{
  "abstract": "Trimethoprim–sulfamethoxazole (SXT) remains central to melioidosis eradication therapy, yet the genetic basis of resistance evolution in Burkholderia pseudomallei is not fully defined. Using Burkholderia thailandensis as a biosafe surrogate, we subjected populations to stepwise in vitro evolution under increasing SXT concentrations. Whole-genome sequencing revealed rapid population diversification followed by selective sweeps leading to fixation of fitter resistant variants. Early adaptation involved mutations in regulators of RND efflux systems and folate-associated genes, consistent with multifactorial resistance. Despite this heterogeneity, all evolutionary trajectories converged on a single nonsynonymous substitution, I99L, in dihydrofolate reductase (DHFR/FolA), which rose to fixation at high SXT concentrations. This substitution mirrors changes reported in SXT-resistant B. pseudomallei isolates from chronic infections. Allelic reconstruction demonstrated that Bt-DHFR(I99L) is sufficient to confer a 4- to 16-fold increase in trimethoprim MIC. Biochemical and structural analyses showed preserved catalytic activity but reduced trimethoprim binding, consistent with an allosteric resistance mechanism. Together, these findings establish DHFR as a dominant evolutionary target under SXT pressure and support B. thailandensis as a robust model for dissecting resistance evolution in B. pseudomallei.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 12,
  "authors": [
    {
      "name": "Sophie Guillier"
    },
    {
      "name": "Christine Lazennec-Schurdevin"
    },
    {
      "name": "Lou Mondange"
    },
    {
      "name": "Véronique Sarilar"
    },
    {
      "name": "Mélissa Marchandeau"
    },
    {
      "name": "Chloé Lemoigne"
    },
    {
      "name": "Ombeline Lamer"
    },
    {
      "name": "Mathilde Lescat"
    },
    {
      "name": "Emmanuelle Schmitt"
    },
    {
      "name": "Yves Mechulam"
    },
    {
      "name": "Julian Garrec"
    },
    {
      "name": "Fabrice Biot"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7k4cvb1c133vx.bib",
  "cited_by": 0,
  "doi": "10.1021/acsinfecdis.5c01132",
  "fulltext_url": null,
  "id": "7k4cvb1c133vx",
  "issns": [
    "2373-8227"
  ],
  "landing_url": "https://polytechnique.hal.science/hal-05768761v1",
  "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.sdv"
    ],
    [
      "openalex",
      "2713|Burkholderia infections and melioidosis"
    ]
  ],
  "openalex": "W7172488204",
  "pdf_url": "https://polytechnique.hal.science/hal-05768761/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-08-05",
  "publisher": "American Chemical Society",
  "ris": "https://research.draconitic.com/paper/7k4cvb1c133vx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:43Z",
      "native_id": "hal-05768761",
      "source": "hal",
      "url": "https://polytechnique.hal.science/hal-05768761v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2713|Burkholderia infections and melioidosis",
      "subfield": "epidemiology-public-health"
    }
  ],
  "title": "Evolutionary Convergence on a Dihydrofolate Reductase Mutation Drives Trimethoprim–Sulfamethoxazole Resistance in Burkholderia thailandensis",
  "title_text": "Evolutionary Convergence on a Dihydrofolate Reductase Mutation Drives Trimethoprim–Sulfamethoxazole Resistance in Burkholderia thailandensis",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:43Z",
  "url": "https://research.draconitic.com/paper/7k4cvb1c133vx",
  "venue": "ACS Infectious Diseases",
  "versions": []
}