Fosmidomycin for malaria

Missinou, Michel A.; Borrmann, Steffen; Schindler, Andreas; Issifou, Saadou; Adegnika, Ayôla Akim; Matsiégui, Pierre-Blaise; Binder, Ronald K.; Lell, Bertrand; Wiesner, Jochen; Baranek, Thomas; Jomaa, Hassan; Kremsner, Peter G.

doi:10.1016/s0140-6736(02)11860-5

Cited by 210 publications

(140 citation statements)

References 2 publications

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“…47,48 Fosmidomycin is also highly active on MtDXR but unfortunately lacks activity on M. tuberculosis whole cells, probably because of poor uptake. Therefore, one of the main challenges is to prepare modified analogues of fosmidomycin that can cross the mycobacterial cell wall.…”

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

et al. 2011

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The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin–DXR complex. Our best inhibitor has an IC50 = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

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Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

et al. 2011

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“…6,7 In recent clinical trials conducted in Gabon and Thailand, fosmidomycin proved to be efficient in the treatment of patients suffering from acute, uncomplicated P. falciparum malaria. 8,9 Fosmidomycin has the advantage to be remarkably nontoxic and to exhibit activity against multiresistant parasite strains. Limitations are the short plasma half-life and the moderate resorption rate.…”

Section: P N Oh O Ho Ho R H or Ch 3 Omentioning

confidence: 99%

Synthesis of α‐Substituted Fosmidomycin Analogues as Highly Potent Plasmodium falciparum Growth Inhibitors.

et al. 2006

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“…1). Patients suffering from acute uncomplicated Plasmodium falciparum infections could be successfully treated with fosmidomycin, but in some patients the parasite reappeared after termination of the treatment [6]. An overall cure rate of 95%, however, was achieved when fosmidomycin was tested in combination with clindamycin [7], an inhibitor of the prokaryote-type translation machinery of the plastid-like organelle (the so-called apicoplast) present in malaria parasites.…”

Section: Introductionmentioning

confidence: 99%

Possible direct involvement of the active‐site [4Fe–4S] cluster of the GcpE enzyme from Thermus thermophilus in the conversion of MEcPP

Adedeji¹,

Hernandez²,

Wiesner³

et al. 2006

FEBS Letters

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The GcpE enzyme converts 2-C-methyl-D D-erythritol-2,4-cyclodiphosphate (MEcPP) into (E)-4-hydroxy-3-methylbut-2-enyl diphosphate (HMBPP) in the penultimate step of the DOXP pathway for isoprene biosynthesis. Purification of the enzyme under exclusion of air leads to a preparation that contains solely [4Fe-4S] clusters. Kinetic studies showed that in the presence of the artificial reductant dithionite and MEcPP a new transient iron-sulfur-based signal is detected in electron paramagnetic resonance (EPR) spectroscopy. Similarity of this EPR signal to that detected in ferredoxin:thioredoxin reductase indicates that during the reaction an intermediate is directly bound to the active-site cluster.

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Fosmidomycin for malaria

Cited by 210 publications

References 2 publications

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

Design, Synthesis, and X-ray Crystallographic Studies of α-Aryl Substituted Fosmidomycin Analogues as Inhibitors of Mycobacterium tuberculosis 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase

Synthesis of α‐Substituted Fosmidomycin Analogues as Highly Potent Plasmodium falciparum Growth Inhibitors.

Possible direct involvement of the active‐site [4Fe–4S] cluster of the GcpE enzyme from Thermus thermophilus in the conversion of MEcPP

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