Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRNA
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DOI：
10.1046/j.1365-2958.2000.01841.x
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发表时间：
2000-04-01
影响因子：
3.6
通讯作者：
Mauvais, P
中科院分区：
文献类型：
--
作者：
Douthwaite, S;Hansen, LH;Mauvais, P
大环内酯类抗生素红霉素及其6-O-甲基衍生物（克拉霉素）主要通过与23 S rRNA结构域II和V中的核苷酸相互作用与细菌核糖体结合。结构域II相互作用发生在核苷酸A752和大环内酯3-克拉定糖部分之间。去除克拉定糖和取代3-酮基（形成酮内酯RU 56006），导致A752相互作用的丧失和药物结合亲和力下降约100倍。在结构域V内，药物结合的关键决定因素是核苷酸A2058，并且在该位置的G取代是一些临床病原体中耐药性的主要原因。2058 G突变破坏了药物-结构域V接触，并导致RU 56006的结合进一步降低> 25000倍。通过与药物11/12位的氨基甲酸酯连接的烷基-芳基与A752形成替代和更有效的接触（在酮内酯抗生素HMR 3647和HMR 3004中），可以将药物与耐药核糖体的结合提高3000倍以上。这些数据表明，同时与域II和V的药物相互作用加强结合，域II接触是特别重要的，以实现结合到核糖体的耐药病原体，其中域V的相互作用被扰乱。
The macrolide antibiotic erythromycin and its 6-O-methyl derivative (clarithromycin) bind to bacterial ribosomes primarily through interactions with nucleotides in domains II and V of 23S rRNA. The domain II interaction occurs between nucleotide A752 and the macrolide 3-cladinose moiety. Removal of the cladinose, and substitution of a 3-keto group (forming the ketolide RU 56006), results in loss of the A752 interaction and an approximate to 100-fold drop in drug binding affinity. Within domain V, the key determinant of drug binding is nucleotide A2058 and substitution of G at this position is the major cause of drug resistance in some clinical pathogens. The 2058G mutation disrupts the drug-domain V contact and leads to a further > 25 000-fold decrease in the binding of RU 56006. Drug binding to resistant ribosomes can be improved over 3000-fold by forming an alternative and more effective contact to A752 via alkyl-aryl groups linked to a carbamate at the drug 11/12 position (in the ketolide antibiotics HMR 3647 and HMR 3004). The data indicate that simultaneous drug interactions with domains II and V strengthen binding and that the domain II contact is of particular importance to achieve binding to the ribosomes of resistant pathogens in which the domain V interaction is perturbed.