Inhibitors of UDP-Galactopyranose Mutase Thwart Mycobacterial Growth

Galactofuranose (Galf) residues are fundamental components of the cell wall of mycobacteria. A key enzyme, UDP-galactopyranose mutase (UGM), that participates in Galf incorporation mediates isomerization of UDP-Galf from UDP-galactopyranose (UDP-Galp). UGM is of special interest as a therapeutic tar...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2008-05, Vol.130 (21), p.6706-6707
Main Authors: Dykhuizen, Emily C, May, John F, Tongpenyai, Aimon, Kiessling, Laura L
Format: Article
Language:English
Subjects:
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Intramolecular Transferases - antagonists & inhibitors
Intramolecular Transferases - metabolism
Klebsiella pneumoniae
Models, Molecular
Molecular Conformation
Mycobacterium tuberculosis
Structure-Activity Relationship
Thiazoles - chemistry
Thiazoles - pharmacology
Thiazolidines - chemistry
Thiazolidines - pharmacology
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Summary:Galactofuranose (Galf) residues are fundamental components of the cell wall of mycobacteria. A key enzyme, UDP-galactopyranose mutase (UGM), that participates in Galf incorporation mediates isomerization of UDP-Galf from UDP-galactopyranose (UDP-Galp). UGM is of special interest as a therapeutic target because the gene encoding it is essential for mycobacterial viability and there is no comparable enzyme in humans. We used structure−activity relationships and molecular design to devise UGM inhibitors. From a focused library of synthetic aminothiazoles, several compounds that block the UGM from Klebsiella pneumoniae or Mycobacterium tuberculosis were identified. These inhibitors block the growth of M. smegmatis.
ISSN:0002-7863
1272-7863
1520-5126
DOI:10.1021/ja8018687