Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum.

In vitro evolution of drug resistance is a powerful approach for identifying antimalarial targets, however, key obstacles to eliciting resistance are the parasite inoculum size and mutation rate. Here we sought to increase parasite genetic diversity to potentiate resistance selections by editing catalytic residues of Plasmodium falciparum DNA polymerase δ. Mutation accumulation assays reveal a ~5-8 fold elevation in the mutation rate, with an increase of 13-28 fold in drug-pressured lines.

Discovery of a Quinoline-4-carboxamide Derivative with a Novel Mechanism of Action, Multistage Antimalarial Activity, and Potent in Vivo Efficacy.

The antiplasmodial activity, DMPK properties, and efficacy of a series of quinoline-4-carboxamides are described. This series was identified from a phenotypic screen against the blood stage of Plasmodium falciparum (3D7) and displayed moderate potency but with suboptimal physicochemical properties and poor microsomal stability. The screening hit (1, EC = 120 nM) was optimized to lead molecules with low nanomolar in vitro potency.

Public-private partnerships for health: their main targets, their diversity, and their future directions.

The global burden of disease, especially the part attributable to infectious diseases, disproportionately affects populations in developing countries. Inadequate access to pharmaceuticals plays a role in perpetuating this disparity. Drugs and vaccines may not be accessible because of weak distribution infrastructures or because development of the desired products has been neglected.