Targeting Dxr/IspC to develop drugs against malaria and tuberculosis

The methylerythritol phosphate pathway (the MEP pathway) of isoprenoid biosynthesis is essential for the survival of many pathogenic organisms, including Plasmodium falciparum and Mycobacterium tuberculosis , causative agents of malaria and tuberculosis, respectively. The MEP pathway is absent in humans, making it an important drug target. There are seven enzymes in this pathway. 1‐Deoxy‐D‐xylose 5‐phosphate reductoisomerase (Dxr/IspC) catalyzes the first committed step in the pathway. It converts the substrate 1‐Deoxy‐D‐xylose 5‐phosphate (DXP) into 2‐C‐methyl‐D‐erythritol 4‐phosphate (MEP), which in turn is the substrate for the downstream enzymatic steps. We have expressed and purified IspC of Plasmodium falciparum (PfIspC) and Mycobacterium tuberculosis (MtIspC) using E. coli as an expression system. Finally, we carried out enzyme inhibition assays using novel IspC inhibitors, showing IC 50 results ranging from 0.28 – 5.3 μM. Support or Funding Information Self‐sponsored. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .