part of the South African Research Chair Initiative, SARChI), was part of an international team that published this discovery in the journal Nature Communications in early January. She directs the parasite cluster of the UP Institute for Sustainable Malaria Control (ISMC), a multidisciplinary institute with a focus on integrated innovations towards malaria elimination in South Africa.
Professor Birkholtz said the ground-breaking discovery involves identifying unique compounds that are able to kill several stages of the malaria-causing parasite and can block the transmission of the parasite between humans and mosquitoes.
The deadly human malaria parasite Plasmodium falciparum also occurs in South Africa. The parasites are transmitted to humans by female Anopheles mosquitoes and the only way of killing the parasite itself is to use chemical drugs. But experts say new antimalarial drugs are urgently needed to address the growing concern of antimalarial drug resistance.
Professor Birkholtz explained the parasite as a “shape shifter” since it can take on multiple forms while in humans. Some of the forms cause disease and others allow the parasite to be transmitted back to mosquitoes to continue the life cycle. Said Professor Birkholtz: “to eliminate malaria, it is essential that we have the necessary tools to kill all these different forms of the parasite. We can then cure patients of the disease but, importantly, also block the malaria transmission cycle. This is the only way to achieve malaria elimination.”
South Africa is a leader in the mobilisation and co-ordination of regional efforts to eliminate malaria. Other frontline countries involved in the initiative in the southern Africa include Namibia, Botswana and Eswatini.
The team’s strategy involves looking for new chemical compounds that are completely new so that the parasite does not have resistance against them. Professor Birkholtz added that the team runs a unique research platform on the African continent, in which all of these stages of the malaria parasite can be produced in the laboratory and be used to test chemical compounds. The team, she said, discovered compounds that kill the disease-causing form and compounds that blocked the parasite from infecting mosquitoes in the laboratory.
How it works, according to Professor Birkholtz, is that two potent compounds target processes essential to the parasite’s survival: one is a clinical candidate against tuberculosis and blocks cell membrane synthesis. And another is an anti-cancer candidate that targets epigenetic mechanisms (mechanisms that control cell fate beyond the genome).
“This is the first time that these compounds were shown to have activity against malaria parasites and since they are not toxic to humans, they show the potential to be developed as anti-malarials for both the treatment and elimination of the disease,” said Professor Birkholtz.
She said the discovery was made possible by the team’s use of an open-source chemical compound set called the Pandemic Response Box, developed by the Switzerland-based Medicines for Malaria Venture (MMV) and the Drugs for Neglected Diseases Initiative (DNDi). This compound box contains compounds that can be used for drug repurposing or repositioning, a process where drugs that have activity against a specific disease (e.g. cancer) can be reused for another disease (e.g. malaria).
Some of the local team members extolled the significance of the project. Dr James Duffy, MMV project director, explained the discovery “as an important breakthrough that emphasises the potential to use existing drugs as inspiration for drug discovery projects targeting different diseases. Never before has this been more important than in light of current outbreaks, where the rapid response to discover new chemicals able to kill infectious organisms is essential.”
Professor Tiaan de Jager, director of the ISMC and dean of Health Sciences at UP said: “a discovery of this kind attests to the leading expertise in antimalarial drug discovery at UP, and in South Africa, addressing African-centred societal challenges. This work also shows the commitment of scientists at UP to contribute to the United Nation’s Sustainable Development Goal for Good Health and Wellbeing.”
Professor Birkholtz’s team led the transmission-blocking drug discovery effort as partner in the South African Malaria Drug Discovery Consortium (SAMDD) that includes two other South African Research Chairs. They are professors Kelly Chibale (Chair in Drug Discovery at the Drug Discovery and Development Centre, H3D, at the University of Cape Town) and Lizette Koekemoer (Chair in Medical Entomology at the WITS Institute for Research on Malaria at the University of the Witwatersrand) as well as scientists from the Council for Scientific and Industrial Research and international partners from the USA and Spain.
Professor Birkholtz, said the work has benefitted from sustained funding from the MMV and the Medical Research Council’s Strategic Health Innovation Programme (SHIP) and affirms that investments in health innovations places South Africa at the forefront of discovery.