C O M M U N I C A T I O N S
that the ability of the compounds to block mycobacterial growth is
related to their ability to inhibit UGM.
Our results support the validity of UGM as a target for
antimycobacterial agents. Our findings also highlight the utility of
the 2-aminothiazole scaffold for targeting the UDP-sugar binding
site of UGM. The similarity between the 2-aminothiazole and
compoundsfoundtoinhibitotherenzymesthatactonnucleotide-sugar
substrates27 suggests that this scaffold could yield inhibitors of other
UDP-sugar utilizing enzymes.
Acknowledgment. We thank R. Risi and T.D. Gruber for their
experimental contributions, and acknowledge the NIH for support
(AI063596). E.C.D. thanks the NIH Biotechnology Training
Program (GM08349) and the ACS Medicinal Chemistry Division
for fellowships. J.F.M. was supported by a National Science
Foundation Graduate Research Fellowship.
24
Figure 5. Model of UGMmyco complexed to (A) UDP-galactopyranose
(black) (the uracil group is on the left and the sugar on the right) or with
(B) inhibitor (red) docked (ring A is on left, ring B on the right). A portion
of the flavin cofactor (orange) is visible in the binding pocket.
Supporting Information Available: Experimental procedures,
compound characterization data, and sample binding curves. This
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used antimycobacterial agents, ethambutol and rifampicin.25
A
direct relationship was observed between UGM inhibitor potency
and the MIC (see Supporting Information). This finding suggests
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