Display options
Share it on

Nature. 2021 Nov;599(7885):507-512. doi: 10.1038/s41586-021-04045-6. Epub 2021 Oct 27.

A synthetic antibiotic class overcoming bacterial multidrug resistance.

Nature

Matthew J Mitcheltree, Amarnath Pisipati, Egor A Syroegin, Katherine J Silvestre, Dorota Klepacki, Jeremy D Mason, Daniel W Terwilliger, Giambattista Testolin, Aditya R Pote, Kelvin J Y Wu, Richard Porter Ladley, Kelly Chatman, Alexander S Mankin, Yury S Polikanov, Andrew G Myers

Affiliations

  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA.
  2. Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA.
  3. Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA.
  4. Harvard Center for Mass Spectrometry, Harvard University, Cambridge, MA, USA.
  5. Department of Biological Sciences, University of Illinois at Chicago, Chicago, IL, USA. [email protected].
  6. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA. [email protected].

PMID: 34707295 PMCID: PMC8549432 DOI: 10.1038/s41586-021-04045-6

Abstract

The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

References

  1. Antibiotic Resistance Threats in the United States, 2019 (Department of Health and Human Services, CDC, 2019); www.cdc.gov/DrugResistance/Biggest-Threats html. - PubMed
  2. Wright, P. M., Seiple, I. B. & Myers, A. G. The evolving role of chemical synthesis in antibacterial drug discovery. Angew. Chem. Int. Ed. 53, 8840–8869 (2014). - PubMed
  3. Scientific Roadmap for Antibiotic Discovery (Pew Charitable Trusts, 2016); http://www.pewtrusts.org/antibiotic-discovery. - PubMed
  4. Charest, M. G., Lerner, C. D., Brubaker, J. D., Siegel, D. R. & Myers, A. G. A convergent enantioselective route to structurally diverse 6-deoxytetracycline antibiotics. Science 308, 395–398 (2005). - PubMed
  5. Seiple, I. B. et al. A platform for the discovery of new macrolide antibiotics. Nature 533, 338–345 (2016). - PubMed
  6. Myers, A. & Clark, R. B. Discovery of macrolide antibiotics effective against multi-drug resistant Gram-negative pathogens. Acc. Chem. Res. 54, 1635–1645 (2021). - PubMed
  7. Li, Q. et al. Synthetic group A streptogramin antibiotics that overcome Vat resistance. Nature 586, 145–150 (2020). - PubMed
  8. Smith, P. A. et al. Optimized arylomycins are a new class of Gram-negative antibiotics. Nature 651, 189–194 (2018). - PubMed
  9. Wilson, D. N. Ribosome-targeting antibiotics and mechanisms of bacterial resistance. Nat. Rev. Microbiol. 12, 35–48 (2014). - PubMed
  10. Lin, J., Zhou, D., Steitz, T. A., Polikanov, Y. S. & Gagnon, M. G. Ribosome-targeting antibiotics: modes of action, mechanisms of resistance, and implications for drug design. Annu. Rev. Biochem. 87, 451–478 (2018). - PubMed
  11. Mason, D. J., Dietz, A. & De Boer, C. Lincomycin, a new antibiotic. I. Discovery and biological properties. Antimicrob. Agents Chemother. 554–559 (1962). - PubMed
  12. Birkenmeyer, R. D. & Kagan, F. Lincomycin. XI. Synthesis and structure of clindamycin. A potent antibacterial agent. J. Med. Chem. 13, 616–619 (1970). - PubMed
  13. Phillips, I. Past and current use of clindamycin and lincomycin. J. Antimicrob. Chemother. 7 (Suppl. A), 11–18, (1981). - PubMed
  14. Birkenmeyer, R. D., Kroll, S. J., Lewis, C., Stern, K. F. & Zurenko, G. E. Synthesis and antimicrobial activity of clindamycin analogs: pirlimycin, a potent antibacterial agent. J. Med. Chem. 27, 216–223 (1984). - PubMed
  15. O’Dowd, H., Erwin, A. L. & Lewis, J. G. in Natural Products in Medicinal Chemistry (ed. Hanessian, S.) (Wiley-VCH, 2014). - PubMed
  16. Hirai, Y. et al. Characterization of compound A, a novel lincosamide derivative active against methicillin-resistant Staphylococcus aureus. J. Antibiot. 74, 124–132 (2021). - PubMed
  17. Leclercq, R. & Courvalin, P. Bacterial resistance to macrolide, lincosamide, and streptogramin antibiotics by target modification. Antimicrob. Agents Chemother. 35, 1267–1272 (1991). - PubMed
  18. Lai, C. J. & Weisblum, B. Altered methylation of ribosomal RNA in an erythromycin-resistant strain of Staphylococcus aureus. Proc. Natl Acad. Sci. USA 68, 856–860 (1971). - PubMed
