Novel antimalarial tetrazoles and amides active against the hemoglobin degradation pathway in Plasmodium falciparum

Malaria control programs continue to be threatened by drug resistance. To identify new antimalarials, we conducted a phenotypic screen and identified a novel tetrazole-based series that shows fast-kill kinetics and a relatively low propensity to develop high-level resistance. Preliminary structure-activity relationships were established including identification of a subseries of related amides with antiplasmodial activity. Assaying parasites with resistance to antimalarials led us to test whether the series had a similar mechanism of action to chloroquine (CQ). Treatment of synchronized Plasmodium falciparum parasites with active analogues revealed a pattern of intracellular inhibition of hemozoin (Hz) formation reminiscent of CQ's action. Drug selections yielded only modest resistance that was associated with amplification of the multidrug resistance gene 1 (pfmdr1). Thus, we have identified a novel chemical series that targets the historically druggable heme polymerization pathway and that can form the basis of future optimization efforts to develop a new malaria treatment

An Update on Artemisinin Resistance

International audienceWhile the precise mode of action of artemisinin (ART) derivatives remains obscure, it is nonetheless commonly accepted that ART generates reactive oxygen intermediates that contribute to cell death. Also, numerous studies confirm that point mutations in the propeller domain of K13 protein play a key role in resistance to ART derivatives. Because of its homology with the KEAP1 protein, it is thought that this protein may have a role in the polyubiquitination of proteins and that its alteration may cause resistance of young parasite stages to the drug. In this chapter, we present our current knowledge of K13-related resistance to ART and its spread in Southeast Asia and discuss its possible emergence and/or diffusion in Africa

Weapons, fighters and combat: spears and swords in Early Bronze Age Scandinavia

This article deals with the use-wear analysis of 204 weapons of Period I of the Early Nordic Bronze Age. The analysed sample contained 154 spearheads and 50 swords and was made up of approximately one-third of the contemporaneous weapons in Southern Scandinavia. The use-wear analysis was undertaken with a source critical view on corrosion and other taphonomic processes. The information obtained was used to see how use-wear and taphonomic processes influence each other. Use-wear analysis was employed to evaluate statements regarding the functionality, or rather non-functionality, of Early Bronze Age weaponry. According to the results, spears and swords were not only functional but also very frequently used. Further deductions can be made from the material. Despite a difference in the scale of fighting, spears and swords show essentially the same kind of combat wear. It is argued that this relates to essentially similar styles of fighting that employ both cutting and stabbing movements and are perhaps most appropriately termed ‘fencing’. This style of fighting possibly emerged from frequent encounters of sword and spear fighters in the closely interconnected world of Southern Scandinavia during Period I of the Early Bronze Age. In these engagements, a partial homogenising effect of warfare and fighting becomes visible. Yet, it is not the only effect that accompanies combat and war. Diversification and homogenisation are not mutually exclusive or contradictive. Accordingly, they took place simultaneously and helped develop fighting styles and weapon technologies