{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T23:38:53Z","timestamp":1790293133872,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T00:00:00Z","timestamp":1690761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada (NSERC)","doi-asserted-by":"publisher","award":["2018-06047"],"award-info":[{"award-number":["2018-06047"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada (NSERC)","doi-asserted-by":"publisher","award":["162159"],"award-info":[{"award-number":["162159"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada (NSERC)","doi-asserted-by":"publisher","award":["169664"],"award-info":[{"award-number":["169664"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR)","doi-asserted-by":"publisher","award":["2018-06047"],"award-info":[{"award-number":["2018-06047"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR)","doi-asserted-by":"publisher","award":["162159"],"award-info":[{"award-number":["162159"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research (CIHR)","doi-asserted-by":"publisher","award":["169664"],"award-info":[{"award-number":["169664"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antibiotics"],"abstract":"<jats:p>Metal ions, including Fe3+, affect the target site binding of some antibiotics and control the porin- and siderophore-mediated uptake of antibiotics. Amphiphilic tobramycins are an emerging class of antibiotic potentiators capable of synergizing with multiple classes of antibiotics against Gram-negative bacteria, including Pseudomonas aeruginosa. To study how the antibiotic-potentiating effect of amphiphilic tobramycins is affected by the presence of intermolecular iron chelators, we conjugated the FDA-approved iron chelator deferiprone (DEF) to tobramycin (TOB). Three TOB-DEF conjugates differing in the length of the carbon tether were prepared and tested for antibacterial activity and synergistic relationships with a panel of antibiotics against clinical isolates of P. aeruginosa. While all TOB-DEF conjugates were inactive against P. aeruginosa, the TOB-DEF conjugates strongly synergized with outer-membrane-impermeable antibiotics, such as novobiocin and rifampicin. Among the three TOB-DEF conjugates, 1c containing a C12 tether showed a remarkable and selective potentiating effect to improve the susceptibility of multidrug-resistant P. aeruginosa isolates to tetracyclines when compared with other antibiotics. However, the antibacterial activity and antibiotic-potentiating effect of the optimized conjugate was not enhanced under iron-depleted conditions, indicating that the function of the antibiotic potentiator is not affected by the Fe3+ concentration.<\/jats:p>","DOI":"10.3390\/antibiotics12081261","type":"journal-article","created":{"date-parts":[[2023,7,31]],"date-time":"2023-07-31T09:22:38Z","timestamp":1690795358000},"page":"1261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Exploring Antibiotic-Potentiating Effects of Tobramycin\u2013Deferiprone Conjugates in Pseudomonas aeruginosa"],"prefix":"10.3390","volume":"12","author":[{"given":"Karan","family":"Gandhi","sequence":"first","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiv","family":"Dhiman","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4662-6485","authenticated-orcid":false,"given":"Rajat","family":"Arora","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danzel Marie","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danyel","family":"Ramirez","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gilbert","family":"Arthur","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8697-5519","authenticated-orcid":false,"given":"Frank","family":"Schweizer","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Faculty of Science, University of Manitoba, Winnipeg, MB R3T 2N2, Canada"},{"name":"Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB R3R 0J9, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,31]]},"reference":[{"key":"ref_1","unstructured":"CDC (2019). Antibiotic Resistance Threats in the United States, 2019."},{"key":"ref_2","unstructured":"World Health Organization (2017). Prioritization of Pathogens to Guide Discovery, Research and Development of New Antibiotics for Drug-Resistant Bacterial Infections, Including Tuberculosis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/S0140-6736(21)02724-0","article-title":"Global burden of bacterial antimicrobial resistance in 2019: A systematic analysis","volume":"399","author":"Murray","year":"2022","journal-title":"Lancet"},{"key":"ref_4","first-page":"fux053","article-title":"Environmental factors influencing the development and spread of antibiotic resistance","volume":"42","author":"Kristiansson","year":"2018","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_5","unstructured":"Planet, P.J. (2018). Principles and Practice of Pediatric Infectious Diseases, Elsevier."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1007\/s11908-018-0609-x","article-title":"Resistance trends and treatment options in gram-negative ventilator-associated pneumonia","volume":"20","author":"Rhodes","year":"2018","journal-title":"Curr. Infect. Dis. