In Vitro and In Vivo Synergy of Fosmidomycin, a Novel Antimalarial Drug, with Clindamycin

Abstract

Fosmidomycin acts through inhibition of 1-deoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, a key enzyme of the nonmevalonate pathway of isoprenoid biosynthesis. It possesses potent antimalarial activity in vitro and in murine malaria. In a recent clinical study, fosmidomycin was effective and well tolerated in the treatment of patients with acute uncomplicated Plasmodium falciparum malaria but resulted in an unacceptably high rate of recrudescence. In order to identify a potential combination partner, the interaction of fosmidomycin with a number of antimalarial drugs in current use was investigated in a series of in vitro experiments. Synergy was observed between fosmidomycin and the lincosamides, lincomycin and clindamycin. The efficacy of a combination of fosmidomycin and clindamycin was subsequently demonstrated in the Plasmodium vinckei mouse model.In humans, isoprenoids are synthesized via the mevalonate pathway. In contrast, they are synthesized by the nonmevalonate pathway (the 1-deoxy-D-xylulose 5-phosphate [DOXP] pathway, also called the MEP pathway) in a number of bacterial species and inside the plastides of algae and higher plants (22). Similarly, the enzymes of the nonmevalonate pathway are located inside the plastide-like organelle (apicoplast) of malaria parasites (7,27). The antibiotic fosmidomycin, originally isolated from Streptomyces lavendulae, represents a potent inhibitor of DOXP reductoisomerase, a key enzyme of the nonmevalonate pathway (15,28). Recently, it was demonstrated that fosmidomycin possesses potent antimalarial activity in vitro and in murine malaria (7). FR900098, a fosmidomycin derivative, was found to be twice as effective, while the prodrug derivatives had increased oral bioavailability in the mouse model (21).In a recent clinical study conducted in Gabon and Thailand, 20 patients with acute uncomplicated Plasmodium falciparum malaria were treated with fosmidomycin administered orally (B. Lell, R. Ruangweerayut, J. Wiesner, M. Missinou, A. Schindler, T. Baranek, M. Hintz, D. Hutchinson, H. Jomaa, and P. Kremsner, unpublished data). The treatment was well tolerated and resulted in rapid parasite and fever clearance times, comparable to those obtained with conventional quinoline antimalarial agents. All patients were clinically and parasitologically cured by day 7. By day 28, however, 9 out of 18 evaluable patients experienced recrudescence. A similarly high rate of recrudescence had been observed previously when the hydroxynaphthoquinone antimalarial agent atovaquone was evaluated as a single entity (17). Subsequently, proguanil was identified as a partner for atovaquone on the basis of in vitro synergistic activity, resulting in a highly effective and welltolerated fixed drug combination, approved and marketed as Malarone (3). Using a similar approach, we have investigated the interaction of fosmidomycin with most antimalarial agents in clinical use. MATERIALS AND METHODSMaterials. Blood components were provided by the local Institute of Clinical Immunology and Tran...

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