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Structural and mechanistic basis for translation inhibition by macrolide and ketolide antibiotics.

<div class='caption-title'>Macrolide-dependent regulation of ermD expression.</div>
<div class='caption-title'>Sequence dependence of translation arrest at ermDL in response to TEL.</div>
<div class='caption-title'>Cryo-EM structure of ErmDL-TEL-SRC.</div>
Beckert B, Leroy EC, Sothiselvam S, Bock LV, Svetlov MS, Graf M, Arenz S, Abdelshahid M, Seip B, Grubmüller H, Mankin AS, Innis CA, Vázquez-Laslop N, Wilson DN
OpenAccess logo Nat Commun 12 4466 (2021)
Related entries: 7nsp, 7nsq

Cited: 30 times
EuropePMC logo PMID: 34294725

Abstract

Macrolides and ketolides comprise a family of clinically important antibiotics that inhibit protein synthesis by binding within the exit tunnel of the bacterial ribosome. While these antibiotics are known to interrupt translation at specific sequence motifs, with ketolides predominantly stalling at Arg/Lys-X-Arg/Lys motifs and macrolides displaying a broader specificity, a structural basis for their context-specific action has been lacking. Here, we present structures of ribosomes arrested during the synthesis of an Arg-Leu-Arg sequence by the macrolide erythromycin (ERY) and the ketolide telithromycin (TEL). Together with deep mutagenesis and molecular dynamics simulations, the structures reveal how ERY and TEL interplay with the Arg-Leu-Arg motif to induce translational arrest and illuminate the basis for the less stringent sequence-specific action of ERY over TEL. Because programmed stalling at the Arg/Lys-X-Arg/Lys motifs is used to activate expression of antibiotic resistance genes, our study also provides important insights for future development of improved macrolide antibiotics.

Reviews - 7nso mentioned but not cited (2)

  1. Scientific Rationale and Clinical Basis for Clindamycin Use in the Treatment of Dermatologic Disease. Armillei MK, Lomakin IB, Del Rosso JQ, Grada A, Bunick CG. Antibiotics (Basel) 13 270 (2024)
  2. Clindamycin: A Comprehensive Status Report with Emphasis on Use in Dermatology. Del Rosso JQ, Armillei MK, Lomakin IB, Grada A, Bunick CG. J Clin Aesthet Dermatol 17 29-40 (2024)

Articles - 7nso mentioned but not cited (3)

  1. Insights into the ribosome function from the structures of non-arrested ribosome-nascent chain complexes. Syroegin EA, Aleksandrova EV, Polikanov YS. Nat Chem 15 143-153 (2023)
  2. Regulation of the macrolide resistance ABC-F translation factor MsrD. Fostier CR, Ousalem F, Leroy EC, Ngo S, Soufari H, Innis CA, Hashem Y, Boël G. Nat Commun 14 3891 (2023)
  3. The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition. Koller TO, Scheid U, Kösel T, Herrmann J, Krug D, Boshoff HIM, Beckert B, Evans JC, Schlemmer J, Sloan B, Weiner DM, Via LE, Moosa A, Ioerger TR, Graf M, Zinshteyn B, Abdelshahid M, Nguyen F, Arenz S, Gille F, Siebke M, Seedorf T, Plettenburg O, Green R, Warnke AL, Ullrich J, Warrass R, Barry CE, Warner DF, Mizrahi V, Kirschning A, Wilson DN, Müller R. J Am Chem Soc 145 851-863 (2023)


Reviews citing this publication (4)

  1. Azithromycin through the Lens of the COVID-19 Treatment. Kournoutou GG, Dinos G. Antibiotics (Basel) 11 1063 (2022)
  2. Ribosome-targeting antibiotics and resistance via ribosomal RNA methylation. Jeremia L, Deprez BE, Dey D, Conn GL, Wuest WM. RSC Med Chem 14 624-643 (2023)
  3. Synthesis of Peptidyl-tRNA Mimics for Structural Biology Applications. Polikanov YS, Etheve-Quelquejeu M, Micura R. Acc Chem Res 56 2713-2725 (2023)
  4. Hibernating ribosomes as drug targets? Ekemezie CL, Melnikov SV. Front Microbiol 15 1436579 (2024)

Articles citing this publication (21)

