{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T19:03:48Z","timestamp":1792091028537,"version":"4.4.0"},"reference-count":45,"publisher":"American Society for Microbiology","issue":"5","license":[{"start":{"date-parts":[[2014,9,30]],"date-time":"2014-09-30T00:00:00Z","timestamp":1412035200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-sa\/3.0\/"},{"start":{"date-parts":[[2014,10,31]],"date-time":"2014-10-31T00:00:00Z","timestamp":1414713600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["mBio"],"published-print":{"date-parts":[[2014,10,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:p>The emerging epidemic of drug resistance places the development of efficacious and safe antibiotics in the spotlight of current research. Here, we report the design of next-generation aminoglycosides. Discovery efforts were driven by rational synthesis focusing on 4\u2032 alkylations of the aminoglycoside paromomycin, with the goal to alleviate the most severe and disabling side effect of aminoglycosides\u2014irreversible hearing loss. Compounds were evaluated for target activity in<jats:italic>in vitro<\/jats:italic>ribosomal translation assays, antibacterial potency against selected pathogens, cytotoxicity against mammalian cells, and<jats:italic>in vivo<\/jats:italic>ototoxicity. The results of this study produced potent compounds with excellent selectivity at the ribosomal target, promising antibacterial activity, and little, if any, ototoxicity upon chronic administration. The favorable biocompatibility profile combined with the promising antibacterial activity emphasizes the potential of next-generation aminoglycosides in the treatment of infectious diseases without the risk of ototoxicity.<\/jats:p><jats:p><jats:bold>IMPORTANCE<\/jats:bold>The ever-widening epidemic of multidrug-resistant infectious diseases and the paucity of novel antibacterial agents emerging from modern screening platforms mandate the reinvestigation of established drugs with an emphasis on improved biocompatibility and overcoming resistance mechanisms. Here, we describe the preparation and evaluation of derivatives of the established aminoglycoside antibiotic paromomycin that effectively remove its biggest deficiency, ototoxicity, and overcome certain bacterial resistance mechanisms.<\/jats:p>","DOI":"10.1128\/mbio.01827-14","type":"journal-article","created":{"date-parts":[[2014,10,1]],"date-time":"2014-10-01T08:13:13Z","timestamp":1412151193000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":40,"title":["Identification and Evaluation of Improved 4\u2032-<i>O<\/i>-(Alkyl) 4,5-Disubstituted 2-Deoxystreptamines as Next-Generation Aminoglycoside Antibiotics"],"prefix":"10.1128","volume":"5","author":[{"given":"Stefan","family":"Duscha","sequence":"first","affiliation":[{"name":"Institut f\u00fcr Medizinische Mikrobiologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heithem","family":"Boukari","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Mikrobiologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitri","family":"Shcherbakov","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Mikrobiologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumantha","family":"Salian","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie, ETH Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrina","family":"Silva","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie, ETH Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Kendall","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayuki","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Wayne State University, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rashid","family":"Akbergenov","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Mikrobiologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Perez-Fernandez","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie, ETH Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruno","family":"Bernet","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie, ETH Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swapna","family":"Vaddi","sequence":"additional","affiliation":[{"name":"Euprotec Limited, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pia","family":"Thommes","sequence":"additional","affiliation":[{"name":"Euprotec Limited, Manchester, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jochen","family":"Schacht","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, Kresge Hearing Research Institute, University of Michigan, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Crich","sequence":"additional","affiliation":[{"name":"Department of Chemistry, Wayne State University, Detroit, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Vasella","sequence":"additional","affiliation":[{"name":"Laboratorium f\u00fcr Organische Chemie, ETH Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik C.","family":"B\u00f6ttger","sequence":"additional","affiliation":[{"name":"Institut f\u00fcr Medizinische Mikrobiologie, Universit\u00e4t Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0924-8579(10)70003-0"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2201"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmed.2007.04.004"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1176667"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1021\/np068054v"},{"key":"e_1_3_3_7_2","unstructured":"World Health Organization . 2007. Critically important antimicrobials for human medicine. Categorization for the development of risk management strategies to contain antimicrobial resistance due to non-human antimicrobial use. Report of the Second WHO Expert Meeting Copenhagen 29 to 31 May 2007. World Health Organization Geneva Switzerland. http:\/\/www.who.int\/foodborne_disease\/resistance\/antimicrobials_human.pdf."},{"key":"e_1_3_3_8_2","first-page":"1103","volume-title":"Goodmann & Gilman\u2019s the pharmaceutical basis of therapeutics","author":"Chambers HF","year":"1996","unstructured":"ChambersHF . 1996. Chemotherapy of microbial diseases, p 1103\u20131121. In HardmanJG LimbirdLE (ed), Goodmann & Gilman\u2019s the pharmaceutical basis of therapeutics, 10th ed. The McGraw-Hill Companies, New York, NY.","edition":"10"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.3109\/00365548.2012.747694"},{"key":"e_1_3_3_10_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0026-895X(25)14722-6","article-title":"Misreading of RNA codewords induced by aminoglycoside antibiotics","volume":"1","author":"Davies J","year":"1965","unstructured":"DaviesJ GoriniL DavisBD . 1965. Misreading of RNA codewords induced by aminoglycoside antibiotics. Mol. Pharmacol. 1:93\u2013106.","journal-title":"Mol. Pharmacol."},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(78)91493-6"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.08.097"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio0310-244a"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/35030019"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gki862"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200300657"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2004.11.073"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.49.12.5112-5118.2005"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.50.4.1489-1496.2006"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/18.11.3133"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/embo-reports\/kve062"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm658"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1261\/rna.805208"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/ijch.201000003"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1159\/000013861"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6815-7-5"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng0793-289"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1086\/381133"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707265105"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811258106"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1204073109"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M113.533588"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00572-10"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/anie.200500903"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/ml200202y"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.16.3.430-450.2003"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1021\/cr0301088"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/cbic.200900779"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3430-12.2013"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4112"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1002\/hlca.200890167"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm3012992"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd3845"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja000575w"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1021\/ja0543144"},{"key":"e_1_3_3_46_2","volume-title":"Resolving the antibiotic paradox.","author":"Wright GD","year":"1998","unstructured":"WrightGD BerghuisAM MobasheryS . 1998. Aminoglycoside antibiotics\u2014structure, function and resistance, p 27\u201369. In RosenB MobasheryS (ed), Resolving the antibiotic paradox. Springer Verlag, New York, NY."}],"container-title":["mBio"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01827-14","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/mBio.01827-14","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,5,4]],"date-time":"2025-05-04T23:10:47Z","timestamp":1746400247000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/mBio.01827-14"}},"subtitle":[],"editor":[{"given":"Julian E.","family":"Davies","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,10,31]]},"references-count":45,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2014,10,31]]}},"alternative-id":["10.1128\/mBio.01827-14"],"URL":"https:\/\/doi.org\/10.1128\/mbio.01827-14","relation":{},"ISSN":["2161-2129","2150-7511"],"issn-type":[{"value":"2161-2129","type":"print"},{"value":"2150-7511","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,10,31]]},"assertion":[{"value":"2014-08-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-08-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-09-30","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e01827-14"}}