Institut für Medizinische Mikrobiologie, Universität Zürich, Gloriastrasse 30/32, 8006 Zürich, Switzerland.
Antimicrob Agents Chemother. 2011 Sep;55(9):4096-102. doi: 10.1128/AAC.01398-10. Epub 2011 Jul 5.
Antibiotics targeting the bacterial ribosome typically bind to highly conserved rRNA regions with only minor phylogenetic sequence variations. It is unclear whether these sequence variations affect antibiotic susceptibility or resistance development. To address this question, we have investigated the drug binding pockets of aminoglycosides and macrolides/ketolides. The binding site of aminoglycosides is located within helix 44 of the 16S rRNA (A site); macrolides/ketolides bind to domain V of the 23S rRNA (peptidyltransferase center). We have used mutagenesis of rRNA sequences in Mycobacterium smegmatis ribosomes to reconstruct the different bacterial drug binding sites and to study the effects of rRNA sequence variations on drug activity. Our results provide a rationale for differences in species-specific drug susceptibility patterns and species-specific resistance phenotypes associated with mutational alterations in the drug binding pocket.
针对细菌核糖体的抗生素通常与高度保守的 rRNA 区域结合，只有微小的系统发育序列变化。目前尚不清楚这些序列变化是否会影响抗生素敏感性或耐药性的发展。为了解决这个问题，我们研究了氨基糖苷类和大环内酯类/酮内酯类抗生素的药物结合口袋。氨基糖苷类抗生素的结合位点位于 16S rRNA 的螺旋 44 内（A 位）；大环内酯类/酮内酯类与 23S rRNA 的结构域 V 结合（肽基转移酶中心）。我们使用分枝杆菌核糖体 rRNA 序列的突变来重建不同的细菌药物结合位点，并研究 rRNA 序列变化对药物活性的影响。我们的结果为不同物种的药物敏感性模式和与药物结合口袋突变相关的特定物种耐药表型的差异提供了依据。
