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Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome.

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Pichkur EB, Paleskava A, Tereshchenkov AG, Kasatsky P, Komarova ES, Shiriaev DI, Bogdanov AA, Dontsova OA, Osterman IA, Sergiev PV, Polikanov YS, Myasnikov AG, Konevega AL
OpenAccess logo RNA 26 715-723 (2020)
Related entries: 6xz7, 6xzb

Cited: 12 times
EuropePMC logo PMID: 32144191

Abstract

Macrolides are one of the most successful and widely used classes of antibacterials, which kill or stop the growth of pathogenic bacteria by binding near the active site of the ribosome and interfering with protein synthesis. Dirithromycin is a derivative of the prototype macrolide erythromycin with additional hydrophobic side chain. In our recent study, we have discovered that the side chain of dirithromycin forms lone pair-π stacking interaction with the aromatic imidazole ring of the His69 residue in ribosomal protein uL4 of the Thermus thermophilus 70S ribosome. In the current work, we found that neither the presence of the side chain, nor the additional contact with the ribosome, improve the binding affinity of dirithromycin to the ribosome. Nevertheless, we found that dirithromycin is a more potent inhibitor of in vitro protein synthesis in comparison with its parent compound, erythromycin. Using high-resolution cryo-electron microscopy, we determined the structure of the dirithromycin bound to the translating Escherichia coli 70S ribosome, which suggests that the better inhibitory properties of the drug could be rationalized by the side chain of dirithromycin pointing into the lumen of the nascent peptide exit tunnel, where it can interfere with the normal passage of the growing polypeptide chain.

Articles - 6xza mentioned but not cited (1)

  1. Insights into the improved macrolide inhibitory activity from the high-resolution cryo-EM structure of dirithromycin bound to the E. coli 70S ribosome. Pichkur EB, Paleskava A, Tereshchenkov AG, Kasatsky P, Komarova ES, Shiriaev DI, Bogdanov AA, Dontsova OA, Osterman IA, Sergiev PV, Polikanov YS, Myasnikov AG, Konevega AL. RNA 26 715-723 (2020)


Reviews citing this publication (3)

  1. Structural Heterogeneities of the Ribosome: New Frontiers and Opportunities for Cryo-EM. Poitevin F, Kushner A, Li X, Dao Duc K. Molecules 25 E4262 (2020)
  2. Advanced Methods for Studying Structure and Interactions of Macrolide Antibiotics. Jednačak T, Mikulandra I, Novak P. Int J Mol Sci 21 E7799 (2020)
  3. Exploring the Structural Variability of Dynamic Biological Complexes by Single-Particle Cryo-Electron Microscopy. DiIorio MC, Kulczyk AW. Micromachines (Basel) 14 118 (2022)

Articles citing this publication (8)

  1. Structure of the bacterial ribosome at 2 Å resolution. Watson ZL, Ward FR, Méheust R, Ad O, Schepartz A, Banfield JF, Cate JH. Elife 9 e60482 (2020)
  2. Sarecycline interferes with tRNA accommodation and tethers mRNA to the 70S ribosome. Batool Z, Lomakin IB, Polikanov YS, Bunick CG. Proc Natl Acad Sci U S A 117 20530-20537 (2020)
  3. Atomistic simulations of the Escherichia coli ribosome provide selection criteria for translationally active substrates. Watson ZL, Knudson IJ, Ward FR, Miller SJ, Cate JHD, Schepartz A, Abramyan AM. Nat Chem 15 913-921 (2023)
  4. Modulation of translational decoding by m6A modification of mRNA. Jain S, Koziej L, Poulis P, Kaczmarczyk I, Gaik M, Rawski M, Ranjan N, Glatt S, Rodnina MV. Nat Commun 14 4784 (2023)
  5. Time resolution in cryo-EM using a PDMS-based microfluidic chip assembly and its application to the study of HflX-mediated ribosome recycling. Bhattacharjee S, Feng X, Maji S, Dadhwal P, Zhang Z, Brown ZP, Frank J. Cell 187 782-796.e23 (2024)
  6. Establishing the fundamental rules for genetic code expansion. Sinha S, Ahsan M, Palermo G. Nat Chem 15 892-893 (2023)
  7. Metagenomic evidence for antibiotic-associated actinomycetes in the Karamay Gobi region. Yang S, Zhang W, Yang B, Feng X, Li Y, Li X, Liu Q. Front Microbiol 15 1330880 (2024)
  8. Proline-Hinged α-Helical Peptides Sensitize Gram-Positive Antibiotics, Expanding Their Physicochemical Properties to Be Used as Gram-Negative Antibiotics. Choi Y, Choe HW, Kook M, Choo S, Park TW, Bae S, Kim H, Yang J, Jeong WS, Yu J, Lee KR, Kim YS, Yu J. J Med Chem 67 1825-1842 (2024)


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