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Targeting extracellular glycans : tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis
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Guy, Collette S., Gibson, Matthew I. and Fullam, Elizabeth (2019) Targeting extracellular glycans : tuning multimeric boronic acids for pathogen-selective killing of Mycobacterium tuberculosis. Chemical Science, 10 (23). 5935-5942 . doi:10.1039/C9SC00415G ISSN 2041-6520.
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WRAP-targeting-extracellular-glycans-tuning-multimeric-boronic-acids-pathogen-selective-killing-Mycobacterium-tuberculosis-Guy-2019.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution. Download (1028Kb) | Preview |
Official URL: http://dx.doi.org/10.1039/C9SC00415G
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.
| Item Type: | Journal Article | |||||||||||||||
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| Subjects: | Q Science > QD Chemistry Q Science > QR Microbiology |
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| Divisions: | Faculty of Science, Engineering and Medicine > Science > Chemistry Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Library of Congress Subject Headings (LCSH): | Mycobacterium tuberculosis, Boronic esters | |||||||||||||||
| Journal or Publication Title: | Chemical Science | |||||||||||||||
| Publisher: | Royal Society of Chemistry | |||||||||||||||
| ISSN: | 2041-6520 | |||||||||||||||
| Official Date: | 21 June 2019 | |||||||||||||||
| Dates: |
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| Volume: | 10 | |||||||||||||||
| Number: | 23 | |||||||||||||||
| Page Range: | 5935-5942 | |||||||||||||||
| DOI: | 10.1039/C9SC00415G | |||||||||||||||
| Status: | Peer Reviewed | |||||||||||||||
| Publication Status: | Published | |||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | |||||||||||||||
| Date of first compliant deposit: | 21 May 2019 | |||||||||||||||
| Date of first compliant Open Access: | 22 May 2019 | |||||||||||||||
| RIOXX Funder/Project Grant: |
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