Development of improved fosmidomycin derivates

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In the malaria parasite Plasmodium falciparum, isoprenoid are synthesised via the 1-deoxy-D-xylulose 5-phosphate (DOXP) pathway which is absent in humans. In a clinical proof-of-concept study fosmidomycin, an inhibitor of DOXP reductoisomerase (DXR), was demonstrated to possess potent antimalarial activity. However, fosmidomycin does not act selectively against DXR in malaria parasites but also inhibits the DXR in a variety of bacterial species. Therefore, new DXR inhibitors which are more specific for P. falciparum DXR need to be developed using a structure-based approach. The available crystal structure of E. coli DXR will be used to create a structural model of the highly homologous DXR from P. falciparum.