Plasmodium falciparum: Detection of the Deoxyxylulose 5-Phosphate Reductoisomerase Activity

Wiesner, Jochen; Hintz, Martin; Altincicek, Boran; Sanderbrand, Silke; Weidemeyer, Claus; Beck, Ewald; Jomaa, Hassan

doi:10.1006/expr.2000.4566

Cited by 32 publications

(25 citation statements)

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“…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).…”

mentioning

confidence: 99%

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

Wiesner¹,

Henschker²,

Hutchinson³

et al. 2002

Antimicrob Agents Chemother

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125

106

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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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mentioning

confidence: 99%

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

Wiesner¹,

Henschker²,

Hutchinson³

et al. 2002

Antimicrob Agents Chemother

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125

106

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“…Three genes for the DOXP pathway, DOXP synthase, DOXP reductoisomerase and MECDP synthase (IspF or YgbB), have recently been identified from Plasmodium falciparum and all possess bipartite presequences (Gardner et al, 1998;Jomaa et al, 1999;Gardner et al, 2002). Moreover, DOXP reductoisomerase is shown to target to apicoplasts, and the recombinant expression of this enzyme verified DOXP reductoisomerase activity which has since also been measured from P. falciparum extracts (Jomaa et al, 1999;Wiesner et al, 2000). This data presents a strong case for a DOXP pathway for isoprenoid synthesis in the apicoplast of P. falciparum.…”

Section: Isoprenoid Biosynthesismentioning

confidence: 89%

The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites

Waller

McFadden²

2005

Current Issues in Molecular Biology

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The apicoplast is a plastid organelle, homologous to chloroplasts of plants, that is found in apicomplexan parasites such as the causative agents of Malaria Plasmodium spp. It occurs throughout the Apicomplexa and is an ancient feature of this group acquired by the process of endosymbiosis. Like plant chloroplasts, apicoplasts are semi-autonomous with their own genome and expression machinery. In addition, apicoplasts import numerous proteins encoded by nuclear genes. These nuclear genes largely derive from the endosymbiont through a process of intracellular gene relocation. The exact role of a plastid in parasites is uncertain but early clues indicate synthesis of lipids, heme and isoprenoids as possibilities. The various metabolic processes of the apicoplast are potentially excellent targets for drug therapy.

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“…[80] The molecular target and the antimalarial activity of fosmidomycin (31) has only been known since 1998. [78,[81][82][83] It was suggested that fosmidomycin (31) binds as a substrate analogue to the active site of the enzyme (Figure 13). Kinetic analyses with E. coli DOXP reductoisomerase revealed that 31 initially binds with relatively low affinity to the active site, thereby inducing alterations in the enzyme conformation that result in a significantly higher affinity.…”

Section: Tafenoquinementioning

confidence: 99%

New Antimalarial Drugs

et al. 2003

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Approximately 40% of the world population live in areas with the risk of malaria. Each year, 300-500 million people suffer from acute malaria, and 0.5-2.5 million die from the disease. Although malaria has been widely eradicated in many parts of the world, the global number of cases continues to rise. The most important reason for this alarming situation is the rapid spread of malaria parasites that are resistant to antimalarial drugs, especially chloroquine, which is by far the most frequently used. The development of new antimalarial drugs has been neglected since the 1970s owing to the end colonialism, changes in the areas of military engagement, and the restricted market potential. Only in recent years, in part supported by public funding programs, has interest in the development of antimalarial drugs been renewed. New data available from the recently sequenced genome of the malaria parasite Plasmodium falciparum and the application of methods of modern drug design promise to bring significant development in the fight against this disease.

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Plasmodium falciparum: Detection of the Deoxyxylulose 5-Phosphate Reductoisomerase Activity

Cited by 32 publications

References 8 publications

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

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

The Apicoplast: A Review of the Derived Plastid of Apicomplexan Parasites

New Antimalarial Drugs

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