GLYCOSYLTRANSFERASES AS DRUG TARGETS IN MYCOBACTERIA

Southern Research Institute, Birmingham AL

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Abstract

DESCRIPTION: (Adapted from Applicant's Abstract) Mycobacterial cell wall synthesis is a potential point of intervention in mycobacterial pathogenesis. The investigators will design and synthesize inhibitors of mycobacterial enzymes rhap and galf (neither are found in mammalian cells). Specifically, glycosyl donor and acceptor analogs of mycobacterial rhamnosyl- galactosyltransferases that utilize nucleoside diphosphate sugar donors UDP-galactofuranose and TDP-rhamnopyranose. Also, the investigators will make disaccharides that bind and inhibit in the acceptor site of the sugar transferases. These compounds will be screened in vitro using a broth dilution assay and cell-free assay transferase. Selected active compounds will be screened in vitro and in vivo in a macrophage assay and a murine TB model, respectively.