Rational design of azepane-glycoside antibiotics targeting the bacterial ribosome |
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Authors: | Barluenga Sofia Simonsen Klaus B Littlefield Ethel S Ayida Benjamin K Vourloumis Dionisios Winters Geoffrey C Takahashi Masayuki Shandrick Sarah Zhao Qiang Han Qing Hermann Thomas |
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Affiliation: | Department of Medicinal Chemistry, Anadys Pharmaceuticals, Inc, 9050 Camino Santa Fe, San Diego, CA 92121, USA. |
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Abstract: | RNA recognition by natural aminoglycoside antibiotics depends on the 2-deoxystreptamine (2-DOS) scaffold which participates in specific hydrogen bonds with the ribosomal decoding-site target. Three-dimensional structure information has been used for the design of azepane-monoglycosides, building blocks for novel antibiotics in which 2-DOS is replaced by a heterocyclic scaffold. Azepane-glycosides showed target binding and translation inhibition in the low micromolar range and inhibited growth of Staphylococcus aureus, including aminoglycoside-resistant strains. |
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