Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds
Abstract
The rise of antimicrobial resistance and the limited pipeline of new antibiotics necessitate innovative strategies, such as targeting bacterial virulence factors. Pseudomonas aeruginosa, a high-priority pathogen, relies on virulence factors like elastase B (LasB) to subvert host defense and cause severe infections. Here, we report the optimisation of a new class of phosphonate-based N-aryl-pyrrolidone inhibitors designed to rigidify the scaffold, enhance chemical stability and preserve efficient zinc coordination. Systematic optimisation of the zinc-binding group (ZBG) and scaffold extension led to the identification of compound 20a, which exhibits submicromolar LasB inhibition (IC₅₀ = 0.31 µM), high selectivity over human metalloproteases and good metabolic stability. Co-crystallisation with LasB confirmed the binding mode, revealing key interactions in the S1' and S2' pockets. In vivo, 20a significantly improved survival in a Galleria mellonella infection model, validating its potential as an antivirulence agent. This study establishes phosphonate pyrrolidones as a scalable and chemically stable framework for LasB inhibition, offering a promising lead series for combating P. aeruginosa infections.
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BibTeX
@misc{jezequel2026stable,
title = {{Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds}},
author = {Gwenaëlle Jézéquel and Dominik Kolling and Roya Shafiei and Katharina Rox and Andreas M Kany and Jesko Koehnke and Jörg Haupenthal and Anna K H Hirsch},
howpublished = {HAL},
year = {2026},
month = aug,
doi = {10.26434/chemrxiv.15007028/v2},
url = {https://hal.science/hal-05770227v1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - UNPB
TI - Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds
AU - Gwenaëlle Jézéquel
AU - Dominik Kolling
AU - Roya Shafiei
AU - Katharina Rox
AU - Andreas M Kany
AU - Jesko Koehnke
AU - Jörg Haupenthal
AU - Anna K H Hirsch
PY - 2026
DA - 2026/08/20
PB - HAL
DO - 10.26434/chemrxiv.15007028/v2
UR - https://hal.science/hal-05770227v1
AB - The rise of antimicrobial resistance and the limited pipeline of new antibiotics necessitate innovative strategies, such as targeting bacterial virulence factors. Pseudomonas aeruginosa, a high-priority pathogen, relies on virulence factors like elastase B (LasB) to subvert host defense and cause severe infections. Here, we report the optimisation of a new class of phosphonate-based N-aryl-pyrrolidone inhibitors designed to rigidify the scaffold, enhance chemical stability and preserve efficient zinc coordination. Systematic optimisation of the zinc-binding group (ZBG) and scaffold extension led to the identification of compound 20a, which exhibits submicromolar LasB inhibition (IC₅₀ = 0.31 µM), high selectivity over human metalloproteases and good metabolic stability. Co-crystallisation with LasB confirmed the binding mode, revealing key interactions in the S1' and S2' pockets. In vivo, 20a significantly improved survival in a Galleria mellonella infection model, validating its potential as an antivirulence agent. This study establishes phosphonate pyrrolidones as a scalable and chemically stable framework for LasB inhibition, offering a promising lead series for combating P. aeruginosa infections.
ER -