resistance

Malaria is an endemic disease, prevalent in tropical and subtropical regions which cost half of million deaths annually. The eradication of malaria is one of the global health priority nevertheless, current therapeutic efforts seem to be insufficient due to the emergence of drug resistance towards most of the available drugs, even first-line treatment ACT, unavailability of the vaccine, and lack of drugs with a new mechanism of action. Intensification of antimalarial research in recent years has resulted into the development of single dose multistage therapeutic agents which has advantage of overcoming the antimalarial drug resistance.

The ubiquitin proteasome system (UPS) is an emerging drug target in malaria due to its essential role in the parasite's life cycle stages as well its contribution to resistance to artemisinins. Polymorphisms in the Kelch13 gene of Plasmodium falciparum are primary markers of artemisinin resistance and among other things are phenotypically characterized by an overactive UPS. Inhibitors targeting the proteasome, critical components of the UPS, display activity in malaria parasites and synergize artemisinin action. Here we report the activity of small molecule inhibitors targeting mammalian deubiquitinating enzymes, DUBs (upstream UPS components), in malaria parasites.

Pyrimethamine was first introduced for the treatment of malaria in Asia and Africa during the early 1980s, replacing chloroquine, and has become the first line of drugs in many countries. In recent years, development of pyrimethamine resistance in Plasmodium vivax has become a barrier to effective malaria control strategies. Here, we describe the use of meta-barcoded deep amplicon sequencing technology to assess the evolutionary origin of pyrimethamine resistance by analysing the flanking region of dihydrofolate reductase (dhfr) locus.