Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents

Since Mycobacterium tuberculosis sets up several multiple anti-tuberculosis drug resistance mechanisms, development of new drugs with innovative target is urgent. The methylerythritol phosphate pathway (MEP) involved in the biosynthesis of essential metabolites for the survival of mycobacteria, represents such a target. Fosmidomycin 1a and FR900098 1b, two inhibitors of DXR, do not affect the viability of M. tuberculosis cells, due to a lack of uptake. To overcome the absence of the mycobacterial cell wall crossing of these compounds, we synthesized and tested the inhibition potency of acyloxymethyl phosphonate esters as prodrugs of fosmidomycin 1a, FR900098 1b and their analogs 2a and 2b on Mycobacterium smegmatis. Only the prodrugs 4b–6b inhibit the bacterial growth and could be effective anti-mycobacterial agents.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Fosmidomycin and analogs do not inhibit mycobacterial growth.
► Resistance to these compounds is due to absence of cell wall crossing.
► Phosphonate groups were masked as acyloxymethyl phosphonate esters.
► Prodrugs 4b–6b inhibit mycobacterial growth, prodrug 4b was the most active.
► Fosmidomycin and FR900098 prodrugs 3a and 3b were inefficient.