Synthesis and biological evaluation of phosphate isosters of fosmidomycin and analogs as inhibitors of Escherichia coli and Mycobacterium smegmatis 1-deoxyxylulose 5-phosphate reductoisomerases

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• 作者：Mathilde Munier^a ; Denis Tritsch^a ; Fanny Krebs^a ; ^b ; Jé ; ré ; my Esque^b ; André ; a Hemmerlin^c ; Michel Rohmer^a ; Roland H. Stote^b ; Catherine Grosdemange-Billiard^a ; ^{grosdemange@unistra.fr}
• 关键词：DXP ; 1-deoxy-d-xylulose 5-phosphate ; DXR ; 1-deoxy-d-xylulose 5-phosphate reductoisomerase ; MEP ; 2-C-methyl-d-erythritol 4-phosphate ; GlpT ; glycerol-3-phosphate transporter ; UhpT ; hexose-6-phosphate transporter ; FosR ; fosmidomycin resistant strain of E. coli
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：25
• 期：2
• 页码：684-689
• 全文大小：439 K
• 卷排序：25

文摘

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 IC50 values 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.