{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T15:01:49Z","timestamp":1786719709922,"version":"build-2736575974"},"reference-count":118,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100005302","name":"University of Illinois at Urbana-Champaign","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005302","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health (NIH)","doi-asserted-by":"crossref","award":["R01AI191595"],"award-info":[{"award-number":["R01AI191595"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Despite extensive efforts over the past \u223c60 years to discover new classes of Gram-negative-active antibiotics, the development pipeline remains relatively dry. These failures can be largely ascribed to the complexity of the Gram-negative membranes and an inadequate understanding of physicochemical properties associated with compound permeation, efflux evasion, and overall accumulation in Gram-negative pathogens. Recent work using unbiased accumulation assays and advanced chemical descriptors has utilized machine learning algorithms, particularly random forest modeling, to correlate physicochemical properties of small molecules with accumulation. The ability of a random forest classifier to effectively process large data sets while still providing human-interpretable insight makes this model a valuable tool in accumulation data analysis. Here, we describe in detail a workflow reliant on random forest modeling to probe physicochemical trends linked to small molecule permeation and\/or efflux liabilities in Gram-negative pathogens. Applications using random forest modeling have led to guidelines for small molecule accumulation in E. coli and P. aeruginosa that have resulted in multiple new Gram-negative-active antibiotics. Random forest modeling possesses several distinct advantages over other machine learning models for the purposes of identifying physicochemical trends in accumulation, and as such, provides valuable hypothesis-generating information for the study of small molecule accumulation in Gram-negative bacteria.<\/jats:p>","DOI":"10.1021\/acsinfecdis.6c00421","type":"journal-article","created":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T14:16:24Z","timestamp":1784384184000},"page":"2558-2571","source":"Crossref","is-referenced-by-count":0,"title":["Random Forest\nModeling to Predict Small Molecule Accumulation\nin Gram-Negative Bacteria"],"prefix":"10.1021","volume":"12","author":[{"given":"Blake R.","family":"Levy","sequence":"first","affiliation":[{"name":"University of Illinois Urbana\u2212Champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9018-3581","authenticated-orcid":true,"given":"Paul J.","family":"Hergenrother","sequence":"additional","affiliation":[{"name":"University of Illinois Urbana\u2212Champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]},{"name":"University of Illinois Urbana\u2212Champaign , , , ,","place":["Urbana, Illinois, United States, 61801"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"issue":"36","key":"2026081410073323400_cit1","doi-asserted-by":"publisher","first-page":"8852","DOI":"10.1073\/pnas.1812779115","article-title":"The Bacterial Outer Membrane Is an Evolving Antibiotic\nBarrier","volume":"115","author":"May","year":"2018","journal-title":"Proc. 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Biochem."},{"issue":"11","key":"2026081410073323400_cit42","doi-asserted-by":"publisher","first-page":"2535","DOI":"10.1021\/cb5003015","article-title":"General\nPlatform for Systematic Quantitative\nEvaluation of Small-Molecule Permeability in Bacteria","volume":"9","author":"Davis","year":"2014","journal-title":"ACS Chem. Biol."},{"issue":"10","key":"2026081410073323400_cit43","doi-asserted-by":"publisher","first-page":"4833","DOI":"10.1038\/s41596-021-00598-y","article-title":"An LC-MS\/MS Assay and Complementary\nWeb-Based Tool to Quantify and Predict Compound Accumulation in E","volume":"16","author":"Geddes","year":"2021","journal-title":"Coli. Nat. 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Biol."},{"issue":"1","key":"2026081410073323400_cit52","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1038\/s41564-024-01883-8","article-title":"Exploiting the Fitness Cost of Metallo-\u03b2-Lactamase\nExpression Can Overcome Antibiotic Resistance in Bacterial Pathogens","volume":"10","author":"Tu","year":"2025","journal-title":"Nat. Microbiol."},{"issue":"4","key":"2026081410073323400_cit53","doi-asserted-by":"publisher","first-page":"e03814-24","DOI":"10.1128\/mbio.03814-24","article-title":"A Novel Plasmid-Encoded Transposon-Derived\nSmall RNA\nReveals the Mechanism of sRNA-Regulated Bacterial Persistence","volume":"16","author":"Lin","year":"2025","journal-title":"mBio"},{"issue":"5","key":"2026081410073323400_cit54","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1038\/s41564-026-02299-2","article-title":"A Drug\u2013Microbiome\u2013Drug Interaction Impacts\nCo-Prescribed Medications for Parkinson\u2019s Disease","volume":"11","author":"Verdegaal","year":"2026","journal-title":"Nat. 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