{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:07:04Z","timestamp":1789085224955,"version":"build-2803163510"},"reference-count":51,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T00:00:00Z","timestamp":1672704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["advanced.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Advanced Science"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>Pseudomonas aeruginosa<\/jats:italic> (PA) is an opportunistic human pathogen, which is involved in a wide range of dangerous infections. It develops alarming resistances toward antibiotic treatment. Therefore, alternative strategies, which suppress pathogenicity or synergize with antibiotic treatments are in great need to combat these infections more effectively. One promising approach is to disarm the bacteria by interfering with their quorum sensing (QS) system, which regulates the release of various virulence factors as well as biofilm formation. Herein, this work reports the rational design, optimization, and in\u2010depth profiling of a new class of <jats:italic>Pseudomonas<\/jats:italic> quinolone signaling receptor (PqsR) inverse agonists. The resulting frontrunner compound features a pyrimidine\u2010based scaffold, high in vitro and in vivo efficacy, favorable pharmacokinetics as well as clean safety pharmacology characteristics, which provide the basis for potential pulmonary as well as systemic routes of administration. An X\u2010ray crystal structure in complex with PqsR facilitated further structure\u2010guided lead optimization. The compound demonstrates potent pyocyanin suppression, synergizes with aminoglycoside antibiotic tobramycin against PA biofilms, and is active against a panel of clinical isolates from bronchiectasis patients. Importantly, this in vitro effect translated into in vivo efficacy in a neutropenic thigh infection model in mice providing a proof\u2010of\u2010principle for adjunctive treatment scenarios.<\/jats:p>","DOI":"10.1002\/advs.202204443","type":"journal-article","created":{"date-parts":[[2023,1,3]],"date-time":"2023-01-03T21:23:22Z","timestamp":1672781002000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Towards Translation of PqsR Inverse Agonists: From In Vitro Efficacy Optimization to In Vivo Proof\u2010of\u2010Principle"],"prefix":"10.1002","volume":"10","author":[{"given":"Mostafa M.","family":"Hamed","sequence":"first","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed S.","family":"Abdelsamie","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"},{"name":"Department of Chemistry of Natural and Microbial Products Institute of Pharmaceutical and Drug Industries Research National Research Centre  El\u2010Buhouth St. Dokki Cairo 12622 Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8020-1384","authenticated-orcid":false,"given":"Katharina","family":"Rox","sequence":"additional","affiliation":[{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"},{"name":"Department of Chemical Biology (CBIO) Helmholtz Centre for Infection Research (HZI)  Inhoffenstr. 7 Braunschweig 38124 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2455-3123","authenticated-orcid":false,"given":"Christian","family":"Sch\u00fctz","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7580-3658","authenticated-orcid":false,"given":"Andreas M.","family":"Kany","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6468-2950","authenticated-orcid":false,"given":"Teresa","family":"R\u00f6hrig","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2511-7593","authenticated-orcid":false,"given":"Stefan","family":"Schmelz","sequence":"additional","affiliation":[{"name":"Department of Structure and Function of Proteins (SFPR) Helmholtz Centre for Infection Research (HZI)  Inhoffenstr. 7 Braunschweig 38124 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9886-9668","authenticated-orcid":false,"given":"Wulf","family":"Blankenfeldt","sequence":"additional","affiliation":[{"name":"Department of Structure and Function of Proteins (SFPR) Helmholtz Centre for Infection Research (HZI)  Inhoffenstr. 7 Braunschweig 38124 Saarbr\u00fccken Germany"},{"name":"Institute for Biochemistry Biotechnology and Bioinformatics Technische Universit\u00e4t Braunschweig  Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2486-401X","authenticated-orcid":false,"given":"Alejandro","family":"Arce\u2010Rodriguez","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Technische Universit\u00e4t Braunschweig  38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6409-8110","authenticated-orcid":false,"given":"Jos\u00e9 Manuel","family":"Borrero\u2010de Acu\u00f1a","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Technische Universit\u00e4t Braunschweig  38106 Braunschweig Germany"},{"name":"Braunschweig Integrated Centre of Systems Biology (BRICS) Technische Universit\u00e4t Braunschweig  38106 Braunschweig Germany"},{"name":"Departamento de Microbiolog\u00eda Facultad de Biolog\u00eda Universidad de Sevilla  Av. de la Reina Mercedes no. 6 Sevilla CP 41012 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4064-9205","authenticated-orcid":false,"given":"Dieter","family":"Jahn","sequence":"additional","affiliation":[{"name":"Institute of Microbiology Technische Universit\u00e4t Braunschweig  38106 Braunschweig Germany"},{"name":"Braunschweig Integrated Centre of Systems Biology (BRICS) Technische Universit\u00e4t Braunschweig  38106 Braunschweig Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2625-8467","authenticated-orcid":false,"given":"Jessica","family":"Rademacher","sequence":"additional","affiliation":[{"name":"Department for Respiratory Medicine Medizinische Hochschule Hannover  Carl\u2010Neuberg\u2010Str. 1 30625 Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) German Center for Lung Research (DZL)  30625 Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9084-4968","authenticated-orcid":false,"given":"Felix C.","family":"Ringshausen","sequence":"additional","affiliation":[{"name":"Department for Respiratory Medicine Medizinische Hochschule Hannover  Carl\u2010Neuberg\u2010Str. 1 30625 Hannover Germany"},{"name":"Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) German Center for Lung Research (DZL)  30625 Hannover Germany"},{"name":"European Reference Network on Rare and Complex Respiratory Diseases (ERN\u2010 LUNG)  