fosmidomycin + piperaquine

Fosmidomycin + piperaquine is an investigational oral fixed-dose combination therapy for the treatment of uncomplicated *Plasmodium falciparum* malaria. It is being developed as a non-artemisinin-based combination to address emerging artemisinin resistance. Fosmidomycin, originally derived from *Streptomyces lavendulae* and now produced synthetically, inhibits 1-deoxy-D-xylulose 5-phosphate reductoisomerase, blocking the non-mevalonate pathway of isoprenoid biosynthesis in the malaria parasite—a pathway absent in humans—resulting in parasite death. Piperaquine acts by inhibiting heme detoxification within the parasite, causing toxic heme accumulation and increased membrane permeability that enhances fosmidomycin uptake. The combination provides rapid blood schizonticidal activity (from fosmidomycin) and prolonged post-treatment prophylaxis (from piperaquine). Phase 2 clinical trials have demonstrated high efficacy (100% cure rate at day 28), good tolerability, and a favorable safety profile with only transient QT interval prolongation observed[1][2][3][6].