{
  "abstract": "The OXA-48 class D {beta}-lactamase and its variants are clinically concerning through their carbapenemase and cephalosporinase activity. Effective inhibitors are therefore urgently needed. Diazabicyclooctanes (DBOs) are newly introduced non {beta}-lactam based inhibitors, but their potency is affected by mutations, with the more recently developed nacubactam consistently less potent than avibactam, the first DBO, towards OXA-48 variants. This difference is most pronounced for OXA-48 compared to its variants OXA-163 and -405, which contain mutations in the {beta}5-{beta}6 loop and preferentially hydrolyse cephalosporins over carbapenems. Here we use multiscale simulations to uncover the origin of these differences after determining that the second step of DBO acylation is rate-limiting. Using QM/MM MD simulations we show that nacubactam exhibits a consistently higher energy barrier than avibactam for covalent inhibition of OXA-48-like enzymes, a difference attributable to DBO-specific changes in the active site electric field. Simulations of non-covalent complexes further indicate that weaker binding, due to electrostatic repulsion between the positively charged nacubactam tail and Arg214 in the {beta}5-{beta}6 loop, partially explains the lower potency of nacubactam towards OXA-48, compared to OXA-163 and -405. Combining computational predictions of covalent reaction rates and non-covalent binding affinities accurately reproduces the relative order of experimental IC50 values, and predicts potency towards OXA-517, a recently discovered OXA-48 variant capable of hydrolysing many antibiotics. This work provides mechanistic insight into the inhibition of class D {beta}-lactamases and reveals the origins of differential DBO potency towards OXA-48 variants, highlighting how subtle differences between enzymes modulate inhibitory effects.",
  "abstract_shown": true,
  "affiliations": [
    "University of Bristol"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "name": "D. Wang"
    },
    {
      "name": "R. Chahal"
    },
    {
      "name": "V. H. A. Hirvonen"
    },
    {
      "name": "J. Spencer"
    },
    {
      "affs": [
        0
      ],
      "name": "M. W. van der Kamp"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e9v8wm4zng5j1.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.11.04.764282",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764282v1.full",
  "id": "e9v8wm4zng5j1",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764282v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biochemistry"
    ]
  ],
  "openalex": null,
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764282v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-11-04",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/e9v8wm4zng5j1.ris",
  "sources": [
    {
      "first_seen": "2026-11-06T12:21:02Z",
      "native_id": "10.64898/2026.11.04.764282",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.11.04.764282v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biochemistry",
      "subfield": "general"
    }
  ],
  "title": "Active site electrostatic effects modulate DBO inhibitor potency against OXA-48 variants",
  "title_text": "Active site electrostatic effects modulate DBO inhibitor potency against OXA-48 variants",
  "type": "preprint",
  "updated_at": "2026-11-08T00:20:58Z",
  "url": "https://research.draconitic.com/paper/e9v8wm4zng5j1",
  "venue": "bioRxiv",
  "versions": []
}