Synthesis and Kinetic evaluation of an azido analogue of methylerythritol phosphate: a Novel Inhibitor of E. coli YgbP/IspD

Zoljargal Baatarkhuu (1) , Philippe Chaignon (1) , Franck Borel (2) , Jean-Luc Ferrer (2) , Alain Wagner (3) , Myriam Seemann (4)

1 Institut de Chimie de Strasbourg
2 IBS - UMR 5075 - Institut de biologie structurale
3 FMTS - Université de Strasbourg - Faculté de Médecine [Strabourg]
4 Institut de Chimie de Strasbourg

As multidrug resistant pathogenic microorganisms are on the horizon, it is crucial to develop continuously novel medicines in order to overcome the emerging resistance. The methylerythritol phosphate pathway (MEP) is an ideal target for antimicrobial development as it is absent in humans but present in most bacteria and in the parasite Plasmodium falciparum. Here, we report the synthesis and the kinetic parameters of a novel potent inhibitor (MEPN3) of Escherichia coli YgbP/IspD, the third enzyme of the MEP pathway. MEPN3 inhibits E. coli YgbP/IspD in mixed type mode regarding both substrates. Interestingly, MEPN3 shows the highest inhibitory activity when compared to known inhibitors of E. coli YgbP/IspD. The mechanism of this enzyme was also studied by steady state kinetic analysis and was found to be sequential where substrates add to the enzyme in sequential manner.

Domaines: Chimie thérapeutique

Zoljargal Baatarkhuu, Philippe Chaignon, Franck Borel, Jean-Luc Ferrer, Alain Wagner, et al.. Synthesis and Kinetic evaluation of an azido analogue of methylerythritol phosphate: a Novel Inhibitor of E. coli YgbP/IspD. Scientific Reports, 2018, 8 (1), pp.17892. ⟨10.1038/s41598-018-35586-y⟩. ⟨hal-02007734⟩