Innovative chemotherapeutic agents that are active against Mycobacterium tuberculosis (Mtb) are urgently required to control the tuberculosis (TB) epidemic. The Mtb cell envelope has distinct (lipo)polysaccharides and glycolipids that play a critical role in Mtb survival and pathogenesis and disruption of pathways involved in the assembly of the Mtb cell envelope are the primary target of anti-tubercular agents.<br/>Here we introduce multivalent glycan-binding agents, designed to target the unique extracellular glycans of Mtb cell and demonstrate that this is selectively lethal. Using boronic acids, and boroxoles, as the glycan-targetting units we show that multimeric (at least 2) presentation of the boronic acids is essential for activity. The distance between glycan-binding units was also found to be crucial, with longer linkers leading to loss in efficacy compared to shorter. Proteomics suggests a broad stress response, and the divalent agents function by a different mechanism compared to monovalent, which are known as beta-lactamase inhibitors. The agents were found to be selective to Mycobacteria and show low cytotoxicity against mammalian cell lines and no observable resistance was achieved. This non-conventional approach shows that targetting extracellular glycans is a potential new avenue for anti-Mtb agents and removes the challenge associated with designing drugs which permeate the TB cell wall.

Targetting mycobacteria extracellular glycans for selective killing of <i>Mycobacterium tuberculosis</i>

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.

Targetting mycobacteria extracellular glycans for selective killing of Mycobacterium tuberculosis