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

Eur J Med Chem. 2012 May:51:277-85. doi: 10.1016/j.ejmech.2012.02.031. Epub 2012 Feb 25.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldose-Ketose Isomerases / antagonists & inhibitors*
  • Aldose-Ketose Isomerases / metabolism
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / metabolism
  • Anti-Bacterial Agents / pharmacology*
  • Enzyme Inhibitors / metabolism*
  • Fosfomycin / analogs & derivatives
  • Fosfomycin / metabolism
  • Hydrophobic and Hydrophilic Interactions
  • Kinetics
  • Microbial Viability / drug effects
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / metabolism
  • Mycobacterium smegmatis / drug effects*
  • Mycobacterium smegmatis / enzymology
  • Mycobacterium smegmatis / growth & development*
  • Mycobacterium smegmatis / metabolism
  • Organophosphonates / chemical synthesis
  • Organophosphonates / chemistry
  • Organophosphonates / metabolism
  • Organophosphonates / pharmacology
  • Oxazines / metabolism
  • Oxidoreductases / antagonists & inhibitors*
  • Oxidoreductases / metabolism
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Prodrugs / metabolism
  • Prodrugs / pharmacology*
  • Xanthenes / metabolism

Substances

  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Organophosphonates
  • Oxazines
  • Prodrugs
  • Xanthenes
  • resazurin
  • Fosfomycin
  • fosmidomycin
  • 3-(N-acetyl-N-hydroxy)aminopropylphosphonic acid
  • Oxidoreductases
  • 1-deoxy-D-xylulose 5-phosphate reductoisomerase
  • Aldose-Ketose Isomerases