%0 Journal Article
%A Winton, Valerie J.
%A Aldrich, Claudia
%A Kiessling, Laura L.
%D 2016
%T Carboxylate Surrogates Enhance the Antimycobacterial
Activity of UDP-Galactopyranose Mutase Probes
%U https://acs.figshare.com/articles/journal_contribution/Carboxylate_Surrogates_Enhance_the_Antimycobacterial_Activity_of_UDP-Galactopyranose_Mutase_Probes/3545994
%R 10.1021/acsinfecdis.6b00021.s001
%2 https://acs.figshare.com/ndownloader/files/5611176
%K mycobacterial cell envelope polysaccharide
%K Carboxylate Surrogates Enhance
%K UGM
%K carboxylate
%K potency
%K antimycobacterial
%K acylsulfonamide group
%K acylsulfonamide group functions
%K inhibitor
%X Uridine
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.
%I ACS Publications