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Aminoglycosides are a well\u2010studied, highly potent class of naturally occurring antibiotics with scaffolds amenable to modification, and therefore, they provide an excellent starting point for the development of semisynthetic, next\u2010generation compounds. To explore the potential of this approach, we synthesized a small library of aminoglycoside derivatives selectively and minimally modified at one or two positions with a guanidine group replacing the corresponding amine or hydroxy functionality. Most guanidino\u2010aminoglycosides showed increased affinity for the ribosomal decoding rRNA site, the cognate biological target of the natural products, when compared with their parent antibiotics, as measured by an in vitro fluorescence resonance energy transfer (FRET) A\u2010site binding assay. Additionally, certain analogues showed improved minimum inhibitory concentration (MIC) values against resistant bacterial strains, including methicillin\u2010resistant <jats:italic>Staphylococcus aureus<\/jats:italic> (MRSA). An amikacin derivative holds particular promise with activity greater than or equal to the parent antibiotic in the majority of bacterial strains tested.<\/jats:p>","DOI":"10.1002\/cmdc.201200150","type":"journal-article","created":{"date-parts":[[2012,5,25]],"date-time":"2012-05-25T16:39:31Z","timestamp":1337963971000},"page":"1237-1244","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Selectively Guanidinylated Aminoglycosides as Antibiotics"],"prefix":"10.1002","volume":"7","author":[{"given":"Richard J.","family":"Fair","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary E.","family":"Hensler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wdee","family":"Thienphrapa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quang N.","family":"Dam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Nizet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yitzhak","family":"Tor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,5,25]]},"reference":[{"key":"e_1_2_7_1_2","unstructured":"\u00a0"},{"key":"e_1_2_7_2_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.43.4.727"},{"key":"e_1_2_7_3_2","doi-asserted-by":"publisher","DOI":"10.1211\/0022357011775514"},{"key":"e_1_2_7_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.45.4.999-1007.2001"},{"key":"e_1_2_7_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/CMR.16.3.430-450.2003"},{"key":"e_1_2_7_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2006.03.038"},{"key":"e_1_2_7_7_2","unstructured":"\u00a0"},{"key":"e_1_2_7_8_2","doi-asserted-by":"publisher","DOI":"10.2217\/fmb.11.23"},{"key":"e_1_2_7_9_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0031-1275527"},{"key":"e_1_2_7_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.00103-06"},{"key":"e_1_2_7_11_2","unstructured":"\u00a0"},{"key":"e_1_2_7_12_2","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.009142-0"},{"key":"e_1_2_7_13_2","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2334-11-187"},{"key":"e_1_2_7_14_2","unstructured":"\u00a0"},{"key":"e_1_2_7_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.amjmed.2005.05.009"},{"key":"e_1_2_7_16_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.2011.05962.x"},{"key":"e_1_2_7_17_2","unstructured":"\u00a0"},{"key":"e_1_2_7_18_2","doi-asserted-by":"publisher","DOI":"10.1021\/np030096l"},{"key":"e_1_2_7_19_2","doi-asserted-by":"publisher","DOI":"10.1021\/np068054v"},{"key":"e_1_2_7_20_2","unstructured":"\u00a0"},{"key":"e_1_2_7_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2201"},{"key":"e_1_2_7_22_2","doi-asserted-by":"publisher","DOI":"10.1039\/b816852k"},{"key":"e_1_2_7_23_2","doi-asserted-by":"publisher","DOI":"10.1517\/17460440903493449"},{"key":"e_1_2_7_24_2","unstructured":"\u00a0"},{"key":"e_1_2_7_25_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986707780362817"},{"key":"e_1_2_7_26_2","doi-asserted-by":"publisher","DOI":"10.1586\/14787210.6.5.593"},{"key":"e_1_2_7_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0025-6196(11)65134-3"},{"key":"e_1_2_7_28_2","unstructured":"\u00a0"},{"key":"e_1_2_7_29_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/S0026-895X(25)14722-6","volume":"1","author":"Davies J.","year":"1965","journal-title":"Mol. 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