小柯机器人

美国哈佛大学Andrew G. Myers、伊利诺伊大学芝加哥分校Yury S. Polikanov等研究人员合作开发出一种克服细菌多药耐药的合成抗生素。这一研究成果于2021年10月27日在线发表在国际学术期刊《自然》上。

研究人员报告了结构指导下的设计和基于成分的刚性oxepanoproline支架合成，当它与克林霉素的氨基辛糖残基连接时，产生了一种具有特殊效力和活性谱的抗生素，研究人员称之为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，这些基因的产物对所有针对大核糖体亚单位的临床相关抗生素，即大环内酯类、林可酰胺类、酚类、噁唑烷酮类、胸腺素类和链霉素类都有抗性。

iboxamycin与细菌核糖体以及与Erm甲基化的核糖体复合物的X射线晶体学研究，揭示了这种活性增强的结构基础，包括抗生素结合后m⁶₂A2058核苷酸的位移。iboxamycin在治疗小鼠的革兰氏阳性和革兰氏阴性细菌感染方面具有口服生物利用性、安全性和有效性，进而证明了在抗药性不断增加的时代，化学合成提供新抗生素的能力。

据悉，对抗抗生素耐药性细菌的新药匮乏，是一个日益严重的全球公共卫生问题。五十多年来，寻找新的抗生素在很大程度上依赖于天然产品的化学修饰（半合成），这种方法不适合对抗快速发展的抗生素威胁。半合成修饰通常在多功能抗生素中范围有限，通常会增加分子量，而且很少允许对基础支架进行修改。如果设计得当，全合成路线可以轻松解决这些缺陷。

附：英文原文

Title: A synthetic antibiotic class overcoming bacterial multidrug resistance

Author: 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.

Issue&Volume: 2021-10-27

Abstract: The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern1. 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 shortcomings2. 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 m62A2058 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.

DOI: 10.1038/s41586-021-04045-6

Source: https://www.nature.com/articles/s41586-021-04045-6

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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