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

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.

Automated summary

This study reports a multiparameter optimization of a fragment-like hit identified through a structure-based virtual-screening campaign on Escherichia coli IspE crystal structure. The resultant novel class of E. coli IspE inhibitors showed activity against Pseudomonas aeruginosa and Acinetobacter baumannii. However, cytotoxicity still remains a challenge. This research provides insights on 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.