In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated Plasmodium falciparum malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.Development of drug resistance and, in some cases, concerns over safety highlight the urgent requirement for new antimalarial drugs. Primarily directed towards the treatment of multidrug-resistant Plasmodium falciparum malaria, such drugs should possess novel modes of action while exhibiting efficacy and safety within the constraints of therapeutic regimens not exceeding 3 days. They should also be affordable in the developing world.Fosmidomycin was formerly under development as an antibacterial agent. As a phosphonic acid derivative with potent activity against gram-negative organisms, its role in the management of urinary tract infections was the focus of clinical studies that were undertaken during the 1980s. However, its early promise in the treatment of uncomplicated urinary tract infections was countered by its relative lack of effectiveness against recurrent infections, although the safety of the drug even in high doses (1.0 g every 6 h for 7 days, per os) was established (7,8,9).As a potent inhibitor of 1-deoxy-D-xylulose 5-phosphate reductoisomerase, an essential enzyme of the nonmevalonate pathway, fosmidomycin blocks the biosynthesis of isopentenyl diphosphate and the subsequent development of isoprenoids in P. falciparum (5). In contrast, isoprenoids are derived from an alternative pathway, known as the mevalonate pathway, in mammals (1). Hence, fosmidomycin exerts its antimalarial activity through a mechanism of selective toxicity that allows the biosynthesis of is...