  19. Griffith, L. J., Ostrander, W. E., Mullins, C. G. & Beswick, D. E. Drug antagonism between lincomycin and erythromycin. Science 147, 746–747 (1965). - PubMed
  20. Toh, S. M. et al. Acquisition of a natural resistance gene renders a clinical strain of methicillin-resistant Staphylococcus aureus resistant to the synthetic antibiotic linezolid. Mol. Microbiol. 64, 1506–1514 (2007). - PubMed
  21. Long, K. S., Poehlsgaard, J., Kehrenberg, C., Schwarz, S. & Vester, B. The Cfr rRNA methyltransferase confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antibiotics. Antimicrob. Agents Chemother. 50, 2500–2505 (2006). - PubMed
  22. Giessing, A. M. et al. Identification of 8-methyladenosine as the modification catalyzed by the radical SAM methyltransferase Cfr that confers antibiotic resistance in bacteria. RNA 15, 327–336 (2009). - PubMed
  23. Smith, L. K. & Mankin, A. S. Transcriptional and translational control of the mlr operon, which confers resistance to seven classes of protein synthesis inhibitors. Antimicrob. Agents Chemother. 52, 1703–1712 (2008). - PubMed
  24. Crowe-McAuliffe, C. et al. Structural basis of ABCF-mediated resistance to pleuromutilin, lincosamide, and streptogramin A antibiotics in Gram-positive pathogens. Nat. Comm. 12 3577 (2021). - PubMed
  25. Murina, V., Kasari, M., Hauryliuk, V. & Atkinson, G. C. Antibiotic resistance ABCF proteins reset the peptidyl transferase centre of the ribosome to counter translational arrest. Nucleic Acids Res. 46, 3753–3763 (2018). - PubMed
  26. Mitcheltree, M. J., Stevenson, J. W., Pisipati, A. & Myers, A. G. A practical, component-based synthetic route to methylthiolincosamine permitting facile northern-half diversification of lincosamide antibiotics. J. Am. Chem. Soc. 143, 6829–6835 (2021). - PubMed
  27. Mitcheltree, M. J. A Platform for the Discovery of New Lincosamide Antibiotics. PhD Dissertation, Harvard University (2018). - PubMed
  28. Silvestre, K. J. Design, Synthesis, and Study of Lincosamide Antibiotics Containing a Bicyclic Amino Acid Moiety. PhD Dissertation, Harvard University (2019). - PubMed
  29. Moga, I. Novel Lincosamide Antibiotics Containing an Azepane Amino Acid Moiety. PhD Dissertation, Harvard University (2019). - PubMed
  30. Dunkle, J. A., Xiong, L., Mankin, A. S. & Cate, J. H. Structures of the Escherichia coli ribosome with antibiotics bound near the peptidyl transferase center explain spectra of drug action. Proc. Natl Acad. Sci. USA 107, 17152–17157 (2010). - PubMed
  31. Seiple, I. B., Mercer, J. A., Sussman, R. J., Zhang, Z. & Myers, A. G. Stereocontrolled synthesis of syn-β-hydroxy-α-amino acids by direct aldolization of pseudoephenamine glycinamide. Angew. Chem. Int. Ed. 53, 4642–4647 (2014). - PubMed
  32. Kingsbury, J. S., Harrity, J. P. A., Bonitatebus, P. J., Jr & Hoveyda, A. H. A recyclable ru-based metathesis catalyst. J. Am. Chem. Soc. 121, 791–799 (1999). - PubMed
  33. Magerlein, B. J. & Kagan, F. Lincomycin. 8. 4′-alkyl-1′-demethyl-4′-depropylclindamycins, potent antibacterial and antimalarial agents. J. Med. Chem. 12, 780–784 (1969). - PubMed
  34. Morandi, B. Wickens, Z. K. & Grubbs, R. H. Regioselective Wacker oxidation of internal alkenes: rapid access to functionalized ketones facilitated by cross-metathesis. Angew. Chem. Int. Ed. 52, 9751–9754 (2013). - PubMed
  35. Scheiper, B., Bonnekessel, M., Krause, H. & Fürstner, A. Selective iron-catalyzed cross-coupling reactions of Grignard reagents with enol triflates, acid chlorides, and dichloroarenes. J. Org. Chem. 69, 3943–3949 (2004). - PubMed
  36. Mason, J. D., Terwilliger, D. T., Pote, A. R. & Myers, A. G. Practical gram-scale synthesis of iboxamycin, a potent antibiotic candidate. J. Am. Chem. Soc. 143, 11019–11025 (2021). - PubMed
  37. Zhao, C. et al. Investigation of antibiotic resistance, serotype distribution, and genetic characteristics of 164 invasive Streptococcus pneumoniae from north China between April 2016 and October 2017. Infect. Drug Resist. 13, 2117–2128 (2020). - PubMed
  38. Weiner-Lastinger, L. M. et al. Antimicrobial-resistant pathogens associated with adult healthcare-associated infections: Summary of data reported to the National Healthcare Safety Network, 2015–2017. Infect. Control Hosp. Epidemiol. 41, 1–18 (2020). - PubMed
