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Adv."],"published-print":{"date-parts":[[2026,9,25]]},"abstract":"<jats:p>\n                    To address drug-resistant tuberculosis, the leading single-pathogen infectious killer, drugs with novel modes of action (MoAs) are urgently needed. Phenotypic screening of chemical libraries can identify antimicrobial compounds, but standard screens cannot reveal the MoA of hits, limiting targeted selection of compounds with novel MoAs. Here, we develop a deep learning (DL) model to screen drug-treated\n                    <jats:italic toggle=\"yes\">Corynebacterium glutamicum<\/jats:italic>\n                    (\n                    <jats:italic toggle=\"yes\">Cglu<\/jats:italic>\n                    ), a surrogate for\n                    <jats:italic toggle=\"yes\">Mycobacterium tuberculosis<\/jats:italic>\n                    . We train our DL model to distinguish between MoAs directly from high-throughput images. Our model robustly classifies MoAs of established antibiotics and recognizes the MoA of previously unseen antibiotics. Inhibitors with a previously unseen MoA cluster together and apart from reference drugs, enabling the detection of novel MoAs. Moreover, our model links images of chemical (drugs) and genetic (mutants) perturbations targeting similar pathways, supporting mutant-based target prediction of compounds with novel MoAs directly from images. Last, our DL model recovers known biological relationships from images alone using the\n                    <jats:italic toggle=\"yes\">Cglu<\/jats:italic>\n                    cell cycle as a case study.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg6806","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:58:53Z","timestamp":1790359133000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Deep learning extracts MoA-specific signatures from high-throughput images of chemically and genetically perturbed\n                    <i>Corynebacteria<\/i>"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6234-7259","authenticated-orcid":true,"given":"Daniel","family":"Krentzel","sequence":"first","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Imaging and Modeling Unit, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2312-4044","authenticated-orcid":true,"given":"Julienne","family":"Petit","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Bacterial Cell Cycle Mechanisms Unit, F-75015 Paris, France."},{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Structural Microbiology Unit, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0021-276X","authenticated-orcid":true,"given":"Yves-Marie","family":"Boudehen","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Bacterial Cell Cycle Mechanisms Unit, F-75015 Paris, France."},{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Structural Microbiology Unit, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1385-4174","authenticated-orcid":true,"given":"Nassim","family":"Mahtal","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Photonic Bio-Imaging, Centre de Ressources et Recherches Technologiques (UTechS-PBI, C2RT), F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Sadowski","sequence":"additional","affiliation":[{"name":"AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Service de bact\u00e9riologie, Centre National de R\u00e9f\u00e9rence des mycobact\u00e9ries et de la r\u00e9sistance des mycobact\u00e9ries aux antituberculeux, F-75013 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0592-1963","authenticated-orcid":true,"given":"Agn\u00e8s","family":"Zettor","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3523, Chemogenomic and Biological Screening Core Facility, C2RT, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4230-4793","authenticated-orcid":true,"given":"Alexandra","family":"Aubry","sequence":"additional","affiliation":[{"name":"AP-HP, H\u00f4pital Piti\u00e9-Salp\u00eatri\u00e8re, Service de bact\u00e9riologie, Centre National de R\u00e9f\u00e9rence des mycobact\u00e9ries et de la r\u00e9sistance des mycobact\u00e9ries aux antituberculeux, F-75013 Paris, France."},{"name":"Sorbonne Universit\u00e9, CNRS, Inserm, Centre d\u2019Immunologie et des Maladies Infectieuses, CIMI, F-75013 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9135-4565","authenticated-orcid":true,"given":"Jeanne","family":"Chiaravalli","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris 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Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, Structural Microbiology Unit, F-75015 Paris, France."