Issue 23, 2019

Targeting extracellular glycans: tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis

Abstract

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. Here we introduce a previously unexplored approach whereby chemical agents directly target the extracellular glycans within the unique Mtb cell envelope, rather than the intracellular biosynthetic machinery. We designed and synthesised multimeric boronic acids that are selectively lethal to Mtb and function by targeting these structurally unique and essential Mtb cell envelope glycans. By tuning the number of, and distance between, boronic acid units high selectivity to Mtb, low cytotoxicity against mammalian cells and no observable resistance was achieved. This non-conventional approach may prevent the development of drug-resistance and will act as a platform for the design of improved, pathogen-specific, next generation antibiotics.

Graphical abstract: Targeting extracellular glycans: tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis

Supplementary files

Article information

Article type
Edge Article
Submitted
24 janv. 2019
Accepted
03 mai 2019
First published
16 mai 2019
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2019,10, 5935-5942

Targeting extracellular glycans: tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis

C. S. Guy, M. I. Gibson and E. Fullam, Chem. Sci., 2019, 10, 5935 DOI: 10.1039/C9SC00415G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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