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To overcome this central challenge in tuberculosis research, we leveraged a dataset of more than 50,000 sequenced isolates to identify Mtb genes that that are functionally preserved during natural infection, disease causation, and transmission between humans. This whole-genome ranking identified polyketide synthase 12 (\n                  <jats:italic>pks12<\/jats:italic>\n                  ) as an exceptionally\n                  <jats:italic>in vivo<\/jats:italic>\n                  essential gene in human tuberculosis, which we validated in zebrafish and mouse models. Though Pks12 produces a mycoketide lipid in only trace amounts,\n                  <jats:italic>pks12<\/jats:italic>\n                  deletion severely altered the host-facing surface and arabinoglycan architecture of Mtb. This amplified effect was explained through the discovery of mannosyl-\u03b2-1-phosphomycoketide monomycolate (MPMMM), which is synthesized from the known Pks12 product at higher abundance by antigen 85 mycolyltransferases. Thus, we used a new host-facing genomic-metabolomic-phenotypic approach to discover the functions of an\n                  <jats:italic>in vivo<\/jats:italic>\n                  essential Mtb gene, which controls the physical structure of the Mtb-host interface.\n                <\/jats:p>","DOI":"10.64898\/2026.09.25.754250","type":"posted-content","created":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:00:17Z","timestamp":1790391617000},"source":"Crossref","is-referenced-by-count":0,"title":["Polyketide synthase 12 is an\n                  <i>in vivo<\/i>\n                  essential source of novel mycolyl lipids in\n                  <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4158-6979","authenticated-orcid":false,"given":"Gregory H.","family":"Babunovic","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanne","family":"van der Niet","sequence":"additional","affiliation":[{"name":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco T.P.","family":"Gontijo","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine","family":"Abrahams","sequence":"additional","affiliation":[{"name":"School of Biosciences and Institute of Microbiology and Infection, University of Birmingham, Edgbaston, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rongfeng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina, Chapel Hill, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiranmai","family":"Bhatt","sequence":"additional","affiliation":[{"name":"Walsall Manor Hospital NHS Trust, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ella","family":"Meirav","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Vilch\u00e8ze","sequence":"additional","affiliation":[{"name":"Department of Microbiology & Immunology, Albert Einstein College of Medicine, New York, NY"},{"name":"Department of Genetics, Albert Einstein College of Medicine, New York, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Young","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Brigham and Women\u2019s Hospital, Boston, MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lara","family":"Rosbach","sequence":"additional","affiliation":[{"name":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ign\u0117","family":"Kanopait\u0117","sequence":"additional","affiliation":[{"name":"Electron Microscopy Center, Amsterdam University Medical Center, Amsterdam, NL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oyinda O.","family":"Adefisayo","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten M.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"},{"name":"University Program in Genetics and Genomics, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Mar\u00eda","family":"Xet-Mull","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, NC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V. 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