Growing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones. While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel. Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes. Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes.

对核糖体靶向大环内酯类抗生素日益增长的耐药性限制了它们的临床用途，并促使人们寻找更优质的化合物。大环酮类药物是具有喹诺酮侧链的合成大环内酯衍生物，其结构与靶向 DNA 拓扑异构酶的氟喹诺酮类药物相似。虽然大环酮表现出增强的活性，但它们的作用方式仍然未知。在这里，我们提出了核糖体结合大环内酯的第一个结构，表明大环内酯部分占据了核糖体出口隧道中的大环内酯结合位点，而喹诺酮部分与隧道建立了新的相互作用。 Macrolones 在体外可有效抑制核糖体和 DNA 拓扑异构酶。然而，在细胞中，它们要么以核糖体或 DNA 旋转酶为目标，要么同时以两者为目标。与单独使用大环内酯类或氟喹诺酮类抗生素相比，双靶向大环酮类抗生素不太容易选择携带靶位点突变的耐药细菌或激活诱导型大环内酯类耐药基因。此外，由于一些大环酮与 Erm 修饰的核糖体结合，因此它们甚至能针对具有组成型erm抗性基因的菌株保留活性。