  1. Ribosome collisions induce mRNA cleavage and ribosome rescue in bacteria. Saito K, Kratzat H, Campbell A, Buschauer R, Burroughs AM, Berninghausen O, Aravind L, Green R, Beckmann R, Buskirk AR. Nature 603 503-508 (2022)
  2. Structural basis for the context-specific action of the classic peptidyl transferase inhibitor chloramphenicol. Syroegin EA, Flemmich L, Klepacki D, Vazquez-Laslop N, Micura R, Polikanov YS. Nat Struct Mol Biol 29 152-161 (2022)
  3. Structural basis for the tryptophan sensitivity of TnaC-mediated ribosome stalling. van der Stel AX, Gordon ER, Sengupta A, Martínez AK, Klepacki D, Perry TN, Herrero Del Valle A, Vázquez-Laslop N, Sachs MS, Cruz-Vera LR, Innis CA. Nat Commun 12 5340 (2021)
  4. Structural basis for the inability of chloramphenicol to inhibit peptide bond formation in the presence of A-site glycine. Syroegin EA, Aleksandrova EV, Polikanov YS. Nucleic Acids Res 50 7669-7679 (2022)
  5. Genome-encoded ABCF factors implicated in intrinsic antibiotic resistance in Gram-positive bacteria: VmlR2, Ard1 and CplR. Obana N, Takada H, Crowe-McAuliffe C, Iwamoto M, Egorov AA, Wu KJY, Chiba S, Murina V, Paternoga H, Tresco BIC, Nomura N, Myers AG, Atkinson GC, Wilson DN, Hauryliuk V. Nucleic Acids Res 51 4536-4554 (2023)
  6. Expression of Bacillus subtilis ABCF antibiotic resistance factor VmlR is regulated by RNA polymerase pausing, transcription attenuation, translation attenuation and (p)ppGpp. Takada H, Mandell ZF, Yakhnin H, Glazyrina A, Chiba S, Kurata T, Wu KJY, Tresco BIC, Myers AG, Aktinson GC, Babitzke P, Hauryliuk V. Nucleic Acids Res 50 6174-6189 (2022)
  7. Folding of VemP into translation-arresting secondary structure is driven by the ribosome exit tunnel. Kolář MH, Nagy G, Kunkel J, Vaiana SM, Bock LV, Grubmüller H. Nucleic Acids Res 50 2258-2269 (2022)
  8. Tetracenomycin X sequesters peptidyl-tRNA during translation of QK motifs. Leroy EC, Perry TN, Renault TT, Innis CA. Nat Chem Biol 19 1091-1096 (2023)
  9. Context-based sensing of orthosomycin antibiotics by the translating ribosome. Mangano K, Marks J, Klepacki D, Saha CK, Atkinson GC, Vázquez-Laslop N, Mankin AS. Nat Chem Biol 18 1277-1286 (2022)
  10. Cryo-EM structure of Mycobacterium tuberculosis 50S ribosomal subunit bound with clarithromycin reveals dynamic and specific interactions with macrolides. Zhang W, Li Z, Sun Y, Cui P, Liang J, Xing Q, Wu J, Xu Y, Zhang W, Zhang Y, He L, Gao N. Emerg Microbes Infect 11 293-305 (2022)
  11. Sarecycline inhibits protein translation in Cutibacterium acnes 70S ribosome using a two-site mechanism. Lomakin IB, Devarkar SC, Patel S, Grada A, Bunick CG. Nucleic Acids Res 51 2915-2930 (2023)
  12. Peptidyl tRNA Hydrolase Is Required for Robust Prolyl-tRNA Turnover in Mycobacterium tuberculosis. Tomasi FG, Schweber JTP, Kimura S, Zhu J, Cleghorn LAT, Davis SH, Green SR, Waldor MK, Rubin EJ. mBio 14 e0346922 (2023)
  13. Structural insights into the mechanism of overcoming Erm-mediated resistance by macrolides acting together with hygromycin-A. Chen CW, Leimer N, Syroegin EA, Dunand C, Bulman ZP, Lewis K, Polikanov YS, Svetlov MS. Nat Commun 14 4196 (2023)
  14. Practical Synthesis of N-Formylmethionylated Peptidyl-tRNA Mimics. Thaler J, Syroegin EA, Breuker K, Polikanov YS, Micura R. ACS Chem Biol 18 2233-2239 (2023)
  15. Binding of the peptide deformylase on the ribosome surface modulates the exit tunnel interior. McGrath H, Černeková M, Kolář MH. Biophys J 121 4443-4451 (2022)
  16. Global regulation via modulation of ribosome pausing by the ABC-F protein EttA. Ousalem F, Ngo S, Oïffer T, Omairi-Nasser A, Hamon M, Monlezun L, Boël G. Nat Commun 15 6314 (2024)
  17. Macrolide resistance through uL4 and uL22 ribosomal mutations in Pseudomonas aeruginosa. Goltermann L, Laborda P, Irazoqui O, Pogrebnyakov I, Bendixen MP, Molin S, Johansen HK, La Rosa R. Nat Commun 15 8906 (2024)
  18. Macrolones target bacterial ribosomes and DNA gyrase and can evade resistance mechanisms. Aleksandrova EV, Ma CX, Klepacki D, Alizadeh F, Vázquez-Laslop N, Liang JH, Polikanov YS, Mankin AS. Nat Chem Biol (2024)
  19. Molecular Dynamics and Other HPC Simulations for Drug Discovery. Kotev M, Diaz Gonzalez C. Methods Mol Biol 2716 265-291 (2024)
  20. Motif-ation matters. Vázquez-Laslop N, Polikanov YS. Nat Chem Biol 19 1044-1045 (2023)
  21. Paenilamicins are context-specific translocation inhibitors of protein synthesis. Koller TO, Berger MJ, Morici M, Paternoga H, Bulatov T, Di Stasi A, Dang T, Mainz A, Raulf K, Crowe-McAuliffe C, Scocchi M, Mardirossian M, Beckert B, Vázquez-Laslop N, Mankin AS, Süssmuth RD, Wilson DN. Nat Chem Biol (2024)


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