AbstractGrowing resistance toward ribosome-targeting macrolide antibiotics has limited their clinical utility and urged the search for superior compounds. Macrolones are synthetic macrolide derivatives with a quinolone side chain, structurally similar to DNA topoisomerase-targeting fluoroquinolones.

摘要对核糖体靶向大环内酯类抗生素的耐药性不断增加，限制了它们的临床应用，并敦促寻找更好的化合物。大环内酯类是具有喹诺酮侧链的合成大环内酯类衍生物，结构类似于靶向氟喹诺酮类的DNA拓扑异构酶。

While macrolones show enhanced activity, their modes of action have remained unknown. Here, we present the first structures of ribosome-bound macrolones, showing that the macrolide part occupies the macrolide-binding site in the ribosomal exit tunnel, whereas the quinolone moiety establishes new interactions with the tunnel.

虽然macrolones显示出增强的活性，但它们的作用方式仍然未知。在这里，我们介绍了核糖体结合的大环内酯的第一个结构，表明大环内酯部分占据了核糖体出口通道中的大环内酯结合位点，而喹诺酮部分与通道建立了新的相互作用。

Macrolones efficiently inhibit both the ribosome and DNA topoisomerase in vitro. However, in the cell, they target either the ribosome or DNA gyrase or concurrently both of them. In contrast to macrolide or fluoroquinolone antibiotics alone, dual-targeting macrolones are less prone to select resistant bacteria carrying target-site mutations or to activate inducible macrolide resistance genes.

Macrolones在体外有效抑制核糖体和DNA拓扑异构酶。然而，在细胞中，它们靶向核糖体或DNA旋转酶或同时靶向两者。。

Furthermore, because some macrolones engage Erm-modified ribosomes, they retain activity even against strains with constitutive erm resistance genes..

此外，由于一些大分子克隆与Erm修饰的核糖体结合，因此即使对具有组成型Erm抗性基因的菌株也能保持活性。。

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Access Nature and 54 other Nature Portfolio journalsGet Nature+, our best-value online-access subscription24,99 € / 30 dayscancel any timeLearn moreSubscription info for Chinese customersWe have a dedicated website for our Chinese customers. Please go to naturechina.com to subscribe to this journal.Go to naturechina.comBuy this articlePurchase on Springer LinkInstant access to full article PDFBuy nowPrices may be subject to local taxes which are calculated during checkout.

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Fig. 1: Macrolones inhibit DNA gyrase and protein synthesis in vivo.Fig. 2: Macrolones inhibit protein synthesis and DNA gyrase in vitro.Fig. 3: Structures of MCX-66, MCX-91 and MCX-128 in complex with the wild-type T. thermophilus 70S ribosome.Fig. 4: Identification of cellular targets of macrolones by selecting resistant mutants.Fig.

图1：Macrolones在体内抑制DNA旋转酶和蛋白质合成。图2：Macrolones在体外抑制蛋白质合成和DNA促旋酶。图3:MCX-66，MCX-91和MCX-128与野生型嗜热链球菌70S核糖体复合的结构。图4：通过选择抗性突变体鉴定大分子克隆的细胞靶标。图。

5: Macrolones are poor inducers of the expression of inducible macrolide resistance genes.Fig. 6: Structure of macrolone MCX-128 bound to the Erm-methylated 70S ribosome..

5： 大环内酯类是诱导型大环内酯类耐药基因表达的不良诱导剂。图6：与Erm甲基化的70S核糖体结合的macrolone MCX-128的结构。。

Data availability

数据可用性

Coordinates and structure factors were deposited to the Research Collaboratory for Structural Bioinformatics (RCSB) PDB under the following accession codes: 8VTU for the wild-type T. thermophilus 70S ribosome in complex with macrolone MCX-66, mRNA, aminoacylated A-site Phe-tRNAPhe, aminoacylated P-site fMet-tRNAiMet and deacylated E-site tRNAPhe; 8VTV for the wild-type T. thermophilus 70S ribosome in complex with macrolone MCX-91, mRNA, aminoacylated A-site Phe-tRNAPhe, aminoacylated P-site fMet-tRNAiMet and deacylated E-site tRNAPhe; 8VTW for the wild-type T. thermophilus 70S ribosome in complex with macrolone MCX-128 and protein Y; 8VTX for the m26A2058 T. thermophilus 70S ribosome in complex with macrolone MCX-128, mRNA, aminoacylated A-site Phe-tRNAPhe, aminoacylated P-site fMet-tRNAiMet and deacylated E-site tRNAPhe; 8VTY for the wild-type T. thermophilus 70S ribosome in complex with CIP and protein Y.

