Carboxylate Surrogates Enhance the Antimycobacterial Activity of UDP-Galactopyranose Mutase Probes Valerie J. Winton Claudia Aldrich Laura L. Kiessling 10.1021/acsinfecdis.6b00021.s001 https://acs.figshare.com/articles/journal_contribution/Carboxylate_Surrogates_Enhance_the_Antimycobacterial_Activity_of_UDP-Galactopyranose_Mutase_Probes/3545994 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 mimican <i>N</i>-acylsulfonamide group. We therefore synthesized a series of <i>N</i>-acylsulfonamide analogs and tested their ability to inhibit UGM. For each inhibitor scaffold tested, the <i>N</i>-acylsulfonamide group functions as an effective carboxylate surrogate. Although the carboxylates and their surrogates show similar activity against UGM in a test tube, several <i>N</i>-acylsulfonamide derivatives more effectively block the growth of <i>Mycobacterium smegmatis</i>. These data suggest that the replacement of a carboxylate with an <i>N</i>-acylsulfonamide group could serve as a general strategy to augment antimycobacterial activity. 2016-06-16 00:00:00 mycobacterial cell envelope polysaccharide Carboxylate Surrogates Enhance UGM carboxylate potency antimycobacterial acylsulfonamide group acylsulfonamide group functions inhibitor