Salian, Sumantha; Matt, Tanja; Akbergenov, Rashid; Harish, Shinde; Meyer, Martin; Duscha, Stefan; Shcherbakov, Dmitri; Bernet, Bruno B; Vasella, Andrea; Westhof, Eric; Böttger, Erik C (2012). Structure-activity relationships among the kanamycin aminoglycosides: role of ring I hydroxy and amino groups. Antimicrobial Agents and Chemotherapy, 56(12):6104-6108.
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The kanamycins form an important subgroup of the 4,6-disubstituted 2-deoxystreptamine aminoglycoside antibiotics, comprising kanamycin A, kanamycin B, tobramycin and dibekacin. These compounds interfere with protein synthesis by targeting the ribosomal decoding A site and they differ in the number and location of amino and hydroxy groups of the glucopyranosyl moiety (ring I). We have synthesized kanamycin analogues characterized by subtle variations of the 2' and 6' substituents of ring I. The functional activities of the kanamycins and the synthesized analogues were investigated i) in cell-free translation assays on wild-type and mutant bacterial ribosomes to study drug-target interaction, ii) in MIC assays to assess antibacterial activity, and iii) in rabbit reticulocyte translation assays to determine activity on eukaryotic ribosomes. Position 2' forms an intramolecular H-bond with O5 of ring II, helping the relative orientations of the two rings with respect to each other. This bond becomes critical for drug activity when a 6' OH substituent is present. Our results point to complex synergistic interactions crucial for aminoglycoside binding and activity.
|Item Type:||Journal Article, refereed, original work|
|Communities & Collections:||04 Faculty of Medicine > Institute of Medical Microbiology|
|DDC:||570 Life sciences; biology|
610 Medicine & health
|Deposited On:||16 Nov 2012 09:00|
|Last Modified:||27 Nov 2013 18:36|
|Publisher:||American Society for Microbiology (ASM)|
|Citations:||Web of Science®. Times Cited: 3|
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