Chemistry Weekly Seminar - Dalia Ahmed, PhD Candidate

Title

Inhibitors of UDP-Galactopyranose Mutase from Mycobacterium tuberculosis, a Potential Antimycobacterial Drug Target

Abstract

Mycobacterium tuberculosis, the causative agent of tuberculosis, has developed multiple antibiotic resistance mechanisms against many of the available drugs. Targeting new biosynthetic pathways; therefore, represents a promising therapeutic strategy. UDP-galactopyranose mutase (UGM), an essential enzyme for M. tuberculosis involved in bacterial cell wall synthesis, is not present in mammalian cells, and is thus an attractive potential drug target.

MS208 was previously identified as an allosteric inhibitor of MtUGM. A model, to better understand the binding pattern of MS208 within the allosteric site, is needed for prospective drug design. Attempts to crystallize MS208 with MtUGM were unsuccessful in the lab. As a result, an indirect method to understand how this molecule binds to MtUGM was required. This method involved developing MS208 analogues, testing these analogues for their ability to inhibit MtUGM, and understanding which structural features are important for binding using a preliminary structure activity relationship (SAR).

My research focused on the design, synthesis, and analysis of MS208 analogues. Most of these analogues showed both inhibition against MtUGM, as well as antituberculosis activity. Additionally, the binding assay gave us unexpected results regarding the effect of MS208 on MtUGM. To provide other insights regarding the behavior of MS208 with MtUGM, biophysical techniques, such as DLS and ¹H-NMR, were used. This research produced novel results that provided further understanding to the behaviour of MS208 with MtUGM.

Date:       Friday, February 12, 2021

Time:      1:30 p.m.

Via Zoom video conference (link available by request to chem.dept@usask.ca)