The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening

Peter Vella; Waleed M. Hussein; Eleanor W.W. Leung; Daniel Clayton; David L. Ollis; Nataša Mitić; Gerhard Schenk; Ross P. McGeary

doi:10.1016/j.bmcl.2011.04.027

The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening

Peter Vella, Waleed M. Hussein, Eleanor W.W. Leung, Daniel Clayton, David L. Ollis, Nataša Mitić, Gerhard Schenk^*, Ross P. McGeary

^*Corresponding author for this work

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

68 Citations (SciVal)

Abstract

The emergence of metallo-β-lactamases (MBLs) capable of hydrolysing a broad spectrum of β-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound Maybridge™ library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies.

Original language	English
Pages (from-to)	3282-3285
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	21
Issue number	11
DOIs	https://doi.org/10.1016/j.bmcl.2011.04.027
Publication status	Published - 1 Jun 2011

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10.1016/j.bmcl.2011.04.027

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abstract = "The emergence of metallo-β-lactamases (MBLs) capable of hydrolysing a broad spectrum of β-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound Maybridge{\texttrademark} library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies.",

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AU - Vella, Peter

AU - Hussein, Waleed M.

AU - Leung, Eleanor W.W.

AU - Clayton, Daniel

AU - Ollis, David L.

AU - Mitić, Nataša

AU - Schenk, Gerhard

AU - McGeary, Ross P.

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AB - The emergence of metallo-β-lactamases (MBLs) capable of hydrolysing a broad spectrum of β-lactam antibiotics is particularly concerning for the future treatment of bacterial infections. This work describes the discovery of lead compounds for the development of new inhibitors using a competitive colorimetric assay based on the chromogenic cephalosporin CENTA, and a 500 compound Maybridge™ library suitable for fragment-based screening. The interactions between identified inhibitory fragments and the active site of the MBL from Klebsiella pneumoniae and Pseudomonas aeruginosa were probed by in silico docking studies.

KW - Antibiotics resistance

KW - Fragment-based screening

KW - Inhibition assays

KW - Metallo-β-lactamases

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JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

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The identification of new metallo-β-lactamase inhibitor leads from fragment-based screening

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