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Metabolic labelling of bacterial isoprenoids produced by the methylerythritol phosphate pathway : a starting point towards a new inhibitor

Abstract : Isoprenoids, present in all living organisms, are synthesised according to two routes: the Mevalonate and the Methylerythritol phosphate (MEP) pathways. The MEP pathway, absent in humans, is extensively investigated as it is a target for the development of new antimicrobials. ME-N3 an azide tagged analogue of methylerythritol was synthesised and utilised for metabolic labelling studies of the MEP pathway using bioorthogonal ligation followed by LC-MS analysis. Interestingly, we found that MEP-N3, an analogue of MEP, inhibits E.coli IspD (3rd enzyme of the MEP pathway). Further inhibition kinetic studies revealed that MEP-N3 possesses the highest inhibitory activity on E.coli ispD when compared to known inhibitors. In addition, the mechanism of inhibition of E.coli ispD by MEP-N3 was found to be best described using a mixed type model. Moreover, determination of the IspD reaction mechanism has been carried out for the first time, by virtue of a bisubstrate steady state kinetic analysis.
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Zoljargal Baatarkhuu. Metabolic labelling of bacterial isoprenoids produced by the methylerythritol phosphate pathway : a starting point towards a new inhibitor. Other. Université de Strasbourg, 2017. English. ⟨NNT : 2017STRAF029⟩. ⟨tel-02003538⟩

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