{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 8,
  "authors": [
    {
      "name": "Gwenaëlle Jézéquel"
    },
    {
      "name": "Dominik Kolling"
    },
    {
      "name": "Roya Shafiei"
    },
    {
      "name": "Katharina Rox"
    },
    {
      "name": "Andreas M Kany"
    },
    {
      "name": "Jesko Koehnke"
    },
    {
      "name": "Jörg Haupenthal"
    },
    {
      "name": "Anna K H Hirsch"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/cfc6h765dptfn.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15007028/v2",
  "fulltext_url": null,
  "id": "cfc6h765dptfn",
  "issns": [],
  "landing_url": "https://hal.science/hal-05770227v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.chim"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://hal.science/hal-05770227/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-20",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/cfc6h765dptfn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "hal-05770227",
      "source": "hal",
      "url": "https://hal.science/hal-05770227v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "hal:0.chim",
      "subfield": "general"
    }
  ],
  "title": "Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds",
  "title_text": "Stable Phosphonate Inhibitors of Elastase LasB Suppress Pseudomonas aeruginosa Virulence via Zinc-Targeting Pyrrolidone Scaffolds",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/cfc6h765dptfn",
  "venue": "HAL",
  "versions": []
}