Design and optimization of simplified inhibitors targeting Escherichia coli and Klebsiella pneumoniae IspE

RSC Medicinal Chemistry 2026 Open access

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Authors: Danica J. Walsh, Rawia A. A. Hamid, Tim Giele, Norbert Reiling, Matthias Rottmann, Mostafa M. Hamed, Anna K. H. Hirsch
DOI: 10.1039/d5md00874c
Cited by: 1
References: 11

Abstract

IspE revealed several low-micromolar inhibitors, confirming the predicted binding interactions. Structure-activity relationships indicated that the hydrophobic pocket adjacent to the cytidine-binding region is a key determinant of potency. Although the compounds showed limited whole-cell activity, these results demonstrate that simplified amide analogues can effectively engage the IspE active site and highlight the importance of the hydrophobic pocket in ligand binding. Overall, this work combines structure-based design, synthesis, and biochemical validation to provide a foundation for further optimization of simplified IspE inhibitors as potential antibacterial leads.

Fields of Study & Subjects

Plant biochemistry and biosynthesis ATP Synthase and ATPases Research Microbial Natural Products and Biosynthesis

Publication details

Journal / source
RSC Medicinal Chemistry
Publisher
Royal Society of Chemistry (RSC)
Volume
17
Issue
3
Pages
1687–1693
Publication date
1 January 2026
Language
EN