  39. Singh, K. V., Weinstock, G. M., Murray, B. E. An Enterococcus faecalis ABC homologue (Lsa) is required for the resistance of this species to clindamycin and quinupristin–dalfopristin. Antimicrob. Agents Chemother. 46, 1845–1850 (2002). - PubMed
  40. Rice, L. B. Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa. Clin. Infect. Dis. 43, S100–S105 (2006). - PubMed
  41. O’Shea, R. & Moser, H. E. Physicochemical properties of antibacterial compounds: implications for drug discovery. J. Med. Chem. 51, 2871–2878 (2008). - PubMed
  42. Richter, M. F. et al. Predictive compound accumulation rules yield a broad-spectrum antibiotic. Nature 545, 299–304 (2017). - PubMed
  43. Orelle, C. et al. Tools for characterizing bacterial protein synthesis inhibitors. Antimicrob. Agents Chemother. 57, 5994–6004 (2013). - PubMed
  44. Vester, B. & Douthwaite, S. Macrolide resistance conferred by base substitutions in 23s rRNA. Antimicrob. Agents Chemother. 45, 1–12 (2001). - PubMed
  45. Böttger, E. C., Springer, B., Prammananan, T., Kidan, Y. & Sander, P. Structural basis for selectivity and toxicity of ribosomal antibiotics. EMBO Rep. 2, 318–323 (2001). - PubMed
  46. Silver, L. L. Multi-targeting by monotherapeutic antibacterials. Nat. Rev. Drug Discov. 6, 41–55 (2007). - PubMed
  47. Orelle, C. et al. Identifying the targets of aminoacyl-tRNA synthetase inhibitors by primer extension inhibition. Nucleic Acids Res. 41, e144 (2013). - PubMed
  48. Tu, D., Blaha, G., Moore, P. B. & Steitz, T. A. Structures of MLS - PubMed
  49. Polikanov, Y. S., Steitz, T. A. & Innis, C. A. A proton wire to couple aminoacyl-tRNA accommodation and peptide-bond formation on the ribosome. Nat. Struct. Mol. Biol. 21, 787–793 (2014). - PubMed
  50. Polikanov, Y. S., Melnikov, S. V., Soll, D. & Steitz, T. A. Structural insights into the role of rRNA modifications in protein synthesis and ribosome assembly. Nat. Struct. Mol. Biol. 22, 342–344 (2015). - PubMed
  51. Svetlov, M. S. et al. Structure of Erm-modified 70S ribosome reveals the mechanism of macrolide resistance. Nat. Chem. Biol. (2021). - PubMed
  52. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, Approved Standard 11th edn (Clinical and Laboratory Standards Institute, 2018). - PubMed
  53. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard 8th edn (Clinical and Laboratory Standards Institute, 2012). - PubMed
  54. Performance Standards for Antimicrobial Susceptibility Testing 27th edn (Clinical and Laboratory Standards Institute, 2017). - PubMed
  55. Odenholt-Tornqvist, I., Löwdin, E., Cars, O. Pharmacodynamic effects of subinhibitory concentrations of β-lactam antibiotics in vitro. Antimicrob. Agents Chemother. 35, 1834–1839 (1991). - PubMed
  56. Niles, A. L. et al. A homogeneous assay to measure live and dead cells in the same sample by detecting different protease markers. Anal. Biochem. 366, 197–206 (2007). - PubMed
  57. Marroquin, L. D., Hynes, J., Dykens, J. A., Jamieson, J. D. & Will, Y. Circumventing the Crabtree effect: replacing media glucose with galactose increases susceptibility of HepG2 cells to mitochondrial toxicants. Toxicol. Sci. 97, 539–547 (2007). - PubMed
  58. Orelle, C. et al. Identifying the targets of aminoacyl-tRNA synthetase inhibitors by primer extension inhibition. Nucleic Acids Res. 41 e144 (2013). - PubMed
  59. Kabsch, W. XDS. Acta Crystallogr. D 66, 125–132 (2010). - PubMed
  60. McCoy, A. J. et al. Phaser crystallographic software. J. Appl. Crystallogr. 40, 658–674 (2007). - PubMed
  61. Liebschner, D. et al. Macromolecular structure determination using X-rays, neutrons and electrons: recent developments in Phenix. Acta Crystallogr. D 75, 861–877 (2019). - PubMed
  62. Emsley, P., Lohkamp, B., Scott, W. G. & Cowtan, K. Features and development of Coot. Acta Crystallogr. D 66 486–501 (2010). - PubMed
  63. Schuttelkopf, A. W. & van Aalten, D. M. F. PRODRG: a tool for high-throughput crystallography of protein-ligand complexes. Acta Crystallogr. D 60, 1355–1363 (2004). - PubMed
  64. The PyMOL Molecular Graphics System v.2.0 (Schrödinger, 2017). - PubMed

Publication Types