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Bacterial bioenergetics is a promising but underdeveloped drug target since the complexes of oxidative phosphorylation are critical to cell survival in these organisms. Building from our previous work using quinoline derivatives to inhibit the ATP synthase of PA, we report a new set of 14 quinoline derivatives that demonstrates potent inhibition of the AB ATP synthase, with the best inhibitor having an IC50 of 230\u2005ng\/mL <jats:italic>in\u2005vitro<\/jats:italic>, expands the quinoline structure\u2010activity relationship against the PA enzyme, and establishes molecular strategies for achieving selectivity between PA and AB. Furthermore, several compounds demonstrated potent antibacterial activity against multidrug resistant strains of AB and PA indicating ATP synthase as a promising new area for broad spectrum antibiotic development in AB.<\/jats:p>","DOI":"10.1002\/cmdc.202400952","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T18:55:57Z","timestamp":1741632957000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quinoline ATP Synthase Inhibitors with Activity Against Multidrug Resistant <i>Acinetobacter baumannii<\/i> and <i>Pseudomonas aeruginosa<\/i>"],"prefix":"10.1002","volume":"20","author":[{"given":"Katie T.","family":"Ward","sequence":"first","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander P. L.","family":"Williams","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angelina L.","family":"Dennison","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Aamir","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darien L.","family":"Allen","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Britza","family":"Chavez\u2010Arellano","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toni A.","family":"Marchlewski","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mars L.","family":"Zappia","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1867-6861","authenticated-orcid":false,"given":"Amanda L.","family":"Wolfe","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5445-0080","authenticated-orcid":false,"given":"P. Ryan","family":"Steed","sequence":"additional","affiliation":[{"name":"Chemistry and Biochemistry University of North Carolina Asheville  One University Heights Asheville NC 28804"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,3,24]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01867-1"},{"key":"e_1_2_9_2_1","unstructured":"Centers for Disease Control and Prevention HAI Pathogens and Antimicrobial Resistance Report 2018\u20132021 U.S. Department Of Health And Human Services CDC 2023."},{"key":"e_1_2_9_3_1","unstructured":"Centers for Disease Control and Prevention (U.S.) Antibiotic Resistance Threats in the United States 2019 Centers For Disease Control And Prevention (U.S.) 2019."},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/mdr.2018.0319"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/pathogens10030373"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/antibiotics12111590"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2017.11.001"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1009126"},{"key":"e_1_2_9_9_1","first-page":"1","volume-title":"Bergey's Manual of Systematics of Archaea and Bacteria","author":"Nemec A.","year":"2022"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1128\/JB.00565-20"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/mmi.12566"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1900570116"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biochem-013118-110903"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1106753"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-3004-3"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abl5966"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.2c03127"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsinfecdis.3c00317"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsmedchemlett.3c00480"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06760-8"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.orglett.3c01286"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.1500106"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.12.002"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-7-95"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1086\/514631"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1128\/jb.124.2.870-883.1975"}],"container-title":["ChemMedChem"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cmdc.202400952","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T15:31:18Z","timestamp":1760283078000},"score":1,"resource":{"primary":{"URL":"https:\/\/chemistry-europe.onlinelibrary.wiley.com\/doi\/10.1002\/cmdc.202400952"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,24]]},"references-count":26,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2025,5,19]]}},"alternative-id":["10.1002\/cmdc.202400952"],"URL":"https:\/\/doi.org\/10.1002\/cmdc.202400952","archive":["Portico"],"relation":{},"ISSN":["1860-7179","1860-7187"],"issn-type":[{"value":"1860-7179","type":"print"},{"value":"1860-7187","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,24]]},"assertion":[{"value":"2024-11-25","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e202400952"}}