Research Summary

Dealing with artemisinin-resistant malaria

One of the most important public heath challenges of our time is the emergence and spread of malaria resistant to artemisinin, our best anti-malarial drug. If it further spreads to Africa it could have devastating consequences.

In order to deal with the challenge of artemisinin resistance, I am interested in evolutionary processes that lead to anti-malarial resistance, the molecular mechanism of artemisinin resistance, and target identification of novel anti-malarial compounds to facilitate discovery of drugs that could replace artemisinin.

Resistance to anti-malarial drugs has often emerged in South-East Asia but the reasons for this are not understood. We recently analysed thousands of Plasmodium falciparum genomes and discovered that South-East Asian strains of P. falciparum have a higher propensity for amino acid changing (non-synonymous) mutations compared to those from Africa (Figure 1), which might be related to their higher propensity to develop drug resistance.

Artemisinin resistance is now known to be associated with more than 20 mutations in a P. falciparum protein Kelch13. We recently mapped these mutations to understand the structural effects of these mutations on this protein (Figure 2).

We are utilizing laboratory evolution and whole genome sequencing to identify the targets of many anti-malarial compounds (Figure 3) from the open source Malaria Box (https://www.mmv.org/research-development/open-access-malaria-box). Target identification is a crucial step in the development of new anti-malarial drugs.

 

Figure 1. Higher ratio of non-synonymous to synonymous polymorphism in P. falciparum samples from South-East Asia compared to Africa.  Full article available at https://f1000research.com/articles/5-1964/v1

Figure 2. Resistant mutations in the propeller domain of Kelch13 protein of P. falciparum. Full article available at https://dx.doi.org/10.1007/s10969-016-9205-1

Figure 3. Target identification of anti-malarial compounds using laboratory evolution and whole-genome sequencing.