{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T07:01:43Z","timestamp":1790146903223,"version":"4.0.1"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Microbiol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>We aimed to develop a liquid-based high-throughput screening (HTS) assay to identify small molecules that target GN bacterial envelope integrity and to assess their antibacterial potential, distinct from traditional viability-based screens.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Envelope disruption in\n                      <jats:italic>Escherichia coli<\/jats:italic>\n                      and\n                      <jats:italic>Pseudomonas aeruginosa<\/jats:italic>\n                      was assessed using a \u03b2-galactosidase (LacZ)\/CPRG reporter assay in LB at 37\u202f\u00b0C. The assay was validated by screening the LOPAC\n                      <jats:sup>1280<\/jats:sup>\n                      and KD\n                      <jats:sub>2<\/jats:sub>\n                      <jats:sup>4761<\/jats:sup>\n                      compound libraries. Hit compounds were further characterized by concentration-response analysis, determination of permeabilization constants (K\n                      <jats:sub>50<\/jats:sub>\n                      ), chloramphenicol combination permeabilization assays, minimal inhibitory concentration (MIC) measurements, and microscopy at sub-MICs. Confocal microscopy served as an orthogonal validation method.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The assay demonstrated robust, reproducible performance across independent optimization runs, as evidenced by high Z\u2019-factor and signal-to-noise (S\/N) ratios. Screening identified 72 active compounds, including \u03b2-lactams and four non-antibiotic molecules (suloctidil, isorotenone, alexidine, and thiram) that showed concentration-dependent increases in CPRG reporter signal, consistent with envelope permeabilization. Thiram was excluded due to its fungicidal use, and the remaining three compounds were further characterized. Alexidine showed the most potent activity, with the lowest K\n                      <jats:sub>50<\/jats:sub>\n                      (2.7\u202f\u00d7\u202f10\n                      <jats:sup>\u22123<\/jats:sup>\n                      \u202fmM) and MICs of 0.004\u202fmM for\n                      <jats:italic>E. coli<\/jats:italic>\n                      and 0.015\u202fmM for\n                      <jats:italic>P. aeruginosa<\/jats:italic>\n                      . Suloctidil and isorotenone induced spherical cell morphology, whereas alexidine induced a filamentous phenotype, indicative of envelope disruption. The assay also identified compounds with both antimicrobial activity and potential antibiotic adjuvant effects. Apicillin, alexidine, and suloctidil enhanced chloramphenicol activity against\n                      <jats:italic>E. coli<\/jats:italic>\n                      MG1655, consistent with increased envelope permeability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The LacZ\/CPRG reporter assay enables rapid identification of compounds targeting bacterial envelopes, including novel molecules active against GN pathogens, providing a high-throughput functional platform that complements established permeability assays and accelerates discovery of new therapeutics.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmicb.2026.1779546","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T06:19:33Z","timestamp":1790144373000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["High-throughput LacZ\/CPRG assay for identifying Gram-negative envelope-targeting antibiotics"],"prefix":"10.3389","volume":"17","author":[{"given":"Fardin","family":"Ghobakhlou","sequence":"first","affiliation":[{"name":"Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Larbi","family":"Mokhtari","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom A.","family":"Pfeifer","sequence":"additional","affiliation":[{"name":"Biofactorial, Life Sciences Center, University of British Columbia","place":["Vancouver, BC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catherine","family":"Paradis-Bleau","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Infectiology and Immunology, Faculty of Medicine, Universit\u00e9 de Montr\u00e9al","place":["Montreal, QC, Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1037","DOI":"10.1016\/j.cell.2007.03.004","article-title":"Molecular mechanisms of antibacterial multidrug resistance","volume":"128","author":"Alekshun","year":"2007","journal-title":"Cell"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"21929","DOI":"10.1021\/acsomega.0c03207","article-title":"Repurposing clinically approved drugs for the treatment of Bacillus cereus, a surrogate for Bacillus anthracis","volume":"5","author":"Amakawa","year":"2020","journal-title":"ACS Omega"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1007\/s12272-015-0645-0","article-title":"Next-generation antimicrobials: from chemical biology to first-in-class drugs","volume":"38","author":"Ang","year":"2015","journal-title":"Arch. 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