A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

Michael J. Austin; Stephen J. Hearnshaw; Lesley A. Mitchenall; Paul J. McDermott; Lesley A. Howell; Anthony Maxwell; Mark Searcey

doi:10.1039/C6MD00229C

A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

Michael J. Austin, Stephen J. Hearnshaw, Lesley A. Mitchenall, Paul J. McDermott, Lesley A. Howell, Anthony Maxwell, Mark Searcey

Research output: Contribution to journal › Article › peer-review

14 Citations (Scopus)

28 Downloads (Pure)

Abstract

The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is of vital importance. The natural product simocyclinone D8 (SD8) is a potent inhibitor of DNA gyrase. Its bi-functional structure and novel mode of action serve as an inspiring lead for antibiotic development. Herein we describe a proof of principle fragment-based approach towards the development of a new class of coumarin-quinolone hybrids. We demonstrate that the coumarin moiety is required for the observed inhibitory activity (IC50 ~3 M) of the hybrid compound, which is in part mediated through stabilisation of a cleaved-DNA intermediate.

Original language	English
Pages (from-to)	1387-1391
Number of pages	5
Journal	MedChemComm
Volume	7
Issue number	7
Early online date	18 May 2016
DOIs	https://doi.org/10.1039/C6MD00229C
Publication status	Published - 1 Jul 2016

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10.1039/C6MD00229C

Searcey MedChemComm SD8 2016Accepted author manuscript, 985 KB

Mark Searcey
- M.Searceyuea.acuk
- School of Chemistry, Pharmacy and Pharmacology - Pro-Vice-Chancellor
- Synthetic and Medicinal Chemistry - Member
Person: Research Group Member, Research Centre Member, Academic, Teaching and Research

Cite this

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abstract = "The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is of vital importance. The natural product simocyclinone D8 (SD8) is a potent inhibitor of DNA gyrase. Its bi-functional structure and novel mode of action serve as an inspiring lead for antibiotic development. Herein we describe a proof of principle fragment-based approach towards the development of a new class of coumarin-quinolone hybrids. We demonstrate that the coumarin moiety is required for the observed inhibitory activity (IC50 ~3 M) of the hybrid compound, which is in part mediated through stabilisation of a cleaved-DNA intermediate.",

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AU - Mitchenall, Lesley A.

AU - McDermott, Paul J.

AU - Howell, Lesley A.

AU - Maxwell, Anthony

AU - Searcey, Mark

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AB - The discovery of new antibiotics with novel modes of action to combat antimicrobial resistance (AMR) is of vital importance. The natural product simocyclinone D8 (SD8) is a potent inhibitor of DNA gyrase. Its bi-functional structure and novel mode of action serve as an inspiring lead for antibiotic development. Herein we describe a proof of principle fragment-based approach towards the development of a new class of coumarin-quinolone hybrids. We demonstrate that the coumarin moiety is required for the observed inhibitory activity (IC50 ~3 M) of the hybrid compound, which is in part mediated through stabilisation of a cleaved-DNA intermediate.

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A natural product inspired fragment-based approach towards the development of novel anti-bacterial agents

Abstract

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Mark Searcey

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