{
  "abstract": "Drug repositioning against bacterial efflux pumps has classically relied on a single criterion: the predicted binding affinity for the target transporter. This approach overlooks a distinct failure modetranscriptional derepression of the pump's own expression, through inhibition of the associated transcriptional regulator. Here we propose a dual-criterion screening protocol, combining (i) a relative selectivity index between affinity for the MexB pump and affinity for its repressor MexR, and (ii) an absolute risk threshold calibrated on a documented derepression inducer (pyocyanin). The method was tested by molecular docking (AutoDock Vina) on 139 compounds spanning four independent chemical families (antidepressants, antipsychotics, H1 antihistamines, phytomolecules), against the MexB (PDB 3W9J) and MexR structures. The ΔG(MexB)–ΔG(MexR) correlation proved robust and generalizable across the four families (r = 0.834–0.924, all p < 10-7 after FDR correction), validated by bootstrap, permutation testing, and leave-one-out analysis. Controlling for molecular weight and LogP across the full dataset (n = 135) confirms a partial but non-exclusive contribution of molecular size to this correlation (partial r = 0.805 vs. raw r = 0.880). The dual-criterion filter revealed that 43.1% of the tested compounds, despite showing a good relative selectivity index, exceed the absolute risk thresholdamong them the historical reference compound PAβN and the previously proposed candidate vilazodone. Ensemble docking on three MexR structures (1LNW, 3ECH, 3MEX), performed on a subset of 14 priority compounds, quantified the associated structural uncertainty (mean standard deviation 0.512 kcal/mol): this test confirms the robustness of vilazodone's at-risk status, but reveals that a candidate initially classified as favorable (mianserin) becomes at-risk once this uncertainty is taken into account. These results indicate that filtering by relative index alone is insufficient to rule out derepression risk, and propose a reproducible methodological framework, including an uncertainty estimate, for drug repositioning in the context of combination therapy.",
  "abstract_shown": true,
  "affiliations": [
    "1Institut Supérieur Mohammed VI de Biosciences et Biotechnologies, Université Mohammed VI des Sciences et de la Santé"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 1,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Divin Stoni MBANIMI",
      "orcid": "0009-0005-7460-9913"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4gyrmn1dmsg95.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15007681/v2",
  "fulltext_url": null,
  "id": "4gyrmn1dmsg95",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007681/v2",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1313|Antibiotic Resistance in Bacteria"
    ]
  ],
  "openalex": "W7205012088",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15007681/v2",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-02",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/4gyrmn1dmsg95.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:17Z",
      "native_id": "10.26434/chemrxiv.15007681",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15007681/v2"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:1313|Antibiotic Resistance in Bacteria",
      "subfield": "general"
    }
  ],
  "title": "Tackling antibiotic resistance: a dual-criterion computational filter for selective MexAB-OprM efflux pump inhibitors",
  "title_text": "Tackling antibiotic resistance: a dual-criterion computational filter for selective MexAB-OprM efflux pump inhibitors",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:17Z",
  "url": "https://research.draconitic.com/paper/4gyrmn1dmsg95",
  "venue": "ChemRxiv",
  "versions": []
}