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5783","DOI":"10.1128\/JCM.42.12.5783-5792.2004","article-title":"Genome diversity of Pseudomonas aeruginosa isolates from cystic fibrosis patients and the hospital environment","volume":"42","author":"Finnan","year":"2004","journal-title":"J. Clin. Microbiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1128\/CMR.00068-09","article-title":"The changing microbial epidemiology in cystic fibrosis","volume":"23","author":"LiPuma","year":"2010","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1128\/CMR.00036-10","article-title":"Clinical significance of microbial infection and adaptation in cystic fibrosis","volume":"24","author":"Hauser","year":"2011","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"527","DOI":"10.4103\/lungindia.lungindia_39_17","article-title":"The emergence of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis patients on inhaled antibiotics","volume":"34","author":"Zahraldin","year":"2017","journal-title":"Lung India Off. Organ Indian Chest Soc."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1007\/s40121-022-00591-2","article-title":"Therapeutic strategies for emerging multidrug-resistant Pseudomonas aeruginosa","volume":"11","author":"Holger","year":"2022","journal-title":"Infect. Dis. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.biotechadv.2018.11.013","article-title":"Antibiotic resistance in Pseudomonas aeruginosa: Mechanisms and alternative therapeutic strategies","volume":"37","author":"Pang","year":"2019","journal-title":"Biotechnol. Adv."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1093\/cid\/ciz826","article-title":"Cefiderocol: Discovery, chemistry, and in vivo profiles of a novel siderophore cephalosporin","volume":"69","author":"Sato","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"75","DOI":"10.3389\/fcimb.2013.00075","article-title":"Pseudomonas aeruginosa adapts its iron uptake strategies in function of the type of infections","volume":"3","author":"Cornelis","year":"2013","journal-title":"Front Cell Infect. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"111615","DOI":"10.1016\/j.ejmech.2019.111615","article-title":"An overview of recent progress in siderophore-antibiotic conjugates","volume":"182","author":"Kong","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1007\/s40121-020-00286-6","article-title":"Cefiderocol: A novel agent for the management of multidrug-resistant gram-negative organisms","volume":"9","author":"Wu","year":"2020","journal-title":"Infect. Dis. Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7396","DOI":"10.1128\/AAC.01405-16","article-title":"Siderophore cephalosporin cefiderocol utilizes ferric iron transporter systems for antibacterial activity against Pseudomonas aeruginosa","volume":"60","author":"Ito","year":"2016","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s40265-019-1055-2","article-title":"Cefiderocol: A Siderophore Cephalosporin with Activity Against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli","volume":"79","author":"Zhanel","year":"2019","journal-title":"Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1128\/MMBR.65.2.232-260.2001","article-title":"Tetracycline Antibiotics: Mode of action, applications, molecular biology, and epidemiology of bacterial resistance","volume":"65","author":"Chopra","year":"2001","journal-title":"Microbiol. Mol. Biol. Rev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Tabcheh, J., Vergalli, J., Davin-R\u00e9gli, A., Ghanem, N., Pages, J.-M., Al-Bayssari, C., and Brunel, J.M. (2023). Rejuvenating the Activity of Usual Antibiotics on Resistant Gram-Negative Bacteria: Recent Issues and Perspectives. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24021515"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1021\/jacsau.2c00532","article-title":"Chemical Basis of Combination Therapy to Combat Antibiotic Resistance","volume":"3","author":"Si","year":"2023","journal-title":"JACS Au"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Rusu, A., and Buta, E.L. (2021). The Development of Third-Generation Tetracycline Antibiotics and New Perspectives. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13122085"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1086\/367622","article-title":"Tetracycline therapy: Update","volume":"36","author":"Eliopoulos","year":"2003","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1101\/cshperspect.a025387","article-title":"Tetracycline antibiotics and resistance","volume":"6","author":"Grossman","year":"2016","journal-title":"Cold Spring Harb Perspect Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1128\/CMR.00043-12","article-title":"Adaptive and mutational resistance: Role of porins and efflux pumps in drug resistance","volume":"25","author":"Hancock","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_26","first-page":"1","article-title":"Distinct roles of outer membrane porins in antibiotic resistance and membrane integrity in Escherichia coli","volume":"953","author":"Choi","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1038\/s42003-020-0966-5","article-title":"Tetracycline-inactivating enzymes from environmental, human commensal, and pathogenic bacteria cause broad-spectrum tetracycline resistance","volume":"3","author":"Gasparrini","year":"2020","journal-title":"Commun. