A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA and for the antiprotozoal activity of aminoglycosides
A structural basis for the antibiotic resistance conferred by an A1408G mutation in 16S rRNA and for the antiprotozoal activity of aminoglycosides
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16S rRNA 中 A1408G 突变赋予的抗生素耐药性和氨基糖苷类抗原虫活性的结构基础
DOI：
10.1002/anie.201106084
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Jiro Kondo
中科院分区：
文献类型：
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作者：
Y. Matsumoto;K. Toh;K. Kataoka;T. Yamasoba;Jiro Kondo
氨基糖苷类抗生素是一种广谱的寡糖抗生素，对多种革兰氏阴性菌和某些革兰氏阳性菌起作用。[1]通过对30 S核糖体颗粒[2]、70 S完整核糖体[3]和与各种2-脱氧链霉胺氨基糖苷复合的模型寡核苷酸[4-14]的几项晶体学研究，在原子水平上揭示了它们的抗菌机制。氨基糖苷类特异性结合16 S rRNA上的A位点（图1a），根据密码子和反密码子之间的碱基对几何形状，可将同源tRNA与近同源tRNA区分开来。结合特异性主要由氨基糖苷类的环I赋予，其堆叠在G1491（大肠杆菌编号）上，并与细菌A位点中普遍保守的A1408形成假对（见图2a右侧和图3a右侧）。这些相互作用迫使A位点采取“开启”状态构象，其中A1492和A1493完全凸出，并与mRNA密码子和tRNA反密码子之间的前两个碱基对的浅沟/小沟发生A-小相互作用，即使当一个近同源的tRNA被递送到A位点时（图2a右侧），从而干扰解码过程的保真度。虽然氨基糖苷类药物已被用于治疗几种细菌感染，但我们几十年来面临的主要问题是耐药菌株的迅速增加。[15]在临床分离的龟分枝杆菌耐药菌株中发现了16 S rRNA 1408位从A到G的单染色体突变（见图1a），[16]
Aminoglycosides are broad spectrum oligosaccharide antibiotics acting against a variety of Gram-negative and certain Gram-positive bacteria.[1] Their antibacterial mechanism has been revealed at the atomic level by several crystallographic studies of the 30Sribosomal particles,[2] the 70S full ribosomes,[3] and model oligonucleotides [4–14] in complex with various 2-deoxystreptamine aminoglycosides. Aminoglycosides specifically bind to the A site on 16S rRNA (Figure 1a) where a cognate tRNA is discriminated from near-cognate tRNAs based on base-pair geometries between codon and anticodon. The binding specificity is mainly conferred by ring I of aminoglycosides, which stacks on G1491 (Escherichia coli numbering) and makes a pseudo pair with the universally conserved A1408 in the bacterial A site (see Figure 2a right and Figure 3a right). These interactions force the A site to adopt the “on” state conformation in which A1492 and A1493 are fully bulged out and make A-minor interactions with the shallow/minor groove of the first two base pairs between mRNA codon and tRNA anticodon even when a nearcognate tRNA is delivered to the A site (Figure 2a right), thereby disturbing the fidelity of the decoding process. While aminoglycosides have been prescribed for several bacterial infections, the major problem we have been facing for decades is the rapid increase of drug-resistant strains.[15] A single chromosomal mutation at position 1408 of 16S rRNA from A to G (see Figure 1a) has been found in clinically isolated drug-resistant strains of Mycobacterium chelonae,[16]