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

• Published in: Scientific reports Vol. 8; no. 1; pp. 17892 - 10
• Main Authors: Baatarkhuu, Zoljargal, Chaignon, Philippe, Borel, Franck, Ferrer, Jean-Luc, Wagner, Alain, Seemann, Myriam
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-12-2018; Nature Publishing Group
• Subjects: 140/131; 631/45/173; 639/638/403/931; 692/699/255/1318; 82/16; 82/29; 82/80; 82/83; Chemical Sciences; Drug Resistance, Multiple - drug effects; Drug Resistance, Multiple - physiology; E coli; Enzyme Inhibitors - pharmacology; Enzymes; Erythritol - metabolism; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - metabolism; Escherichia coli Proteins - metabolism; Humanities and Social Sciences; Humans; Kinetics; Medicinal Chemistry; Microorganisms; Models, Molecular; multidisciplinary; Multidrug resistance; Parasites; Phosphates - metabolism; Plasmodium falciparum - drug effects; Plasmodium falciparum - metabolism; Science; Science (multidisciplinary); Sugar Phosphates - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-35586-y

As multidrug resistant pathogenic microorganisms are a serious health menace, it is crucial to continuously develop 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 steady-state kinetics of a novel potent inhibitor (MEPN
3
) of
Escherichia coli
YgbP/IspD, the third enzyme of the MEP pathway. MEPN
3
inhibits
E
.
coli
YgbP/IspD in mixed type mode regarding both substrates. Interestingly, MEPN
3
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 it was found that the substrates add to the enzyme in sequential manner.