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Better therapeutics are urgently needed for the human pathogen\n                    <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                    , yet the cell envelope, including the mycobacterial outer membrane, represents a significant barrier for drug entry, and the chemical features governing permeation remain poorly understood. Here we used the bioorthogonal click chemistry-based PAC-MAN assay to profile mycomembrane permeation of 1,572 azide-tagged compounds in\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    and the model organism\n                    <jats:italic>M. smegmatis<\/jats:italic>\n                    . Cheminformatics and machine learning identified chemical features associated with mycomembrane permeation, which in turn had predictive value in three molecule series. Chemical predictors of mycomembrane permeation include nitrogen-containing aromatic scaffolds, such as indole, which in some cases were associated with increased anti-\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    activity. Our data suggest a rational framework for improving mycomembrane permeation and whole-cell activity of antibiotics targeting\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    .\n                  <\/jats:p>","DOI":"10.1038\/s41564-026-02412-5","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T09:53:56Z","timestamp":1782813236000},"page":"2647-2665","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification of chemical features for improved outer membrane permeation in mycobacteria using machine learning"],"prefix":"10.1038","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1602-0490","authenticated-orcid":false,"given":"Irene","family":"Lepori","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-0295-5076","authenticated-orcid":false,"given":"Zichen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0408-5016","authenticated-orcid":false,"given":"Nelson","family":"Evbarunegbe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3394-6911","authenticated-orcid":false,"given":"Shasha","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Turner P.","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kishor","family":"Mane","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachita","family":"Dash","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"family":"Shivangi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitchell","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5669-4317","authenticated-orcid":false,"given":"Ananya","family":"Naick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amir","family":"George","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taijie","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anil M.","family":"Shelke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6051-1599","authenticated-orcid":false,"given":"K. 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