Rivalta André, Fedorenko Aliza, Le Scornet Alexandre, Thompson Sophie, Halfon Yehuda, Breiner Goldstein Elinor, Çavdaroglu Sude, Melenitzky Tal, Hiregange Disha-Gajanan, Zimmerman Ella, Bashan Anat, Yap Mee-Ngan Frances, Yonath Ada
Department of Chemical and Structural Biology, Weizmann Institute of Science, Rehovot, Israel.
Department of Microbiology-Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
Life Sci Alliance. 2025 Jun 9;8(8). doi: 10.26508/lsa.202503325. Print 2025 Aug.
Antimicrobial resistance is a major global health challenge, diminishing the efficacy of many antibiotics, including macrolides. In , an opportunistic pathogen, macrolide resistance is primarily mediated by Erm-family methyltransferases, which mono- or dimethylate A2058 in the 23S ribosomal RNA, reducing drug binding. Although macrolide-ribosome interactions have been characterized in nonpathogenic species, their structural basis in clinically relevant pathogens remains limited. In this study, we investigate the impact of -mediated resistance on drug binding by analyzing ribosomes from strains with varying levels of expression and activity. Using cryo-electron microscopy, we determined the high-resolution structures of solithromycin-bound ribosomes, including those with dimethylated A2058. Our structural analysis reveals the specific interactions that enable solithromycin binding despite double methylation and resistance, as corroborated by microbiological and biochemical data, suggesting that further optimization of ketolide-ribosome interactions could enhance macrolide efficacy against resistant strains.
抗菌药物耐药性是一项重大的全球健康挑战，它降低了包括大环内酯类药物在内的许多抗生素的疗效。在机会致病菌中，大环内酯类耐药性主要由Erm家族甲基转移酶介导，该酶使23S核糖体RNA中的A2058发生单甲基化或二甲基化，从而减少药物结合。尽管大环内酯类与核糖体的相互作用已在非致病物种中得到表征，但其在临床相关病原体中的结构基础仍然有限。在本研究中，我们通过分析来自具有不同表达水平和活性的菌株的核糖体，研究介导的耐药性对药物结合的影响。使用冷冻电子显微镜，我们确定了与索利霉素结合的核糖体的高分辨率结构，包括那些具有二甲基化A2058的核糖体。我们的结构分析揭示了尽管存在双甲基化和耐药性但仍能使索利霉素结合的特定相互作用，微生物学和生化数据证实了这一点，这表明进一步优化酮内酯-核糖体相互作用可以提高大环内酯类药物对耐药菌株的疗效。
