id6b00021_si_001.pdf (8.82 MB)
Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes
journal contribution
posted on 2016-06-16, 00:00 authored by Valerie J. Winton, Claudia Aldrich, Laura L. KiesslingUridine
diphosphate galactopyranose mutase (UGM also known as Glf) is a biosynthetic
enzyme required for construction of the galactan, an essential mycobacterial
cell envelope polysaccharide. Our group previously identified two
distinct classes of UGM inhibitors; each possesses a carboxylate moiety
that is crucial for potency yet likely detrimental for cell permeability.
To enhance the antimycobacterial potency, we sought to replace the
carboxylate with a functional group mimican N-acylsulfonamide group. We therefore synthesized a series of N-acylsulfonamide analogs and tested their ability to inhibit
UGM. For each inhibitor scaffold tested, the N-acylsulfonamide
group functions as an effective carboxylate surrogate. Although the
carboxylates and their surrogates show similar activity against UGM
in a test tube, several N-acylsulfonamide derivatives
more effectively block the growth of Mycobacterium smegmatis. These data suggest that the replacement of a carboxylate with an N-acylsulfonamide group could serve as a general strategy
to augment antimycobacterial activity.