{
  "abstract": "Anti-TB drugs act non-uniformly on Mycobacterium tuberculosis (Mtb) because of its distinct physiological states across diverse infection niches shaped by host-derived nutrients and stresses. Agonists of the adenylyl cyclase Rv1625c are a novel drug class that selectively inhibits Mtb growth in macrophages and cholesterol-rich conditions by an unknown mechanism. Combining condition-resolved transcriptomics, genome-scale metabolic modeling, and genetic perturbation, we show these agonists cause a blockade in the electron transport chain, which likely activates Rv1625c. The elevated cAMP in turn drives global transcriptional and post-translational remodeling of central carbon and lipid metabolism. The resulting methylcitrate cycle reversal chokes cholesterol breakdown products from entering central metabolism, diverting carbon toward cell wall and virulence-lipid (phthiocerol dimycocerosate) synthesis and inhibiting growth. These drugs thus hijack an endogenous switch that reroutes carbon from biomass to virulence-lipid production. Hence, nutrients that restore carbon flux and relieve ETC blockade reduce activity, whereas Rv1625c overexpression and ETC inhibitors potentiate drug action even in refractory conditions.",
  "abstract_shown": true,
  "affiliations": [
    "Institute for Systems Biology, Seattle, WA 98109, USA"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 10,
  "authors": [
    {
      "name": "S. R. C. Immanuel"
    },
    {
      "name": "J. Do"
    },
    {
      "name": "E. J. R. Peterson"
    },
    {
      "name": "K. A. Hunt"
    },
    {
      "name": "A. Kaur"
    },
    {
      "name": "M. Pan"
    },
    {
      "name": "A. Singh"
    },
    {
      "name": "W.-J. Wu"
    },
    {
      "name": "A. Bhatt"
    },
    {
      "affs": [
        0
      ],
      "name": "N. S. Baliga"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/2nvdpy8tfxjnr.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.09.10.750769",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1.full",
  "id": "2nvdpy8tfxjnr",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "systems biology"
    ],
    [
      "openalex",
      "2725|Tuberculosis Research and Epidemiology"
    ]
  ],
  "openalex": "W7213459856",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-10",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/2nvdpy8tfxjnr.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:22:43Z",
      "native_id": "10.64898/2026.09.10.750769",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.09.10.750769v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:systems biology",
      "subfield": "systems-synthetic"
    }
  ],
  "title": "An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis",
  "title_text": "An adenylyl cyclase switch reroutes carbon from growth to virulence lipids in Mycobacterium tuberculosis",
  "type": "preprint",
  "updated_at": "2026-10-30T12:22:43Z",
  "url": "https://research.draconitic.com/paper/2nvdpy8tfxjnr",
  "venue": "bioRxiv",
  "versions": []
}