Inhibitors of the non-mevalonate pathway

The mevalonate independent pathway of isoprenoid biosynthesis, the so-called DOXP pathway represents an attractive and validated drug target. Most bacteria, but also P. falciparum, use this pathway to produce isoprenoids. In a joint ITN project we are aiming to develop inhibitors of selected enzymes of the DOXP pathway as new antimalarial or antibacterial agents. We mainly focus on DOXP reducto-isomerase (DR). Starting from the structure of fosmidomycin, a potent inhibitor of this enzyme, we aim to synthesize analogues that also exhibit activity against clinically relevant bacteria (P. aeruginosa and M. tuberculosis) and have superior PK properties.