Frankfurt Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Cramer","sequence":"additional","affiliation":[{"name":"Department for Pediatric Pneumology Allergology and Neonatology Medizinische Hochschule Hannover  Carl\u2010Neuberg\u2010Str. 1 30625 Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Burkhard","family":"T\u00fcmmler","sequence":"additional","affiliation":[{"name":"Biomedical Research in Endstage and Obstructive Lung Disease (BREATH) German Center for Lung Research (DZL)  30625 Hannover Germany"},{"name":"Department for Pediatric Pneumology Allergology and Neonatology Medizinische Hochschule Hannover  Carl\u2010Neuberg\u2010Str. 1 30625 Hannover Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8734-4663","authenticated-orcid":false,"given":"Anna K. H.","family":"Hirsch","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University Campus E8.1  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5871-5231","authenticated-orcid":false,"given":"Rolf W.","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University Campus E8.1  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0503-5830","authenticated-orcid":false,"given":"Martin","family":"Empting","sequence":"additional","affiliation":[{"name":"Helmholtz\u2010Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI) Campus E8.1  66123 Saarbr\u00fccken Germany"},{"name":"German Centre for Infection Research (DZIF) Partner Site Hannover\u2010Braunschweig Saarbr\u00fccken  66123 Saarbr\u00fccken Germany"},{"name":"Department of Pharmacy Saarland University Campus E8.1  66123 Saarbr\u00fccken Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,1,3]]},"reference":[{"key":"e_1_2_8_1_1","doi-asserted-by":"publisher","DOI":"10.1093\/clinids\/5.2.279"},{"key":"e_1_2_8_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00039"},{"key":"e_1_2_8_1_3","doi-asserted-by":"publisher","DOI":"10.3201\/eid0404.980405"},{"key":"e_1_2_8_1_4","doi-asserted-by":"publisher","DOI":"10.1002\/mbo3.1021"},{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1093\/emph\/eow012"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.2147\/IDR.S327652"},{"key":"e_1_2_8_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aba0150"},{"key":"e_1_2_8_3_3","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2007.01681.x"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41570-021-00313-1"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3013"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro1818"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2019.00074"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jmedchem.5b01698"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/155.1.93"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.00913"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.000466"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2017.02.003"},{"key":"e_1_2_8_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.mib.2016.06.001"},{"key":"e_1_2_8_12_3","first-page":"185","volume-title":"Topics in Medicinal Chemistry","author":"Kamal A. A. M.","year":"2018"},{"key":"e_1_2_8_12_4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1819801116"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep34083"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009425"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3762\/bjoc.14.241"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-014-0100-x"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003508"},{"key":"e_1_2_8_17_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb300208g"},{"key":"e_1_2_8_17_3","doi-asserted-by":"publisher","DOI":"10.1021\/jm400830r"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2012.01.015"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201307547"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202004369"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2021.113797"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1004321"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/cmdc.201900621"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2018.00230"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.00924"},{"key":"e_1_2_8_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2015.11.056"},{"key":"e_1_2_8_25_3","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1002192"},{"key":"e_1_2_8_25_4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080140"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12864-015-2276-8"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.37.6.1771-1776.1999"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2010.71"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01650-15"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00306-13"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1093\/toxsci\/kfx125"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2198"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2010.08.012"},{"key":"e_1_2_8_34_1","unstructured":"WHO https:\/\/www.who.int\/news\/item\/27\u201002\u20102017\u2010who\u2010publishes\u2010list\u2010of\u2010bacteria\u2010for\u2010which\u2010new\u2010antibiotics\u2010are\u2010urgently\u2010needed 2017."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiab102"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.3389\/fchem.2020.00204"},{"key":"e_1_2_8_36_2","unstructured":"b)R.Zahler WO2016112088A1 2016."},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/anie.202001407"}],"container-title":["Advanced Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202204443","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/advs.202204443","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/advs.202204443","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T12:57:34Z","timestamp":1759755454000},"score":1,"resource":{"primary":{"URL":"https:\/\/advanced.onlinelibrary.wiley.com\/doi\/10.1002\/advs.202204443"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,1,3]]},"references-count":51,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/advs.202204443"],"URL":"https:\/\/doi.org\/10.1002\/advs.202204443","archive":["Portico"],"relation":{},"ISSN":["2198-3844","2198-3844"],"issn-type":[{"value":"2198-3844","type":"print"},{"value":"2198-3844","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,3]]},"assertion":[{"value":"2022-08-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-01-03","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2204443"}}