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A synthetic antibiotic class overcoming bacterial multidrug resistance

机译：克服细菌多药抗性的合成抗生素类

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摘要

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern(1). For more than five decades, the search for new antibiotics has relied heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings(2). Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the m(2)(6)A2058 nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.
机译：对抗生素抗性细菌有效的新药的缺乏呈现出越来越多的全球公共卫生关注（1）。五十多年来，对新抗生素的搜索很大程度上依赖于天然产物（半合成）的化学改性，这是一种能够发挥迅速发展的抵抗威胁的方法。半合成修饰通常在多官能抗生素中的范围有限，通常会增加分子量，并且很少允许潜在的支架的修饰。当正确设计时，完全合成路线可以轻松解决这些缺点（2）。在这里，我们报告了结构引导的设计和基于组分的合成刚性氧己糖素支架，当与克林霉素的氨杂蛋白的氨偶联残留物连接时，产生具有卓越效力和活性的抗生素，我们称之为Iboxamycin。 Iboxamycin对Eskape病原体有效，包括表达ERM和CFR核糖体RNA甲基转移酶的菌株，赋予所有临床相关抗生素的基因产物，靶向大核糖体亚基，即大溴磷酸，林膦酰胺，苯上酚，恶唑烷酮，葡萄糖素和链图。 X射线晶体与天然细菌核糖体中复合物的X射线晶体研究，以及ERM-甲基化核糖体，揭示这种增强活性的结构基础，包括抗生素上的M（2）（6）A2058核苷酸的位移捆绑。 Iboxamycin是口服生物的，安全有效地治疗小鼠的革兰氏阳性和革兰氏阴性细菌感染，证明了化学合成的能力，以在耐受性增加的时代提供新的抗生素。

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  • 来源
    《Nature》 |2021年第7885期|507-512|共6页
  • 作者

    Mitcheltree Matthew J.; Pisipati Amarnath; Syroegin Egor A.; Silvestre Katherine J.; Klepacki Dorota; Mason Jeremy D.; Terwilliger Daniel W.; Testolin Giambattista; Pote Aditya R.; Wu Kelvin J. Y.; Ladley Richard Porter; Chatman Kelly; Mankin Alexander S.; Polikanov Yury S.; Myers Andrew G.;

  • 作者单位

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Univ Illinois Dept Biol Sci Chicago IL 60680 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Univ Illinois Dept Pharmaceut Sci Chicago IL USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

    Harvard Univ Harvard Ctr Mass Spectrometry Cambridge MA 02138 USA;

    Univ Illinois Dept Pharmaceut Sci Chicago IL USA;

    Univ Illinois Dept Biol Sci Chicago IL 60680 USA;

    Harvard Univ Dept Chem & Chem Biol Cambridge MA 02138 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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