LY2183240 regioisomers act as competitive and selective inhibitors of class C β-lactamases

Pedro Ernesto de Resende; Sarah Soares; Mire Zloh; Simon Gibbons; Paul Stapleton

doi:10.1016/j.ijantimicag.2023.106774

LY2183240 regioisomers act as competitive and selective inhibitors of class C β-lactamases

Int J Antimicrob Agents. 2023 May;61(5):106774. doi: 10.1016/j.ijantimicag.2023.106774. Epub 2023 Mar 7.

Authors

Pedro Ernesto de Resende¹, Sarah Soares², Mire Zloh², Simon Gibbons³, Paul Stapleton²

Affiliations

¹ UCL School of Pharmacy, Research Department of Pharmaceutical and Biological Chemistry, University College London, London, UK. Electronic address: pedroderesende@gmail.com.
² UCL School of Pharmacy, Research Department of Pharmaceutical and Biological Chemistry, University College London, London, UK.
³ UCL School of Pharmacy, Research Department of Pharmaceutical and Biological Chemistry, University College London, London, UK; Centre for Natural Products Discovery, Liverpool John Moores University, Liverpool, UK.

PMID: 36893812
DOI: 10.1016/j.ijantimicag.2023.106774

Abstract

The regioisomers of the anandamide-acting drug LY2183240 exhibited specific potent and competitive inhibitory activities against class C β-lactamases. More explicitly, the 1,5- and 2,5-regioisomers inhibited AmpC from Enterobacter hormaechei (formerly Enterobacter cloacae) with inhibitor binding affinity values of 1.8 µM and 2.45 µM, respectively. Structural molecular modelling studies revealed the interaction of the regioisomers with the relevant residues of the catalytic site of cephalosporinase from E. hormaechei P99, which included Tyr¹⁵⁰, Lys³¹⁵ and Thr³¹⁶.

Keywords: Antimicrobial resistance; Competitive inhibitor; LY2183240; Tetrazole; β-lactamases.

MeSH terms

Cephalosporinase*
Enterobacter cloacae / metabolism
Heterocyclic Compounds, 1-Ring
beta-Lactamases* / metabolism

Substances

beta-Lactamases
LY2183240
Cephalosporinase
Heterocyclic Compounds, 1-Ring