title: Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis 1-deoxyxylulose 5-phosphate reductoisomerases.
abstract: Hydroxamate analogs of fosfoxacin, the phosphate homolog of fosmidomycin, have been synthesized and their activity tested on Escherichia coli and Mycobacterium smegmatis DXRs. Except for compound 4b, the IC50values of phosphate derivatives are approximately 10-fold higher than those of the corresponding phosphonates. Although their inhibitory activity on Escherichia coli DXR is less efficient than their phosphonate analogs, we report the ability of phosphate compounds to inhibit the growth of Escherichia coli. This work points out that the uptake of fosfoxacin and its analogs is taking place via the GlpT and UhpT transporters. As expected, these compounds are inefficient to inhibit the growth of M. smegmatis growth inhibition probably due to a lack of uptake.
authors.affiliation: Laboratoire Chimie et Biochimie de Molécules Bioactives - Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Munier
authors.affiliation: Laboratoire Chimie et Biochimie de Molécules Bioactives - Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Tritsch
authors.affiliation: Laboratoire Chimie et Biochimie de Molécules Bioactives - Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France; Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Fanny
authors.initials: F
authors.lastname: Krebs
authors.affiliation: Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Esque
authors.affiliation: Université de Strasbourg, CNRS, IBMP UPR 2357, 12 rue Général Zimmer, F-67084 Strasbourg, France.
authors.forename: Andréa
authors.initials: A
authors.lastname: Hemmerlin
authors.affiliation: Laboratoire Chimie et Biochimie de Molécules Bioactives - Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Rohmer
authors.affiliation: Department of Integrative Structural Biology, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut National de la Santé et de la Recherche Médicale (INSERM) U964, Centre National de la Recherche Scientifique (CNRS) UMR 7104, Université de Strasbourg, 67404 Illkirch, France.
authors.forename: Roland H
authors.initials: RH
authors.lastname: Stote
authors.affiliation: Laboratoire Chimie et Biochimie de Molécules Bioactives - Université de Strasbourg/CNRS, UMR 7177, Institut Le Bel, 4 rue Blaise Pascal, 67081 Strasbourg, France. Electronic address: grosdemange@unistra.fr.
authors.forename: Catherine
authors.initials: C
authors.lastname: Grosdemange-Billiard
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D020102:Mycobacterium smegmatis / Q000201:enzymology*; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010710:Phosphates; D005578:Fosfomycin; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases
keywords: Antimicrobials; DXR; Fosfoxacin; Fosmidomycin; GlpT and UhpT transporters