坐标和结构因子以以下登录号保藏到结构生物信息学研究合作组织（RCSB）PDB：野生型嗜热链球菌70S核糖体的8VTU与macrolone MCX-66，mRNA，氨基酰化的A位点Phe-tRNAPhe，氨基酰化的P位点fMet-tRNAPhe和脱酰基的E位点tRNAPhe复合；8VTV用于野生型嗜热链球菌70S核糖体与macrolone MCX-91，mRNA，氨基酰化的A位点Phe-tRNAPhe，氨基酰化的P位点fMet-tRNAPhe和脱酰的E位点tRNAPhe复合；8VTW用于与macrolone MCX-128和蛋白Y复合的野生型嗜热链球菌70S核糖体；8VTX用于m26A2058嗜热链球菌70S核糖体与macrolone MCX-128，mRNA，氨基酰化的A位点Phe-tRNAPhe，氨基酰化的P位点fMet-tRNAPhe和脱酰的E位点tRNAPhe复合；8VTY用于与CIP和蛋白Y复合的野生型嗜热链球菌70S核糖体。

All previously published structures that were used in this work for structural comparisons were retrieved from the RCSB PDB under accession codes 6XHW, 6XHX and 7ZTA. No sequence data were generated in this study. Source data are provided with this paper..

本工作中用于结构比较的所有先前发布的结构均以登录号6XHW，6XHX和7ZTA从RCSB PDB中检索。本研究未产生序列数据。本文提供了源数据。。

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Download referencesAcknowledgementsWe thank M. Svetlov for valuable discussions and assistance with the data processing. We thank the Analysis and Testing Center at the Beijing Institute of Technology for collecting and analyzing the spectral data. We thank the staff at Northeastern Collaborative Access Team (NE-CAT) beamlines 24ID-C and 24ID-E for help with X-ray diffraction data collection, especially M.

下载参考文献致谢我们感谢M.Svetlov在数据处理方面的宝贵讨论和帮助。我们感谢北京理工大学分析测试中心收集和分析光谱数据。我们感谢东北合作访问团队（NE-CAT）光束线24ID-C和24ID-E的工作人员在X射线衍射数据收集方面的帮助，尤其是M。

Capel, F. Murphy, S. Banerjee, I. Kourinov, D. Neau, J. Schuermann, N. Sukumar, A. Lynch, J. Withrow, K. Perry, A. Kaya and C. Salbego. This work is based upon research conducted at the NE-CAT beamlines, which are funded by the National Institute of General Medical Sciences from the National Institutes of Health (NIH; grant P30-GM124165 to NE-CAT).

卡佩尔（Capel）、F.墨菲（F.Murphy）、S.班纳吉（S.Banerjee）、I.库里诺夫（I.Kourinov）、D.尼奥（D.Neau）、J.舒尔曼（J.Schuermann）、N.苏库马尔（N.Sukumar）、A.林奇（A.Lynch）、J.维思罗（J.Withrow）、K.佩里（K.Perry。这项工作是基于在NE-CAT光束线上进行的研究，该光束线由美国国立卫生研究院（NIH；授予NE-CAT P30-GM124165）的国家普通医学科学研究所资助。

The Eiger 16M detector on the 24ID-E beamline is funded by an NIH-ORIP HEI grant (S10-OD021527 to NE-CAT). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no.

24ID-E光束线上的Eiger 16M探测器由NIH-ORIP HEI资助（NE-CAT的S10-OD021527）。这项研究使用了先进光子源的资源，这是美国能源部（DOE）科学办公室用户设施，由阿贡国家实验室根据合同号为DOE科学办公室运营。

DE-AC02-06CH11357. This work was supported by the National Institute of General Medical Sciences of the NIH (grant R35-GM127134 to A.S.M.), the National Institute of Allergy and Infectious Diseases of the NIH (grant R21-AI137584 to A.S.M. and Y.S.P.), the Illinois State startup funds (to Y.S.P.), the National Key Research and Development Program of China (grant 2018YFA0901800 to J.-H.L.) and the National Natural Science Foundation of China (grant 81673335 to J.-H.L.).

DE-AC02-06CH11357。这项工作得到了美国国立卫生研究院国家普通医学科学研究所的支持，美国国立卫生研究院国家过敏与传染病研究所的支持，美国国立卫生研究院和美国国立卫生研究院的支持，伊利诺伊州启动资金，中国国家重点研究与发展计划，中国国家自然科学委员会的支持，美国国立卫生研究院和美国国立卫生研究院的支持，美国伊利诺伊州国家重点研究与发展计划，中国国家自然科学基金，美国国立卫生研究院的支持，美国国立卫生研究院的支持，美国国立卫生研究院的支持，美国国立卫生研究院的支持，美国国立卫生研究院的支持，美国伊利诺伊州国家重点研究与发展计划的支持，美国国立卫生研究院的支持2018YFA0901800，美国国立卫生研究院。

The funders had no role in study design, data collection and analysis, decision to publish or manuscript preparation.Author informationAuthor notesThese authors contributed equally: Elena V. Aleksandrova, Cong-Xuan Ma, Dorota Klep.

