{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T01:55:17Z","timestamp":1778550917429,"version":"3.51.4"},"update-to":[{"DOI":"10.1371\/journal.pcbi.1008857","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2021,4,8]],"date-time":"2021-04-08T00:00:00Z","timestamp":1617840000000}}],"reference-count":40,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01AI118687"],"award-info":[{"award-number":["P01AI118687"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01AI118687"],"award-info":[{"award-number":["P01AI118687"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["P01AI118687"],"award-info":[{"award-number":["P01AI118687"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>To better combat the expansion of antibiotic resistance in pathogens, new compounds, particularly those with novel mechanisms-of-action [MOA], represent a major research priority in biomedical science. However, rediscovery of known antibiotics demonstrates a need for approaches that accurately identify potential novelty with higher throughput and reduced labor. Here we describe an explainable artificial intelligence classification methodology that emphasizes prediction performance and human interpretability by using a Hierarchical Ensemble of Classifiers model optimized with a novel feature selection algorithm called <jats:italic>Clairvoyance<\/jats:italic>; collectively referred to as a CoHEC model. We evaluated our methods using whole transcriptome responses from <jats:italic>Escherichia coli<\/jats:italic> challenged with 41 known antibiotics and 9 crude extracts while depositing 122 transcriptomes unique to this study. Our CoHEC model can properly predict the primary MOA of previously unobserved compounds in both purified forms and crude extracts at an accuracy above 99%, while also correctly identifying darobactin, a newly discovered antibiotic, as having a novel MOA. In addition, we deploy our methods on a recent <jats:italic>E<\/jats:italic>. <jats:italic>coli<\/jats:italic> transcriptomics dataset from a different strain and a <jats:italic>Mycobacterium smegmatis<\/jats:italic> metabolomics timeseries dataset showcasing exceptionally high performance; improving upon the performance metrics of the original publications. We not only provide insight into the biological interpretation of our model but also that the concept of MOA is a non-discrete heuristic with diverse effects for different compounds within the same MOA, suggesting substantial antibiotic diversity awaiting discovery within existing MOA.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1008857","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T17:40:28Z","timestamp":1617039628000},"page":"e1008857","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":35,"title":["Predicting antimicrobial mechanism-of-action from transcriptomes: A generalizable explainable artificial intelligence approach"],"prefix":"10.1371","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3447-3845","authenticated-orcid":true,"given":"Josh L.","family":"Espinoza","sequence":"first","affiliation":[]},{"given":"Chris L.","family":"Dupont","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2890-1682","authenticated-orcid":true,"given":"Aubrie","family":"O\u2019Rourke","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0906-7538","authenticated-orcid":true,"given":"Sinem","family":"Beyhan","sequence":"additional","affiliation":[]},{"given":"Pavel","family":"Morales","sequence":"additional","affiliation":[]},{"given":"Amy","family":"Spoering","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9487-7361","authenticated-orcid":true,"given":"Kirsten J.","family":"Meyer","sequence":"additional","affiliation":[]},{"given":"Agnes P.","family":"Chan","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4017-9669","authenticated-orcid":true,"given":"Yongwook","family":"Choi","sequence":"additional","affiliation":[]},{"given":"William C.","family":"Nierman","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1335-9982","authenticated-orcid":true,"given":"Kim","family":"Lewis","sequence":"additional","affiliation":[]},{"given":"Karen E.","family":"Nelson","sequence":"additional","affiliation":[]}],"member":"340","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"issue":"3","key":"pcbi.1008857.ref001","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1128\/MMBR.00016-10","article-title":"Origins and Evolution of Antibiotic Resistance","volume":"74","author":"J Davies","year":"2010","journal-title":"Microbiology and Molecular Biology Reviews"},{"issue":"12","key":"pcbi.1008857.ref002","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1016\/S1473-3099(13)70318-9","article-title":"Antibiotic resistance\u2014the need for global solutions","volume":"13","author":"R Laxminarayan","year":"2013","journal-title":"The Lancet Infectious Diseases"},{"issue":"7","key":"pcbi.1008857.ref003","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s10295-005-0077-9","article-title":"Marcel Faber Roundtable: is our antibiotic pipeline unproductive because of starvation, constipation or lack of inspiration?","volume":"33","author":"RH Baltz","year":"2006","journal-title":"Journal of industrial microbiology & biotechnology"},{"key":"pcbi.1008857.ref004","year":"2016","journal-title":"Group PCTRSW. 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