{
  "abstract": "Mycobacterium tuberculosis (Mtb) cultured in minimal medium at acidic pH arrests growth when provided specific single carbon sources, including glycerol, propionate, and lactate, a phenomenon we refer to as acid growth arrest. To define the mechanisms of acid growth arrest on lactate, we selected transposon mutants that grew under these conditions. Five mutants carried insertions in phoT or pstC2, which encode components of a phosphate ABC transporter. Depleting phosphate restored Mtb growth in minimal medium supplemented with lactate at acidic pH, demonstrating that growth arrest on lactate depended on phosphate. The combination of lactate and phosphate at acidic pH acidified the cytoplasm to below pH 6.7, whereas the phoT mutant maintained a cytoplasmic pH > 7.2. Lactate slightly increased membrane potential in wild-type Mtb, whereas the phoT mutant maintained a higher membrane potential. Transcriptional profiling identified a lactate-associated PMF stress signature, including upregulation of electron transport chain genes. Together, these findings associate lactate- and phosphate-dependent cytoplasmic acidification with proton motive force (PMF) stress and acid growth arrest. The phoT mutant grown in lactate at acidic pH upregulated the senX3/regX3 regulon. Using a regX3 mutant, we found that growth on lactate under low-phosphate conditions required regX3. We propose a model in which (1) acidic pH, lactate, and phosphate together modulate cytoplasmic pH homeostasis and are associated with PMF stress and acid growth arrest; and (2) low phosphate induces SenX3-RegX3 activity, which may alter cell-envelope physiology through ESX-5- and PE/PPE-dependent pathways and promote growth on lactate at acidic pH. Author summary: Mycobacterium tuberculosis (Mtb) grows well on lactate as a sole carbon source at neutral pH but not at acidic pH. This study investigated the basis of this pH-dependent growth restriction. A genetic selection for mutants that grew on lactate at acidic pH identified insertions in genes encoding phosphate-transporter components. We found that depleting extracellular phosphate or disrupting a phosphate-transporter component promoted growth on lactate at acidic pH and that this growth required the phosphate-responsive two-component regulatory system SenX3-RegX3. We further found that lactate, phosphate, and acidic pH acted together to acidify the cytoplasm, a metabolic stress associated with acid growth arrest on lactate.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Microbiology, Genetics, and Immunology, Michigan State University, East Lansing, Michigan, United States of America",
    "Department of Microbiology and Immunology, University of Minnesota, Minneapolis, United States of America"
  ],
  "article_type": "Research Article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Adam P. Kibiloski",
      "orcid": "0009-0001-2506-7610"
    },
    {
      "affs": [
        0
      ],
      "name": "Shelby J. Dechow"
    },
    {
      "affs": [
        0
      ],
      "name": "Bassel J. Abdalla",
      "orcid": "0009-0003-9158-6552"
    },
    {
      "affs": [
        0
      ],
      "name": "Heather M. Murdoch"
    },
    {
      "affs": [
        1
      ],
      "name": "Anna D. Tischler",
      "orcid": "0000-0001-8404-0250"
    },
    {
      "affs": [
        0
      ],
      "name": "Robert B. Abramovitch",
      "orcid": "0000-0002-4119-4169"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/006bg8r0nx1rn.bib",
  "cited_by": 0,
  "doi": "10.1371/journal.pgen.1012331",
  "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012331",
  "id": "006bg8r0nx1rn",
  "issns": [
    "1553-7404",
    "1553-7390"
  ],
  "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012331",
  "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": [
    [
      "heading",
      "Acids"
    ],
    [
      "heading",
      "Actinobacteria"
    ],
    [
      "heading",
      "Bacteria"
    ],
    [
      "heading",
      "Biology and Life Sciences"
    ],
    [
      "heading",
      "Chemical Compounds"
    ],
    [
      "heading",
      "Chemistry"
    ],
    [
      "heading",
      "Electrophysiology"
    ],
    [
      "heading",
      "Gene Expression"
    ],
    [
      "heading",
      "Gene Regulation"
    ],
    [
      "heading",
      "Genetic Elements"
    ],
    [
      "heading",
      "Genetics"
    ],
    [
      "heading",
      "Genomics"
    ],
    [
      "heading",
      "Glycerol"
    ],
    [
      "heading",
      "Ketones"
    ],
    [
      "heading",
      "Membrane Potential"
    ],
    [
      "heading",
      "Mobile Genetic Elements"
    ],
    [
      "heading",
      "Monomers"
    ],
    [
      "heading",
      "Mycobacterium Tuberculosis"
    ],
    [
      "heading",
      "Organisms"
    ],
    [
      "heading",
      "Phosphates"
    ],
    [
      "heading",
      "Physical Sciences"
    ],
    [
      "heading",
      "Physiology"
    ],
    [
      "heading",
      "Polymer Chemistry"
    ],
    [
      "heading",
      "Propionates"
    ],
    [
      "heading",
      "Pyruvate"
    ],
    [
      "heading",
      "Research Article"
    ],
    [
      "heading",
      "Transposable Elements"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Gene expression/Gene regulation"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genetic elements/Mobile genetic elements/Transposable elements"
    ],
    [
      "plos",
      "/Biology and life sciences/Genetics/Genomics/Mobile genetic elements/Transposable elements"
    ],
    [
      "plos",
      "/Biology and life sciences/Organisms/Bacteria/Actinobacteria/Mycobacterium tuberculosis"
    ],
    [
      "plos",
      "/Biology and life sciences/Physiology/Electrophysiology/Membrane potential"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Acids/Ketones/Pyruvate"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Phosphates"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Chemical compounds/Propionates"
    ],
    [
      "plos",
      "/Physical sciences/Chemistry/Polymer chemistry/Monomers/Glycerol"
    ]
  ],
  "openalex": "W7221089949",
  "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012331&type=printable",
  "pmcid": "PMC13716317",
  "pmid": "42853884",
  "published": "2026-10-09",
  "publisher": "Public Library of Science",
  "ris": "https://research.draconitic.com/paper/006bg8r0nx1rn.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:30Z",
      "native_id": "10.1371/journal.pgen.1012331",
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      "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012331"
    },
    {
      "first_seen": "2026-11-01T12:23:20Z",
      "native_id": "PMC13716317",
      "source": "pmc",
      "url": "https://doi.org/10.1371/journal.pgen.1012331"
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  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "plos:gene expression",
      "subfield": "molecular-biology"
    },
    {
      "field": "biology",
      "origin": "plos:genetics",
      "subfield": "genetics-genomics"
    },
    {
      "field": "chemistry",
      "origin": "heading:Polymer Chemistry",
      "subfield": "materials-polymers"
    },
    {
      "field": "medicine",
      "origin": "plos:physiology",
      "subfield": "physiology"
    }
  ],
  "title": "Combined lactate- and phosphate-dependent cytoplasmic acidification is associated with Mycobacterium tuberculosis growth arrest at acidic pH",
  "title_text": "Combined lactate- and phosphate-dependent cytoplasmic acidification is associated with Mycobacterium tuberculosis growth arrest at acidic pH",
  "type": "peer-reviewed",
  "updated_at": "2026-11-01T12:23:20Z",
  "url": "https://research.draconitic.com/paper/006bg8r0nx1rn",
  "venue": "PLOS Genetics",
  "versions": []
}