{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T08:17:57Z","timestamp":1790324277611,"version":"4.1.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2019,5,29]],"date-time":"2019-05-29T00:00:00Z","timestamp":1559088000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"crossref","award":["2018-06047"],"award-info":[{"award-number":["2018-06047"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Objectives<\/jats:title>\n                  <jats:p>To develop a multifunctional adjuvant molecule that can rescue \u03b2-lactam antibiotics and \u03b2-lactam\/\u03b2-lactamase inhibitor combinations from resistance in carbapenem-resistant Pseudomonas aeruginosa clinical isolates.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Preparation of adjuvant was guided by structure\u2013activity relationships, following standard protocols. Susceptibility and chequerboard studies were assessed using serial 2-fold dilution assays. Toxicity was evaluated against porcine erythrocytes, human embryonic kidney (HEK293) cells and liver carcinoma (HepG2) cells via MTS assay. Preliminary in vivo efficacy was evaluated using a Galleria mellonella infection model.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Conjugation of tobramycin and cyclam abrogates the ribosomal effects of tobramycin but confers a potent adjuvant property that restores full antibiotic activity of meropenem and aztreonam against carbapenem-resistant P. aeruginosa. Therapeutic levels of susceptibility, as determined by CLSI susceptibility breakpoints, were attained in several MDR clinical isolates, and time\u2013kill assays revealed a synergistic dose-dependent pharmacodynamic relationship. A triple combination of the adjuvant with ceftazidime\/avibactam (approved), aztreonam\/avibactam (Phase III) and meropenem\/avibactam enhances the efficacies of \u03b2-lactam\/\u03b2-lactamase inhibitors against recalcitrant strains, suggesting rapid access of the combination to their periplasmic targets. The newly developed adjuvants, and their combinations, were non-haemolytic and non-cytotoxic, and preliminary in vivo evaluation in G. mellonella suggests therapeutic potential for the double and triple combinations.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>Non-ribosomal tobramycin\u2013cyclam conjugate mitigates the effect of OprD\/OprF porin loss in P. aeruginosa and potentiates \u03b2-lactam\/\u03b2-lactamase inhibitors against carbapenem-resistant clinical isolates, highlighting the complexity of resistance to \u03b2-lactam antibiotics. Our strategy presents an avenue to further preserve the therapeutic utility of \u03b2-lactam antibiotics.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/jac\/dkz228","type":"journal-article","created":{"date-parts":[[2019,5,6]],"date-time":"2019-05-06T10:37:04Z","timestamp":1557139024000},"page":"2640-2648","source":"Crossref","is-referenced-by-count":47,"title":["Potentiation of \u03b2-lactam antibiotics and \u03b2-lactam\/\u03b2-lactamase inhibitor combinations against MDR and XDR Pseudomonas aeruginosa using non-ribosomal tobramycin\u2013cyclam conjugates"],"prefix":"10.1093","volume":"74","author":[{"given":"Temilolu","family":"Idowu","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Derek","family":"Ammeter","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, 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