title: Growth inhibition of Mycobacterium smegmatis by prodrugs of deoxyxylulose phosphate reducto-isomerase inhibitors, promising anti-mycobacterial agents.
abstract: 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.
authors.affiliation: Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ponaire
authors.forename: Catherine
authors.initials: C
authors.lastname: Zinglé
authors.forename: Denis
authors.initials: D
authors.lastname: Tritsch
authors.forename: Catherine
authors.initials: C
authors.lastname: Grosdemange-Billiard
authors.forename: Michel
authors.initials: M
authors.lastname: Rohmer
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005578:Fosfomycin / Q000031:analogs & derivatives / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D050296:Microbial Viability / Q000187:drug effects; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020102:Mycobacterium smegmatis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development* / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010078:Oxazines / Q000378:metabolism; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014966:Xanthenes / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D063065:Organophosphonates; D010078:Oxazines; D011355:Prodrugs; D014966:Xanthenes; C005843:resazurin; D005578:Fosfomycin; C024640:fosmidomycin; C024639:3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid; D010088:Oxidoreductases; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases