Development of mycobacterial growth inhibitors that target UGM

ORGN 658

Emily Dykhuizen, edykhuiz@chem.wisc.edu1, John F. May, jmay@biochem.wisc.edu2, Aimon Tongpenyai, ai_mon@yahoo.com1, and Laura L. Kiessling, kiessling@chem.wisc.edu3. (1) Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave, Madison, WI 53706, (2) Department of Biochemistry, University of Wisconsin, Madison, 433 Babcock Drive, Madison, WI 53706, (3) Departments of Chemistry and Biochemistry, University of Wisconsin - Madison, Madison, WI 53706
Galactofuranose residues play important roles in the virulence and fidelity of pathogenic bacteria. For example, galactofuranose residues are essential components of the arabinogalactan layer of Mycobacterium tuberculosis, the causative agent of tuberculosis. One potential target for anti-mycobacterial agents is UDP-galactofuranose mutase (UGM), the enzyme responsible for the isomerization of UDP- galactofuranose from UDP-galactopyranose. Although the gene encoding UGM has been found to be essential for mycobacterial viability, it is not known whether inhibitors of UGM would function as anti-mycobacterial agents. We have developed a strategy to generate UGM inhibitors. By analyzing data from a high throughput screen, we designed and synthesized a focused library of compounds. Many members were found to inhibit UGM from K. pneumoniae and M. tuberculosis. Moreover, several inhibitors were also able to inhibit the growth of Mycobacterium smegmatis but not Escherichia coli. Our data suggest that UGM is a new target for anti-mycobacterial agents.

 

Asymmetric Reactions, Combinatorial Chemistry, Molecular Recognition and Self-Assembly, Proteins, Peptides, Amino Acids and Enzyme Inhibitors
8:00 PM-10:00 PM, Wednesday, March 28, 2007 Hyatt Regency Chicago -- Riverside Center, Poster

Division of Organic Chemistry

The 233rd ACS National Meeting, Chicago, IL, March 25-29, 2007