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 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.
Dykhuizen
Emily C
EC
Departments of Chemistry and Biochemistry, University of WisconsinMadison, Madison, Wisconsin 53706, USA.
May
John F
JF
Tongpenyai
Aimon
A
Kiessling
Laura L
LL
D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019751:Intramolecular Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*; D053778:Thiazolidines / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D013844:Thiazoles; D053778:Thiazolidines; D019751:Intramolecular Transferases; C098051:UDP-galactopyranose mutase