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 \({\text{m}}_{2}^{6}\text{A}2058\) 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.

有效对抗抗生素耐药细菌的新药的缺乏引起了全球日益严重的公共卫生问题¹。五十多年来，新抗生素的寻找在很大程度上依赖于天然产物的化学修饰（半合成），这种方法不足以应对快速发展的耐药性威胁。半合成修饰在多功能抗生素中的范围通常有限，通常会增加分子量，并且很少允许对基础支架进行修饰。如果设计得当，全合成路线可以轻松解决这些缺点²。在这里，我们报告了刚性氧杂脯氨酸支架的结构引导设计和基于成分的合成，当该支架与克林霉素的氨基辛糖残基连接时，产生一种具有特殊效力和活性谱的抗生素，我们将其命名为伊博霉素。Iboxamycin 可有效对抗 ESKAPE 病原体，包括表达 Erm 和 Cfr 核糖体 RNA 甲基转移酶的菌株，这些基因产物赋予针对大核糖体亚基的所有临床相关抗生素（即大环内酯类、林可酰胺类、苯酚类、恶唑烷酮类、截短侧耳素和链阳菌素）的抗性。伊博霉素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 \({ \text{m}}_{抗生素结合后的2}^{6}\text{A}2058\)核苷酸。伊博霉素具有口服生物活性，可安全有效地治疗小鼠革兰氏阳性和革兰氏阴性细菌感染，这证明了化学合成在耐药性日益增强的时代提供新抗生素的能力。