Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides
Structure of Dirithromycin Bound to the Bacterial Ribosome Suggests New Ways for Rational Improvement of Macrolides
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DOI：
10.1128/aac.02266-18
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发表时间：
2019-06-01
影响因子：
4.9
通讯作者：
Polikanov, Yury S.
中科院分区：
文献类型：
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作者：
Khabibullina, Nelli F.;Tereshchenkov, Andrey G.;Polikanov, Yury S.
虽然大环内酯类药物被认为是优良的抗菌药物，但由于细菌耐药性的传播，它们的医疗用途受到了极大的限制。因此，有必要开发新的强效大环内酯类药物来对抗耐药病原体的出现。合理药物设计的关键步骤之一是鉴定介导药物与其靶标结合的化学基团，以及随后的衍生化以加强药物-靶标相互作用。在大环内酯类药物的情况下，已知一些基团对于药物与核糖体的结合是重要的，例如desosamine。寻找能够改善大环内酯与70 S核糖体相互作用的新化学部分对于新大环内酯的发明可能至关重要。为此目的，在这里，我们研究了一个经典的大环内酯，地红霉素，它有一个扩展的（2-甲氧基乙氧基）-甲基侧链连接到大环内酯环的C-9/C-11原子，可以占地红霉素的70 S核糖体的强结合。通过解决与地红霉素复合的70 S核糖体的晶体结构，我们发现其侧链与新生肽出口隧道的壁以特异的方式相互作用：其侧链与核糖体蛋白uL 4中His 69残基的芳香族咪唑环形成孤对π堆积相互作用。据我们所知，这种侧链在大环内酯结合口袋中形成接触的能力以前没有报道过，并且可能为药物化学家开发下一代大环内酯抗生素对抗耐药病原体的进一步探索开辟新的途径。
Although macrolides are known as excellent antibacterials, their medical use has been significantly limited due to the spread of bacterial drug resistance. Therefore, it is necessary to develop new potent macrolides to combat the emergence of drug-resistant pathogens. One of the key steps in rational drug design is the identification of chemical groups that mediate binding of the drug to its target and their subsequent derivatization to strengthen drug-target interactions. In the case of macrolides, a few groups are known to be important for drug binding to the ribosome, such as desosamine. Search for new chemical moieties that improve the interactions of a macrolide with the 70S ribosome might be of crucial importance for the invention of new macrolides. For this purpose, here we studied a classic macrolide, dirithromycin, which has an extended (2-methoxyethoxy)-methyl side chain attached to the C-9/C-11 atoms of the macrolactone ring that can account for strong binding of dirithromycin to the 70S ribosome. By solving the crystal structure of the 70S ribosome in complex with dirithromycin, we found that its side chain interacts with the wall of the nascent peptide exit tunnel in an idiosyncratic fashion: its side chain forms a lone pair-pi stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4. To our knowledge, the ability of this side chain to form a contact in the macrolide binding pocket has not been reported previously and potentially can open new avenues for further exploration by medicinal chemists developing next-generation macrolide antibiotics active against resistant pathogens.