{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T05:02:08Z","timestamp":1790226128683,"version":"4.1.0"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T00:00:00Z","timestamp":1790208000000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Gram-negative bacteria express several efflux pump complexes extruding a broad spectrum of antibiotics. The major efflux pump in\n                      <jats:italic>E. coli<\/jats:italic>\n                      is the AcrAB-TolC complex that expels a broad spectrum of antibiotics from the bacterium, resulting in impaired efficacy of these drugs. Therefore, the inhibition of efflux pump function is an attractive approach to restore the susceptibility of Gram-negative bacteria for antibiotics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A virtual screening campaign was utilized to identify potential TolC binders. Virtual hits were investigated using a functional efflux assay, followed by synergy tests with piperacillin and determination of the intrinsic antibacterial potential. Bindings studies with individual efflux pump proteins were carried out. Synthetic chemistry was applied to improve the efficacy of the compound. Microbiological and biophysical tests were used to characterize the compounds with respect to synergistic activity with antibiotics and efflux pump binding.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified a small molecule interfering with efflux pump function, showing synergistic activity with piperacillin and binding to TolC which was further optimized at various positions. The most promising compounds revealed TolC-selective binding and shifted the minimum inhibitory concentration of piperacillin and levofloxacin at low micromolar concentrations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study provides evidence that TolC may represent a valid target for the development of an antibiotic adjuvant.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1895729","type":"journal-article","created":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T04:34:33Z","timestamp":1790224473000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the AcrAB-TolC efflux pump by small molecules selectively addressing the outer membrane factor TolC"],"prefix":"10.3389","volume":"17","author":[{"given":"Janis","family":"Veliks","sequence":"first","affiliation":[{"name":"Latvian Institute of Organic Synthesis","place":["Riga, Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina D.","family":"Cruz","sequence":"additional","affiliation":[{"name":"Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki","place":["Helsinki, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Szal","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort","place":["Hamburg, Germany"]},{"name":"Constructor University, School of Science","place":["Bremen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Madre","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis","place":["Riga, Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Leite","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis","place":["Riga, Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Paunina","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis","place":["Riga, Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp","family":"Lewe","sequence":"additional","affiliation":[{"name":"Centre for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maren","family":"Hinz","sequence":"additional","affiliation":[{"name":"Centre for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Witt","sequence":"additional","affiliation":[{"name":"Centre for Structural Systems Biology (CSSB), University Medical Center Hamburg-Eppendorf","place":["Hamburg, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P\u00e4ivi","family":"Tammela","sequence":"additional","affiliation":[{"name":"Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki","place":["Helsinki, Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aigars","family":"Jirgensons","sequence":"additional","affiliation":[{"name":"Latvian Institute of Organic Synthesis","place":["Riga, Latvia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn","family":"Windsh\u00fcgel","sequence":"additional","affiliation":[{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Discovery Research ScreeningPort","place":["Hamburg, Germany"]},{"name":"Constructor University, School of Science","place":["Bremen, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,24]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1021\/acsinfecdis.6b00167","article-title":"Reviving antibiotics: efflux pump inhibitors that interact with AcrA, a membrane fusion protein of the AcrAB-TolC multidrug efflux pump","volume":"3","author":"Abdali","year":"2017","journal-title":"ACS Infect. 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