Small molecule probes of mycobacterial cell wall assembly

Abstract

Carbohydrates mediate fundamental processes in humans; they also can be essential for pathogen survival. For example, oligosaccharides serve as essential components of the mycobacterial cell wall. Agents that inhibit key biosynthetic steps in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), would be valuable, because TB results in approximately 2 million deaths/year. A key component of the mycobacterial cell wall is the arabinogalactan polysaccharide, which contains galactofuranose (Galf) residues. Because Galf residues are not constituents of human glycoproteins or glycolipids, we have focused on understanding galactofuranose incorporation. To this end, we have discovered a fundamentally new catalytic role for the heterocyclic cofactor flavin (vitamin B2), and we have found that an essential glycosyltransferase mediates oligosaccharide assembly by a processive mechanism. Moreover, we have discovered small molecule inhibitors of galactofuranose incorporation. Small molecules targeting this pathway block mycobacterial growth, a result that highlights the benefits of blocking this glycoconjugate biosynthetic pathway. We anticipate that these inhibitors can illuminate carbohydrate function and lead to the generation of therapeutics effective against strains resistant to current anti‐mycobacterial agents. This research was supported by the National Institute of Allergy and Infectious Diseases.