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/0022-2836(71)90255-5","article-title":"Role of magnesium in the binding of tetracycline to Escherichia coli ribosomes","volume":"58","author":"White","year":"1971","journal-title":"J. Mol. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"106438","DOI":"10.1016\/j.ijantimicag.2021.106438","article-title":"Effect of iron chelation on anti-pseudomonal activity of doxycycline","volume":"58","author":"Faure","year":"2021","journal-title":"Int. J. Antimicrob. Agents."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yang, X., Domalaon, R., Lyu, Y., Zhanel, G.G., and Schweizer, F. (2018). Tobramycin-linked efflux pump inhibitor conjugates synergize fluoroquinolones, rifampicin and fosfomycin against multidrug-resistant Pseudomonas aeruginosa. J. Clin. Med., 7.","DOI":"10.3390\/jcm7070158"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"864","DOI":"10.1021\/acsinfecdis.2c00549","article-title":"Chimeric Tobramycin-Based Adjuvant TOB-TOB-CIP Potentiates Fluoroquinolone and \u03b2-Lactam Antibiotics against Multidrug-Resistant Pseudomonas aeruginosa","volume":"9","author":"Dhiman","year":"2023","journal-title":"ACS Infect. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1002\/anie.201508330","article-title":"Adjuvants based on hybrid antibiotics overcome resistance in Pseudomonas aeruginosa and enhance fluoroquinolone efficacy","volume":"55","author":"Gorityala","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e00077-17","DOI":"10.1128\/CMR.00077-17","article-title":"Antibiotic hybrids: The next generation of agents and adjuvants against gram-negative pathogens?","volume":"31","author":"Domalaon","year":"2018","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"553","DOI":"10.2165\/00003495-199958030-00021","article-title":"Deferiprone: A review of its clinical potentitial in iron overload in beta-thalassaemia and other transfusion-dependent diseases","volume":"58","author":"Foster","year":"1999","journal-title":"Drugs"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5999","DOI":"10.1039\/c2dt32373g","article-title":"In vitro studies of lanthanide complexes for the treatment of osteoporosis","volume":"42","author":"Mawani","year":"2013","journal-title":"Dalton Trans."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/jac\/dkg301","article-title":"Synergy, antagonism, and what the chequerboard puts between them","volume":"52","author":"Odds","year":"2003","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_37","unstructured":"Clinical and Laboratory Standards Institute (2021). Performance Standards for Antimicrobial Susceptibility Testing, Clinical and Laboratory Standards Institute. [31st ed.]. CLSI Supplement M100."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1021\/la504407v","article-title":"Effect of divalent cation removal on the structure of gram-negative bacterial outer membrane models","volume":"31","author":"Clifton","year":"2015","journal-title":"Langmuir"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1021\/acschembio.1c00179","article-title":"Chemical Screen for Vancomycin Antagonism Uncovers Probes of the Gram-Negative Outer Membrane","volume":"16","author":"Klobucar","year":"2021","journal-title":"ACS Chem. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1007\/BF01975036","article-title":"Antibiotic uptake into Gram-negative bacteria","volume":"7","author":"Hancock","year":"1988","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1146\/annurev.mi.38.100184.001321","article-title":"Alterations in outer membrane permeability","volume":"38","author":"Hancock","year":"1984","journal-title":"Annu. Rev. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"6379","DOI":"10.1016\/j.bmc.2016.06.044","article-title":"A gestalt approach to Gram-negative entry","volume":"24","author":"Silver","year":"2016","journal-title":"Bioorg. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e00935-19","DOI":"10.1128\/AAC.00935-19","article-title":"Outer Membrane Interaction Kinetics of New Polymyxin B Analogs in Gram-Negative Bacilli","volume":"63","author":"Akhoundsadegh","year":"2019","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1128\/AAC.01538-07","article-title":"Canadian antimicrobial resistance alliance (CARA) Hoban DJ; Antimicrobial resistant pathogens in intensive care units in Canada: Results of the Canadian National Intensive Care Unit (CAN-ICU) study, 2005\u20132006","volume":"52","author":"Zhanel","year":"2008","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"i3","DOI":"10.1093\/jac\/dkt021","article-title":"Introduction to the CANWARD study (2007\u201311)","volume":"68","author":"Hoban","year":"2013","journal-title":"J. Antimicrob. Chemother."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1565","DOI":"10.1039\/D1MD00206F","article-title":"A niclosamide\u2013tobramycin hybrid adjuvant potentiates cefiderocol against P. aeruginosa","volume":"12","author":"Berry","year":"2021","journal-title":"RSC Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Ramirez, D.M., Ramirez, D., Arthur, G., Zhanel, G., and Schweizer, F. (2022). Guanidinylated polymyxins as outer membrane permeabilizers capable of potentiating rifampicin, erythromycin, ceftazidime and aztreonam against gram-negative bacteria. 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