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While the combination of \u03b2\u2010lactam antibiotics and \u03b2\u2010lactamase inhibitors has been successful in restoring antibacterial efficacy in MDR bacteria, the use of adjuvants to restore fluoroquinolone efficacy in MDR Gram\u2010negative pathogens has been challenging. We describe tobramycin\u2013ciprofloxacin hybrid adjuvants that rescue the activity of fluoroquinolone antibiotics against MDR and extremely drug\u2010resistant Pseudomonas aeruginosa isolates in\u2005vitro and enhance fluoroquinolone efficacy in\u2005vivo. Structure\u2013activity studies reveal that the presence of both tobramycin and ciprofloxacin, which are separated by a C12 tether, is critical for the function of the adjuvant. Mechanistic studies indicate that the antibacterial modes of ciprofloxacin are retained while the role of tobramycin is limited to destabilization of the outer membrane in the hybrid.<\/jats:p>","DOI":"10.1002\/anie.201508330","type":"journal-article","created":{"date-parts":[[2015,11,26]],"date-time":"2015-11-26T13:32:16Z","timestamp":1448544736000},"page":"555-559","source":"Crossref","is-referenced-by-count":93,"title":["Adjuvants Based on Hybrid Antibiotics Overcome Resistance in <i>Pseudomonas aeruginosa<\/i> and Enhance Fluoroquinolone Efficacy"],"prefix":"10.1002","volume":"55","author":[{"given":"Bala Kishan","family":"Gorityala","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Goutam","family":"Guchhait","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dinesh M.","family":"Fernando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soumya","family":"Deo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sean A.","family":"McKenna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George G.","family":"Zhanel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayush","family":"Kumar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Schweizer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2015,11,26]]},"reference":[{"key":"e_1_2_3_1_2","doi-asserted-by":"publisher","DOI":"10.1086\/421946"},{"key":"e_1_2_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tim.2011.04.005"},{"key":"e_1_2_3_3_2","doi-asserted-by":"publisher","DOI":"10.1086\/595011"},{"key":"e_1_2_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.04099-14"},{"key":"e_1_2_3_5_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-200262010-00002"},{"key":"e_1_2_3_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201200761"},{"key":"e_1_2_3_6_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201200761"},{"key":"e_1_2_3_7_2","doi-asserted-by":"publisher","DOI":"10.1002\/chem.201406404"},{"key":"e_1_2_3_8_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm401148j"},{"key":"e_1_2_3_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02536-13"},{"key":"e_1_2_3_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt1267"},{"key":"e_1_2_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/43.1.61"},{"key":"e_1_2_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0040-4020(02)01624-1"},{"key":"e_1_2_3_13_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.201500598"},{"key":"e_1_2_3_13_3","doi-asserted-by":"publisher","DOI":"10.1002\/ange.201500598"},{"key":"e_1_2_3_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm900028n"},{"key":"e_1_2_3_15_2","first-page":"365","volume-title":"Antibiotics in Laboratory Medicine","author":"Pillai S. 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