Mosquito-transmitted Plasmodium parasites caused ~229 million malaria infections in 2019 and ~409 thousand deaths, mainly in children under 5. In partnership with researchers and pharmaceutical industry partners, Medicines for Malaria Venture (MMV) have recently deployed artemisinin combination therapies (ACTs) with improved efficacy against multi-drug resistant malaria and improved drug formulations for the treatment of pregnant women and children. For World Malaria Day, we invited malaria researchers Juliana Oliveira de Souza, Sonja Frölich and Danny Wilson to discuss for the #FEMSmicroBlog current efforts to develop next-generation antimalarial drugs. #MicrobiologyEvents
We are currently at an important crossroads in malaria control. We face spreading resistance to frontline ACTs for the most lethal P. falciparum malaria and declining efficacy of mosquito control measures. Also, climate change impacts vector and parasite dynamics in affected communities, while the current COVID-19 pandemic influences malaria control programs. Thus, it is timely to consider potential new drug treatment strategies to tackle this infectious disease.
Antimalarial drugs treating the blood-stage
The human infection starts with the bite of a mosquito vector and the release of the malaria parasite into the liver and later into the bloodstream. Blood stage parasites cause malaria pathology, resulting in clinical symptoms and diagnosis of infection.
Hence, it is critical for malaria control to provide effective antimalarials to treat red blood cell (RBC)-infecting parasite stages. Current goals for blood-stage antimalarial development include single-dose cures with novel chemotypes and/or modes of action. Additional activities against other parasite life stages and low propensity to select for drug resistance are further needed.
Since blood-stage parasites cause malaria pathology with clinical symptoms, we need to control this parasite stage.
Targeting malaria’s unique cell machines
Malaria’s unique biology offers many potential drug targets that are not shared with, or vary significantly to, human cells. These are for example the parasite-host cell-invasion machinery, food vacuole and metabolic pathways in the mitochondria.
The malaria parasite also has an essential organelle called the apicoplast that houses bacterial-like metabolic pathways and is sensitive to antibiotics. However, drugs targeting the apicoplast take a few days to kill blood-stage parasites. This limits their use for treating sick people.
We recently showed that the widely used antibiotic azithromycin can be modified to kill parasites quickly. Interestingly, it maintains slow killing apicoplast targeting activity, reducing the parasite’s chances to develop resistance by having two mechanisms of action.
Host-directed therapies
It is increasingly recognised that malaria parasites need host-cell systems to survive. This also opens up host targets for antimalarial development.
Recent studies showed that malaria imports nutrients through the human aquaporin-3 channel. Interestingly, blocking this channel with the compound auphen inhibits blood and liver stage development. Similarly, we and others have shown that malaria co-opts host-cell signaling proteins called kinases while pharmacological inhibition of human kinases kills blood-stage parasites.
These strategies potentially reduce the chances of the parasite developing resistance since the drugs target host cells. Furthermore, exploring existing human-disease drug development programs helps lowering development costs.
Stopping transmission to reduce the malaria burden
Community-wide protection from infections could be supported by antimalarials blocking parasite transmission stages. These are also understood as important tools for malaria eradication.
Some drugs, such as cipargamin, MMV183 and azithromycin, show activity against blood and transmission stages. This broad-stage activity is valuable. However, in the past, blood-stage activity was often prioritized during drug screens before the transmission-blocking potential. Recent improvements in the sensitivity of transmission-blocking assays will hopefully lead to the identification of new drugs with activities against transmission.
New antimalarial drugs that block transmission could help with malaria eradication efforts.
Meeting the challenge
The path to eradicating malaria disease which has been ever-present in humanity’s history is not easy. However, researchers around the world in partnership with MMV and the pharmaceutical industry are taking on this challenge. Their aim is to improve the efficacy of existing treatments and develop next-generation antimalarials.
On World Malaria Day 2021, it is important to acknowledge the challenges malaria control programs face and to recognise these and many other efforts to improve treatments for malaria.
Juliana Oliveira de Souza obtained her Master’s degree in Physics with a Biomolecular Emphasis at the University of São Paulo (Brazil), focusing on the evaluation of compounds as antimalarial drug candidates. She is currently a PhD Student at Dr. Danny Wilson’s laboratory at the University of Adelaide (Australia). Her research is focused on the modulation of human erythrocyte kinases infected with Plasmodium spp.
Dr Sonja Frölich completed her PhD on Eimeria maxima gametocytogenesis and oocyst wall formation at the University of Technology Sydney (UTS) in 2014, and since then devoted her career to studying how parasites and their hosts interact, with a particular interest in adaptations driving parasite invasion of the host, intracellular growth, secretion of virulence factors, replication and transmission. Applying a variety of techniques in biochemistry and proteomics, molecular biology, cell culture, super-resolution and quantitative microscopy, immunology and vaccinology, Dr Frölich aims to discover innovative ways to control parasitic diseases.
Dr Danny Wilson completed his PhD at the Walter & Eliza Hall Institute (Melbourne) with a focus on vaccine and drug development targeting human malaria parasites. Danny established his group in the Research Centre for Infectious Diseases at the University of Adelaide in 2014 where he is developing new drug and vaccine approaches to defeat malaria and super-resolution microscopy techniques to understand its complex biology.
About this blog section
The section #MicrobiologyEvents for the #FEMSmicroBlog reports about events and meetings relevant to our network. These include world awareness days, FEMS-sponsored meetings or meetings of Member Societies and many more.
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