Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, 60607, USA.
Department of Biology, Northeastern University, Boston, MA, 02115, USA.
Nat Commun. 2023 Jul 14;14(1):4196. doi: 10.1038/s41467-023-39653-5.
The ever-growing rise of antibiotic resistance among bacterial pathogens is one of the top healthcare threats today. Although combination antibiotic therapies represent a potential approach to more efficiently combat infections caused by susceptible and drug-resistant bacteria, only a few known drug pairs exhibit synergy/cooperativity in killing bacteria. Here, we discover that well-known ribosomal antibiotics, hygromycin A (HygA) and macrolides, which target peptidyl transferase center and peptide exit tunnel, respectively, can act cooperatively against susceptible and drug-resistant bacteria. Remarkably, HygA slows down macrolide dissociation from the ribosome by 60-fold and enhances the otherwise weak antimicrobial activity of the newest-generation macrolide drugs known as ketolides against macrolide-resistant bacteria. By determining a set of high-resolution X-ray crystal structures of drug-sensitive wild-type and macrolide-resistant Erm-methylated 70S ribosomes in complex with three HygA-macrolide pairs, we provide a structural rationale for the binding cooperativity of these drugs and also uncover the molecular mechanism of overcoming Erm-type resistance by macrolides acting together with hygromycin A. Altogether our structural, biochemical, and microbiological findings lay the foundation for the subsequent development of synergistic antibiotic tandems with improved bactericidal properties against drug-resistant pathogens, including those expressing erm genes.
抗生素耐药性在细菌病原体中的不断上升是当今医疗保健面临的最大威胁之一。尽管联合抗生素疗法代表了一种更有效地对抗敏感和耐药细菌引起的感染的潜在方法，但只有少数已知的药物对在杀死细菌方面表现出协同作用/协同作用。在这里，我们发现，靶向肽基转移酶中心和肽出口隧道的两种已知核糖体抗生素，潮霉素 A（HygA）和大环内酯类抗生素，可以协同作用于敏感和耐药细菌。值得注意的是，HygA 将大环内酯类药物从核糖体上的解离速度减慢了 60 倍，并增强了新型大环内酯类药物酮内酯对大环内酯类耐药细菌的弱抗菌活性。通过确定一组高分辨率的药物敏感野生型和大环内酯类耐药 Erm 甲基化 70S 核糖体与三种 HygA-大环内酯类药物对的复合物的 X 射线晶体结构，我们为这些药物的结合协同作用提供了结构基础，还揭示了大环内酯类药物与 HygA 一起作用克服 Erm 型耐药性的分子机制。总的来说，我们的结构、生化和微生物学发现为随后开发具有改善杀菌特性的协同抗生素对包括表达 erm 基因的耐药病原体奠定了基础。
