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Co-produced natural ketolides methymycin and pikromycin inhibit bacterial growth by preventing synthesis of a limited number of proteins
Nucleic Acids Research ( IF 14.9 ) Pub Date : 2017-07-29 , DOI: 10.1093/nar/gkx673
Mashal M. Almutairi , Maxim S. Svetlov , Douglas A. Hansen , Nelli F. Khabibullina , Dorota Klepacki , Han-Young Kang , David H. Sherman , Nora Vázquez-Laslop , Yury S. Polikanov , Alexander S. Mankin

Antibiotics methymycin (MTM) and pikromycin (PKM), co-produced by Streptomyces venezuelae, represent minimalist macrolide protein synthesis inhibitors. Unlike other macrolides, which carry several side chains, a single desosamine sugar is attached to the macrolactone ring of MTM and PKM. In addition, the macrolactone scaffold of MTM is smaller than in other macrolides. The unusual structure of MTM and PKM and their simultaneous secretion by S. venezuelae bring about the possibility that two compounds would bind to distinct ribosomal sites. However, by combining genetic, biochemical and crystallographic studies, we demonstrate that MTM and PKM inhibit translation by binding to overlapping sites in the ribosomal exit tunnel. Strikingly, while MTM and PKM readily arrest the growth of bacteria, ∼40% of cellular proteins continue to be synthesized even at saturating concentrations of the drugs. Gel electrophoretic analysis shows that compared to other ribosomal antibiotics, MTM and PKM prevent synthesis of a smaller number of cellular polypeptides illustrating a unique mode of action of these antibiotics.

中文翻译:

共同生产的天然酮酚内酯霉素和吡咯霉素可通过阻止有限数量的蛋白质合成来抑制细菌生长

委内瑞斯链霉菌(Streptomyces委内瑞拉)共同生产的抗生素甲霉素(MTM)和吡咯霉素(PKM)代表了简约的大环内酯类蛋白质合成抑制剂。与带有多个侧链的其他大环内酯类化合物不同,单个去氨胺糖附着在MTM和PKM的大内酯环上。另外,MTM的大内酯支架比其他大环内酯类中的小。MTM和PKM的异常结构以及委内瑞拉链球菌同时分泌的MTM和PKM导致两种化合物结合到不同的核糖体位点的可能性。但是,通过结合遗传,生化和晶体学研究,我们证明了MTM和PKM通过与核糖体出口通道中的重叠位点结合来抑制翻译。令人惊讶的是,尽管MTM和PKM可以轻易阻止细菌的生长,但即使在药物浓度达到饱和的情况下,仍有约40%的细胞蛋白继续合成。凝胶电泳分析表明,与其他核糖体抗生素相比,MTM和PKM阻止了更少量细胞多肽的合成,说明了这些抗生素的独特作用方式。
更新日期:2017-09-21
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