{
  "abstract": "Multidrug-resistant (MDR), ESBL- and carbapenemase-producing Enterobacterales represent a major global health concern requiring novel therapeutic strategies. One promising approach is the development of efflux pump inhibitors (EPIs) targeting the predominant AcrAB-TolC system to sensitize these pathogens to antibiotics predominantly used for Gram-positive infections. PyridylPiperazine (PyrPip)-based EPIs are novel allosteric AcrB inhibitors that block antibiotic efflux in Enterobacterales. Medicinal chemistry optimization identified BDM100004 ( 3 ), an alkyne-modified PyrPip analog with improved drug-like properties. In vitro susceptibility profiling of 48 clinical MDR Klebsiella pneumoniae isolates showed that BDM100004 ( 3 ) potentiated macrolide activity in most MDR isolates, with particularly strong effects observed for azithromycin. A small fraction of MDR isolates was found to be highly resistant to macrolides, and poorly potentiated by BDM100004 ( 3 ). Genome analysis revealed these isolates to carry specific macrolide resistance genes, and together with reverse genetics, it was validated that BDM100004 ( 3 ) could not reverse Mph(A) and Mph(E) mediated azithromycin resistance. Interestingly, however, BDM100004 ( 3 ) was found to overcome azithromycin resistance mediated by Erm(B), Msr(E) and Mrx. In vivo, BDM100004 ( 3 ) enhanced azithromycin efficacy both in a Galleria mellonella infection model and in a murine lung infection model of K. pneumoniae . Overall, these findings demonstrate the potential of a PyrPip EPI to repurpose azithromycin against ESBL- and carbapenemase-producing K. pneumoniae with limitations in mph(A) and mph(E) -expressing strains.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "name": "Cécilia Sobieski"
    },
    {
      "name": "Virginie Meurillon"
    },
    {
      "name": "Jonathan Chatagnon"
    },
    {
      "name": "Rodolphe Vatinel"
    },
    {
      "name": "Elizabeth Pradel"
    },
    {
      "name": "Gabriele Lucca"
    },
    {
      "name": "Lea Lebre"
    },
    {
      "name": "Delphine Cayet"
    },
    {
      "name": "Reinke Müller"
    },
    {
      "name": "Catherine Piveteau"
    },
    {
      "name": "Julie Dumont"
    },
    {
      "name": "Florence Leroux"
    },
    {
      "name": "Klaas Pos"
    },
    {
      "name": "Benoit Deprez"
    },
    {
      "name": "Nicolas Willand"
    },
    {
      "name": "Richard Bonnet"
    },
    {
      "name": "Laurye van Maele"
    },
    {
      "name": "Marion Flipo"
    },
    {
      "name": "Ruben C. Hartkoorn"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/e7fta7yv67ht9.bib",
  "cited_by": 0,
  "doi": "10.1038/s44259-026-00263-y",
  "fulltext_url": null,
  "id": "e7fta7yv67ht9",
  "issns": [
    "2731-8745"
  ],
  "landing_url": "https://hal.science/hal-05780372v1",
  "language": "en",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.chim"
    ],
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.chim.ther"
    ],
    [
      "hal",
      "1.sdv.mhep"
    ],
    [
      "openalex",
      "1313|Antibiotic Resistance in Bacteria"
    ]
  ],
  "openalex": "W7204842125",
  "pdf_url": "https://www.nature.com/articles/s44259-026-00263-y_reference.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-31",
  "publisher": "Springer Nature",
  "ris": "https://research.draconitic.com/paper/e7fta7yv67ht9.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:48Z",
      "native_id": "hal-05780372",
      "source": "hal",
      "url": "https://hal.science/hal-05780372v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "hal:0.sdv",
      "subfield": "general"
    },
    {
      "field": "chemistry",
      "origin": "hal:1.chim.ther",
      "subfield": "medicinal"
    },
    {
      "field": "medicine",
      "origin": "hal:1.sdv.mhep",
      "subfield": "general"
    }
  ],
  "title": "Optimized alkyne-modified pyridylpiperazine efflux pump inhibitors overcome intrinsic macrolide resistance in multidrug-resistant Klebsiella pneumoniae isolates",
  "title_text": "Optimized alkyne-modified pyridylpiperazine efflux pump inhibitors overcome intrinsic macrolide resistance in multidrug-resistant Klebsiella pneumoniae isolates",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:48Z",
  "url": "https://research.draconitic.com/paper/e7fta7yv67ht9",
  "venue": "npj Antimicrobials and Resistance",
  "versions": []
}