{
  "abstract": "Isoniazid remains a cornerstone of tuberculosis therapy, yet resistance-associated mutations in its target, InhA, are not fully explained by reduced NADH binding alone. Here, we combine X-ray crystallography, cryo-electron microscopy, calorimetry, thermal stability profiling, and multi-scale molecular dynamics to dissect ten clinically observed InhA missense variants. The structures show that many substitutions preserve the canonical cofactor-bound architecture, but thermodynamic and simulation analyses reveal divergent routes to resistance. Active-site variants remodel water and hydrophobic networks to weaken NADH binding, whereas I95P and several interface-proximal variants populate a coenzyme closed-loop state that occludes the nicotinamide/adduct-binding pocket. A190S and Y259H instead appear to preserve NADH affinity while rigidifying the Phe149-Asp150 region required to accommodate the larger INH-NAD adduct. These findings establish InhA coding-region resistance as a spectrum of local, allosteric, and adduct-selective mechanisms, providing a framework for interpreting clinical variants and designing next-generation InhA inhibitors.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "Nicolas de Oliveira Rossini"
    },
    {
      "name": "Sair Máximo Chavéz-Pacheco"
    },
    {
      "name": "Gerardo Andrés Libreros-Zúñiga"
    },
    {
      "name": "Stephanie Portelli"
    },
    {
      "name": "Jademilson Celestino dos Santos"
    },
    {
      "name": "Douglas Eduardo Valente Pires"
    },
    {
      "name": "David B Ascher"
    },
    {
      "name": "Pierre-Damien Coureux"
    },
    {
      "name": "Paulo Cesar Telles de Souza"
    },
    {
      "name": "Marcio Vinicius Bertacine Dias"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7c93ny7bf31h0.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15004869/v1",
  "fulltext_url": null,
  "id": "7c93ny7bf31h0",
  "issns": [],
  "landing_url": "https://hal.science/hal-05787659v1",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "hal",
      "0.chim"
    ],
    [
      "hal",
      "0.info"
    ],
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.chim.theo"
    ],
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      "hal",
      "1.info.info-mo"
    ],
    [
      "hal",
      "1.sdv.bbm"
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    [
      "hal",
      "1.sdv.mp"
    ],
    [
      "hal",
      "2.sdv.bbm.bs"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ]
  ],
  "openalex": "W7165004950",
  "pdf_url": "https://hal.science/hal-05787659/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-06-17",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/7c93ny7bf31h0.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:51Z",
      "native_id": "hal-05787659",
      "source": "hal",
      "url": "https://hal.science/hal-05787659v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "hal:2.sdv.bbm.bs",
      "subfield": "structural-biology"
    },
    {
      "field": "biology",
      "origin": "hal:1.sdv.mp",
      "subfield": "microbiology"
    },
    {
      "field": "chemistry",
      "origin": "hal:1.chim.theo",
      "subfield": "theoretical"
    }
  ],
  "title": "Dynamic closure of the Mycobacterium tuberculosis InhA cofactor site reveals heterogeneous routes to isoniazid resistance",
  "title_text": "Dynamic closure of the Mycobacterium tuberculosis InhA cofactor site reveals heterogeneous routes to isoniazid resistance",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:51Z",
  "url": "https://research.draconitic.com/paper/7c93ny7bf31h0",
  "venue": "HAL",
  "versions": []
}