A synthetic antibiotic class overcoming bacterial multidrug resistance
A synthetic antibiotic class overcoming bacterial multidrug resistance
复制标题
DOI：
10.1038/s41586-021-04045-6
复制
发表时间：
2021-10-27
期刊：
影响因子：
64.8
通讯作者：
Myers, Andrew G.
中科院分区：
文献类型：
--
作者：
Mitcheltree, Matthew J.;Pisipati, Amarnath;Myers, Andrew G.
有效对抗耐药性细菌的新药的缺乏是一个日益严重的全球公共卫生问题（1）。五十多年来，寻找新的抗生素在很大程度上依赖于天然产物的化学修饰（半合成），这是一种无法应对快速演变的耐药性威胁的方法。半合成修饰通常在多官能抗生素中具有有限的范围，通常增加分子量，并且很少允许底层支架的修饰。如果设计得当，全合成路线可以很容易地解决这些缺点（2）。在这里，我们报告的结构指导设计和组件为基础的合成刚性oxepanoproline支架，当连接到克林霉素的氨基辛糖残基，产生一种抗生素的特殊效力和活性谱，我们命名为iboxamycin。伊博霉素对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，这些酶是赋予对靶向核糖体大亚基的所有临床相关抗生素（即大环内酯类、林可酰胺类、酚类、恶唑烷酮类、截短侧耳素和链阳性菌素）耐药性的基因产物。对iboxamycin与天然细菌核糖体以及Erm-甲基化核糖体复合物的X射线晶体学研究揭示了这种增强活性的结构基础，包括抗生素结合后m（2）（6）A2058核苷酸的置换。伊博霉素是口服生物可利用的，安全有效地治疗小鼠中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，以提供新的抗生素在耐药性增加的时代。
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.