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-1589","authenticated-orcid":true,"given":"Christophe","family":"Zimmer","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, Imaging and Modeling Unit, F-75015 Paris, France."},{"name":"Machine Biophotonics Lab, Rudolf Virchow Center for Integrative and Translational Bioimaging, University of W\u00fcrzburg, W\u00fcrzburg, Germany."},{"name":"Center for Artificial Intelligence and Data Science, University of W\u00fcrzburg, W\u00fcrzburg, Germany."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2327-6512","authenticated-orcid":true,"given":"Anne Marie","family":"Wehenkel","sequence":"additional","affiliation":[{"name":"Institut Pasteur, Universit\u00e9 Paris Cit\u00e9, CNRS UMR 3528, 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Krentzel K. Kho J. Petit N. Mahtal J. Chiaravalli S. L. Shorte A. M. Wehenkel I. G. Boneca C. Zimmer Deep learning recognises antibiotic modes of action from brightfield images. bioRxiv 645928 [Preprint] (2025). https:\/\/doi.org\/10.1101\/2025.03.30.645928.","DOI":"10.1101\/2025.03.30.645928"},{"key":"e_1_3_2_34_2","doi-asserted-by":"crossref","unstructured":"E. Scocchera D. L. Wright \u201cThe antifolates \u201d in Antibacterials: Volume II J. F. Fisher S. Mobashery M. J. Miller Eds. (Springer International Publishing 2018) pp. 123\u2013149; https:\/\/doi.org\/10.1007\/7355_2017_16.","DOI":"10.1007\/7355_2017_16"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.10114"},{"key":"e_1_3_2_36_2","doi-asserted-by":"crossref","unstructured":"Y. Wormser E. Yab A. Sogues F. Gubellini E. Capton E. Lecat M. Ben Assaya A. Aubry A. Mechaly P. M. Alzari A. M. Wehenkel A. Gedeon S. Petrella Assessing Corynebacterium glutamicum as a surrogate of Mycobacterium tuberculosis for DNA gyrase inhibitor design. Microbiology [Preprint] (2026). https:\/\/doi.org\/10.64898\/2026.06.24.734172.","DOI":"10.64898\/2026.06.24.734172"},{"key":"e_1_3_2_37_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a025320"},{"key":"e_1_3_2_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-15490-8"},{"key":"e_1_3_2_39_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.03700-25"},{"key":"e_1_3_2_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-023-01473-0"},{"key":"e_1_3_2_41_2","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01153-26"},{"key":"e_1_3_2_42_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcsw.2023.100116"},{"key":"e_1_3_2_43_2","doi-asserted-by":"crossref","unstructured":"G. Carloni Q. Gaday J. Petit M. Martinez D. Megrian A. Sogues M. Ben Assaya M. Kakonyi A. Haouz P. M. Alzari A. M. 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Le EfficientNet: Rethinking model scaling for convolutional neural networks. arXiv:1905.11946 [cs.LG] (2020)."},{"key":"e_1_3_2_53_2","unstructured":"D. P. Kingma J. Ba Adam: A method for stochastic optimization. arXiv:1412.6980 [cs.LG] (2017)."},{"key":"e_1_3_2_54_2","doi-asserted-by":"crossref","unstructured":"F. Schroff D. Kalenichenko J. Philbin \u201cFacenet: A unified embedding for face recognition and clustering \u201d in Proceedings of the IEEE Conference on Computer Vision and Pattern Recognition (IEEE 2015) pp. 815\u2013823.","DOI":"10.1109\/CVPR.2015.7298682"},{"key":"e_1_3_2_55_2","doi-asserted-by":"crossref","unstructured":"Y. Wen K. Zhang Z. Li Y. Qiao \u201cA discriminative feature learning approach for deep face recognition \u201d in European Conference on Computer Vision (Springer 2016) pp. 499\u2013515.","DOI":"10.1007\/978-3-319-46478-7_31"},{"key":"e_1_3_2_56_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-020-00805-7"}],"container-title":["Science Advances"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.science.org\/doi\/pdf\/10.1126\/sciadv.aeg6806","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T18:01:31Z","timestamp":1790359291000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.science.org\/doi\/10.1126\/sciadv.aeg6806"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":55,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2026,9,25]]}},"alternative-id":["10.1126\/sciadv.aeg6806"],"URL":"https:\/\/doi.org\/10.1126\/sciadv.aeg6806","relation":{},"ISSN":["2375-2548"],"issn-type":[{"value":"2375-2548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"assertion":[{"value":"2026-02-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-12","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-25","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"eaeg6806"}}