Inhibitors of the non-mevalonate pathway

A mevalonate independent pathway of isoprenoid biosynthesis, the so-called DOXP pathway, has been discovered recently and validated as new drug target. Most bacteria, but also P. falciparum, seem to use this pathway to produce isoprenoids. In a joint project we are aiming to develop inhibitors of selected enzymes of the DOXP pathway as new antimalarial or antibacterial agents. Initially, we focused on DOXP reducto-isomerase (DR). Starting from the structure of fosmidomycin, an interesting lead inhibitor of this enzyme, we have synthesized several analogues that exhibit comparable or even improved inhibitory activity, both on the enzyme level as in vitro on P. falciparum.

project 3

Currently, we are also designing inhibitors for two enzymes that catalyze the last two steps of the DOXP patway, i.e., GcpE and LytB. Since these enzymes contain oxygen-sensitive iron-sulphur clusters, a screening assay under anaerobic conditions had to be developed by our partner in Giessen.
Inhibitors can be anticipated to display activity against a variety of bacterial and protozoan pathogens.

Superposition of a home-made conformationally restricted fosmidomycin analogue (in gold) with fosmidomycin (in grey) in its enzyme-bond conformation. The purple ball represents a Mg-ion.

Researchers: René Chofor, Charlotte Courtens

Collaborators: Prof. T. Alwyn Jones & Prof. Sherry L. Mowbray