UP researcher's team discovers new compounds with the potential to eliminate malaria

The University of Pretoria (UP) has discovered 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 on 11 January. “The breakthrough involves the identification of 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,” she explained. 

The deadly human malaria parasite Plasmodium falciparum occurs in South Africa. These parasites are transmitted to humans by female Anopheles mosquitoes. The only means of killing the parasite itself is to use chemical drugs, but new antimalarial drugs are urgently needed to address the growing concern of antimalarial drug resistance.

Prof Birkholtz describes 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. Prof Birkholtz states: “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 leading regional malaria elimination efforts as part of four frontline countries in southern Africa including Namibia, Botswana and Eswatini.

In an innovative strategy, the team looked for new chemical compounds that can do exactly this, but that are completely new so that the parasite does not have resistance against them. 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 lab and be used to test chemical compounds. The team discovered compounds that kill the disease-causing form and compounds that blocked the parasite from infecting mosquitoes in the lab.

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 antimalarials for both the treatment and elimination of the disease,” said Prof Birkholtz.

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/repositioning, a process where drugs that have activity against a specific disease (e.g. cancer) can be reused for another disease (e.g. malaria). Dr James Duffy, MMV Project Director, describes 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.”

Prof Birkholtz 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 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.”

Prof 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, Professor Kelly Chibale (Chair in Drug Discovery at the Drug Discovery and Development Centre, H3D, at the University of Cape Town) and Professor 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. 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.

Click on the video in the sidebar to learn more about malaria and this discovery.

Researchers

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  Professor Lyn-Marie Birkholtz

  Professor Lyn-Marie Birkholtz is a full professor in Biochemistry at the University of Pretoria (UP) and has been the South African Research Chair (SARChI) in Sustainable Malaria Control since 2013. She leads efforts to target malaria parasites to contribute to malaria elimination strategies. Her work recently led to the discovery of new chemical entities that have the potential to block malaria parasite transmission and aid malaria elimination strategies (Nature Communications, January 2021).
  
  Prof Birkholtz did her BSc in Genetics, Human Physiology and Biochemistry, and her PhD in Biochemistry at UP (jointly performed in South Africa and Germany). This was followed by postdoctoral fellowships in Germany and the US. She leads the Parasite Cluster within the UP Institute for Sustainable Malaria Control.
  
  “With key platforms like the UP Institute for Sustainable Malaria Control, the Genomics Institute and continuous new developments – for example, under a One Health sphere with transdisciplinary research – UP is perfectly positioned for our research focus,” she says.
  
  Prof Birkholtz is principal investigator of the Malaria Parasite Molecular Laboratory, and has a keen interest in the fundamental processes that drive parasitism and how this sustains global health challenges. She hopes to translate her research outcomes into meaningful, tangible health innovations, particularly to discover new antimalarial drugs.
  
  Her research group works at the interface of parasite biology and drug discovery, and uses new biological insights as a catalyst for drug discovery. They do this by obtaining an in-depth understanding of the essential processes that drive the survival and pathogenesis of malaria parasites; this is a substantial research challenge that they approach from a systems level.
  Prof Birkholtz’s work focuses on the pathogenic processes that drive the proliferation and differentiation of malaria parasites to deliver drugs that are able to target both these forms of the parasite. In line with international endeavours to achieve malaria elimination, her research uses high-content biological information of malaria parasites to support sustained discovery of malaria control chemotherapies in order to contribute to the global Malaria Eradication Research Agenda.
  
  The Parasite Cluster of the UP Institute for Sustainable Malaria Control is a transdisciplinary research entity that spans all 11 UP faculties. Prof Birkholtz works closely with various experts in several faculties, specifically driving projects between the Natural and Agricultural Sciences and Health Sciences faculties.
  
  Internationally, she leads the transdisciplinary Community of Practice (CoP), which brings researchers across South Africa, Africa and the world together to evaluate malaria elimination innovations. “As a group, we work directly with external stakeholders, such as provincial and government-level malaria control programmes and international bodies, including the World Health Organisation and Medicines for Malaria Venture,” the professor explains. “This allows for meaningful translation of our work. The CoP synergised the work by six SARChI Chairs from UP, Stellenbosch University, the University of Cape Town [UCT] and Wits University, allowing for an extraordinary opportunity for cooperation in South Africa.”
  
  A recent milestone for Prof Birkholtz was the delivery of chemical entities that are able to kill malaria parasites, but specifically, able to kill multiple forms of malaria parasites including the elusive transmissible forms. This discovery was part of a long-standing collaboration between UP, Wits, UCT and the Council for Scientific and Industrial Research. “We are building on this discovery by further profiling and developing these transmission-blocking entities through a Grand Challenges Africa grant, awarded by the Bill & Melinda Gates Foundation and managed by the Alliance for Accelerating Excellence in Science in Africa and the African Academy of Sciences,” she says.
  
  Prof Birkholtz is a National Research Foundation B2-rated scientist and was recognised by UP as an Exceptional Young Researcher in 2010 and 2013, and as an Exceptional Academic Achiever between 2019 and 2021. She received the Vice-Chancellor’s Exceptional Supervisor Award and the National Science and Technology Forum’s Science Communication Award in 2018. She is also an elected member of the Academy of Science of South Africa.
  
  Prof Birkholtz is passionate about training the next generation of young scientists in the cutting-edge technologies used in her programme. To date, 19 PhD and 30 master’s students have worked under her (co)-supervision, with several graduates having been awarded international fellowships.
  

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  UP researcher's team discovers new compounds with the potential to eliminate malaria