资助者在研究设计，数据收集和分析，决定出版或稿件准备方面没有任何作用。作者信息作者注意到这些作者做出了同样的贡献：Elena V.Aleksandrova，Cong Xuan Ma，Dorota Klep。

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PubMed Google ScholarContributionsC.-X.M. performed the chemical synthesis, purification and microbiological characterization of MCX compounds. D.K. and F.A. performed the in vivo dual-reporter assay, mutant selection and microbiological characterization of the selected MCX-resistant mutant strains.

-十、 M.进行了MCX化合物的化学合成，纯化和微生物表征。D、 K.和F.A.对所选MCX抗性突变株进行了体内双报告基因测定，突变体选择和微生物学表征。

D.K. also performed the in vitro translation inhibition, gyrase inhibition and toeprinting assays. E.V.A. and Y.S.P. designed and performed X-ray crystallography experiments. A.S.M., N.V.-L., Y.S.P. and J.-H.L. designed and supervised the experiments. All authors interpreted the results. A.S.M., N.V.-L., Y.S.P.

D、 K.还进行了体外翻译抑制，促旋酶抑制和脚趾印试验。E、 V.A.和Y.S.P.设计并进行了X射线晶体学实验。A、 S.M.，N.V.L.，Y.S.P.和J.H.L.设计并监督了实验。所有作者都解释了结果。A、 S.M.，N.V.-L.，Y.S.P。

and J.-H.L. wrote the manuscript.Corresponding authorsCorrespondence to.

J.-H.L.写了手稿。通讯作者通讯。

Jian-Hua Liang, Yury S. Polikanov or Alexander S. Mankin.Ethics declarations

梁建华、尤里·S·波利卡诺夫或亚历山大·S·曼金。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

Peer review

同行评审

Peer review information

同行评审信息

Nature Chemical Biology thanks Graeme Conn, Suparna Sanyal and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

自然化学生物学感谢Graeme Conn，Suparna Sanyal和其他匿名审稿人对这项工作的同行评议做出的贡献。

Additional informationPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Extended dataExtended Data Fig. 1 Inhibition of translation and ribosome binding of macrolones.(a) Inhibition of production of the green flourescent protein (GFP) in cell-free translation system by varying concentrations of macrolones relative to uninhibited reaction.

。扩展数据扩展数据图1抑制大分子克隆的翻译和核糖体结合。（a） 相对于不受抑制的反应，通过改变大分子克隆的浓度来抑制无细胞翻译系统中绿色荧光蛋白（GFP）的产生。

Shown are the results of two independent experiments. (b) Competitive binding of [14C]-ERY and macrolones to the E. coli ribosome. Unlabeled ERY was used as a control (black circles). Experimental details are presented in the Online Methods section. Shown are the results of two independent experiments.Extended Data Fig.

显示了两个独立实验的结果。（b） [14C]-ERY和大分子克隆与大肠杆菌核糖体的竞争性结合。未标记的ERY用作对照（黑色圆圈）。在线方法部分介绍了实验细节。显示了两个独立实验的结果。扩展数据图。

2 Effects of macrolones on in vitro translation.Mapping the sites of macrolone-mediated ribosome arrests (blue arrows) at the early codons of the model ORF derived from the E. coli yrbA gene. The classic macrolide ERY is included for comparison. Due to the presence of the Thr-RS inhibitor borrelidin, the ribosomes that did not stall at the early codons are eventually trapped at the Gln12 codon when Thr13 needs to be incorporated into the growing protein (grey arrow).

2 macrolones对体外翻译的影响。在源自大肠杆菌yrbA基因的模型ORF的早期密码子处绘制大分子介导的核糖体停滞（蓝色箭头）的位点。包括经典的大环内酯类ERY用于比较。由于存在Thr-RS抑制剂borrelidin，当Thr13需要掺入生长中的蛋白质中时，在早期密码子处不停滞的核糖体最终被捕获在Gln12密码子处（灰色箭头）。

The AUG start codon is marked with a black arrow. The sample labeled as ‘NONE’ contained only borrelidin but no ERY or macrolones. Amino acid and nucleotide sequences of yrbA gene are shown on the left. Sequencing lanes are marked as C, U, A, G. This experiment was repeated independently twice and produced similar results.Extended Data Fig.

AUG起始密码子用黑色箭头标记。标记为“无”的样品仅含有borrelidin，但不含ERY或macrolones。yrbA基因的氨基酸和核苷酸序列显示在左侧。测序泳道标记为C，U，A，G。该实验独立重复两次并产生相似的结果。扩展数据图。

3 Electron density maps of ribosome-bound MCX-66, MCX-91, and MCX-128.(a-c) 2Fo-Fc Fourier electron density maps of MCX-66 (a, magenta), MCX-91 (b, green), and MCX-128 (c, yellow) in complex with the T. thermophilus 70S ribosome (blue me.

3核糖体结合的MCX-66，MCX-91和MCX-128的电子密度图。（a-c）MCX-66（a，品红色），MCX-91（b，绿色）和MCX-128（c，黄色）与嗜热链球菌70S核糖体（蓝色me）复合。

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