Project: targeting the terpenoid biosynthesis pathway

Inhibition of synthesis of terpenoids to fight antibiotic resistance in human pathogens

Contact : Franck Borel

Terpenoids are key metabolites present in all kingdoms of life. They are produced by condensation of two building blocks: Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). Two pathways produce these building blocks: the mevalonate (MVA) and methylerythritol phosphate (MEP) pathways. The MEP pathway, found in many pathogens, is built on seven consecutive enzymes - namely DXS, IspC, IspD, IspE, IspF, IspG and IspH - the last one producing both IPP and DMAPP. At the opposite, the MVA pathway produces IPP that is transformed into DMAPP using Idi, a specific isomerase. Human uses exclusively the MVA pathway and a type 1 Idi, making the MEP pathway and type 2 Idi (Idi-2) valuable therapeutic bacterial targets, especially for multi-drug resistant (MDR) pathogens.
The goal of the project is the inhibition of the biosynthesis of DMAPP in resistant pathogens that were listed as critical or high priority by WHO. For species depending solely on the MEP pathway to produce DMAPP, we will specifically target the IspD, IspE, and IspF enzymes (steps 3 to 5 of the MEP pathway). To address those that use the MVA pathway (S. aureus, E. faecium and E. faecalis) we will target Idi-2.
The design of specific inhibitors against these enzymes is carried out by combining fragment-based crystallography screening at both room and cryogenic temperatures, and in silico virtual screening supplemented by activity assays.

Selected publications:

1. Synthesis and Kinetic evaluation of an azido analogue of methylerythritol phospate: a Novel Inhibitor of E. coli YgbP/IspD. Baatarkhuu Z, Chaignon P, Borel F, Ferrer J-L, Wagner A, Seemann M (2018) Sci. Rep. 8:17892.

2. Further insight into crystal structures of E. coli IspH/LytB in complex with two potent inhibitors of the MEP pathway: a starting point for rational design of new antimicrobials. Borel F, Barbier E, Krasutsky S, Janthawornpong K, Chaignon P, Dale Poulter C, Ferrer J-L, Seemann M (2017) ChemBioChem 18, 2137-2144.