Discovery of novel antibiotics needs multidisciplinary approaches to gain target enzyme and bacterial activities while aiming for selectivity over mammalian cells. Here, we report a multiparameter optimisation of a fragment-like hit that was identified through a structure-based virtual-screening campaign on Escherichia coli IspE crystal structure. Subsequent medicinal-chemistry design resulted in a novel class of E. coli IspE inhibitors, exhibiting activity also against the more pathogenic bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. While cytotoxicity remains a challenge for the series, it provides new insights on the molecular properties for balancing enzymatic target and bacterial activities simultaneously as well as new starting points for the development of IspE inhibitors with a predicted new mode of action.

Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors / Ropponen, Henni-Karoliina; Diamanti, Eleonora; Johannsen, Sandra; Illarionov, Boris; Hamid, Rawia; Jaki, Miriam; Sass, Peter; Fischer, Markus; Haupenthal, Jörg; Hirsch, Anna K H. - In: CHEMMEDCHEM. - ISSN 1860-7179. - ELETTRONICO. - 18:19(2023), pp. e202300346-1. [10.1002/cmdc.202300346]

Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors

Diamanti, Eleonora;
2023

Abstract

Discovery of novel antibiotics needs multidisciplinary approaches to gain target enzyme and bacterial activities while aiming for selectivity over mammalian cells. Here, we report a multiparameter optimisation of a fragment-like hit that was identified through a structure-based virtual-screening campaign on Escherichia coli IspE crystal structure. Subsequent medicinal-chemistry design resulted in a novel class of E. coli IspE inhibitors, exhibiting activity also against the more pathogenic bacteria Pseudomonas aeruginosa and Acinetobacter baumannii. While cytotoxicity remains a challenge for the series, it provides new insights on the molecular properties for balancing enzymatic target and bacterial activities simultaneously as well as new starting points for the development of IspE inhibitors with a predicted new mode of action.
2023
Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors / Ropponen, Henni-Karoliina; Diamanti, Eleonora; Johannsen, Sandra; Illarionov, Boris; Hamid, Rawia; Jaki, Miriam; Sass, Peter; Fischer, Markus; Haupenthal, Jörg; Hirsch, Anna K H. - In: CHEMMEDCHEM. - ISSN 1860-7179. - ELETTRONICO. - 18:19(2023), pp. e202300346-1. [10.1002/cmdc.202300346]
Ropponen, Henni-Karoliina; Diamanti, Eleonora; Johannsen, Sandra; Illarionov, Boris; Hamid, Rawia; Jaki, Miriam; Sass, Peter; Fischer, Markus; Haupenthal, Jörg; Hirsch, Anna K H
File in questo prodotto:
File Dimensione Formato  
ChemMedChem - 2023 - Ropponen - Exploring the Translational Gap of a Novel Class of Escherichia coli IspE Inhibitors.pdf

accesso aperto

Tipo: Versione (PDF) editoriale
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione 1.24 MB
Formato Adobe PDF
1.24 MB Adobe PDF Visualizza/Apri
downloadSupplement.pdf

accesso aperto

Descrizione: Supporting information
Tipo: File Supplementare
Licenza: Licenza per Accesso Aperto. Creative Commons Attribuzione (CCBY)
Dimensione 5.66 MB
Formato Adobe PDF
5.66 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/952644
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 0
  • ???jsp.display-item.citation.isi??? 0
social impact