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Peer-reviewedCC BYNature

A natural depsipeptide antibiotic binds the E-site of the bacterial ribosome

  • Manpreet Kaur1,2,3
  • Dmitrii Y. Travin4,5
  • Max J. Berger6
  • Manoj Jangra1,2,3
  • Martino Morici6
  • Haaris Ahsan Safdari6
  • Dorota Klepacki4,5
  • Wenliang Wang1,2,3
  • Michael A. Cook1,2,3
  • Sommer Chou1,2,3
  • Allison K. Guitor1,2,3
  • Kalinka K. Koteva1,2,3
10 more authors
  • Min Xu1,2,3
  • Linda J. Ejim1,2,3
  • Aline Fiebig‐Comyn1,2,3
  • Yeganeh Yousefi1,2,3
  • Brian K. Coombes1,2,3
  • Lesley T. MacNeil1,2,3
  • Nora Vázquez‐Laslop4,5
  • Alexander S. Mankin7,8
  • Daniel N. Wilson9
  • Gerard D. Wright10,11,12
12 affiliations
  1. 1David Braley Centre for Antibiotics Discovery, McMaster University, Hamilton, Ontario, Canada
  2. 2Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
  3. 3M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada
  4. 4Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA
  5. 5Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA
  6. 6Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany
  7. 7Center for Biomolecular Sciences, University of Illinois at Chicago, Chicago, IL, USA. [email protected]
  8. 8Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, USA. [email protected]
  9. 9Institute for Biochemistry and Molecular Biology, University of Hamburg, Hamburg, Germany. [email protected]
  10. 10David Braley Centre for Antibiotics Discovery, McMaster University, Hamilton, Ontario, Canada. [email protected]
  11. 11Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. [email protected]
  12. 12M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario, Canada. [email protected]
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Abstract

A significant challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favor due to the frequent rediscovery of known drug scaffolds. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield. Here, we demonstrate that by using improved fractionation approaches that enrich previously overlooked minor products, even well-studied strains of antibiotic-producing actinomycetes can provide new chemical scaffolds with unique modes of action. By fractionating a library of natural product extracts from soil bacteria, we show that Streptomyces rimosus, the source of the well-known antibiotic oxytetracycline, produces a previously overlooked cyclic depsipeptide antibiotic that we called manikomycin. Manikomycin can kill multi-drug-resistant Enterobacteriaceae and is not susceptible to resistance associated with clinically used antibiotics. Biochemical, genetic, and structural analyses reveal that manikomycin binds in the 'exit' or E site of the large subunit of the bacterial ribosome preventing the entry of the 3' end of the tRNA into the E site and effectively hindering the translocation step of protein synthesis in a sequence context-specific manner. Manikomycin is the first antibacterial agent to target the critical but underexplored E site in the large ribosomal subunit, highlighting its value as a lead for developing new antibiotics.

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Cite

BibTeXRIS
BibTeX
@article{kaur2026natural,
  title = {{A natural depsipeptide antibiotic binds the E-site of the bacterial ribosome}},
  author = {Manpreet Kaur and Dmitrii Y. Travin and Max J. Berger and Manoj Jangra and Martino Morici and Haaris Ahsan Safdari and Dorota Klepacki and Wenliang Wang and Michael A. Cook and Sommer Chou and Allison K. Guitor and Kalinka K. Koteva and Min Xu and Linda J. Ejim and Aline Fiebig‐Comyn and Yeganeh Yousefi and Brian K. Coombes and Lesley T. MacNeil and Nora Vázquez‐Laslop and Alexander S. Mankin and Daniel N. Wilson and Gerard D. Wright},
  journal = {Nature},
  year = {2026},
  month = jun,
  doi = {10.1038/s41586-026-10589-2},
  url = {https://doi.org/10.1038/s41586-026-10589-2},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - A natural depsipeptide antibiotic binds the E-site of the bacterial ribosome
AU  - Manpreet Kaur
AU  - Dmitrii Y. Travin
AU  - Max J. Berger
AU  - Manoj Jangra
AU  - Martino Morici
AU  - Haaris Ahsan Safdari
AU  - Dorota Klepacki
AU  - Wenliang Wang
AU  - Michael A. Cook
AU  - Sommer Chou
AU  - Allison K. Guitor
AU  - Kalinka K. Koteva
AU  - Min Xu
AU  - Linda J. Ejim
AU  - Aline Fiebig‐Comyn
AU  - Yeganeh Yousefi
AU  - Brian K. Coombes
AU  - Lesley T. MacNeil
AU  - Nora Vázquez‐Laslop
AU  - Alexander S. Mankin
AU  - Daniel N. Wilson
AU  - Gerard D. Wright
PY  - 2026
DA  - 2026/06/03
JO  - Nature
DO  - 10.1038/s41586-026-10589-2
UR  - https://doi.org/10.1038/s41586-026-10589-2
AB  - A significant challenge in addressing the antibiotic resistance crisis is identifying new antimicrobial compounds. Although natural products produced by fungi and bacteria, particularly actinomycetes, have been the source of most antibiotics discovered over the past 80 years, they have fallen out of favor due to the frequent rediscovery of known drug scaffolds. The current perception is that antibiotic-producing actinomycetes have been over-mined and possess little novelty left to yield. Here, we demonstrate that by using improved fractionation approaches that enrich previously overlooked minor products, even well-studied strains of antibiotic-producing actinomycetes can provide new chemical scaffolds with unique modes of action. By fractionating a library of natural product extracts from soil bacteria, we show that Streptomyces rimosus, the source of the well-known antibiotic oxytetracycline, produces a previously overlooked cyclic depsipeptide antibiotic that we called manikomycin. Manikomycin can kill multi-drug-resistant Enterobacteriaceae and is not susceptible to resistance associated with clinically used antibiotics. Biochemical, genetic, and structural analyses reveal that manikomycin binds in the 'exit' or E site of the large subunit of the bacterial ribosome preventing the entry of the 3' end of the tRNA into the E site and effectively hindering the translocation step of protein synthesis in a sequence context-specific manner. Manikomycin is the first antibacterial agent to target the critical but underexplored E site in the large ribosomal subunit, highlighting its value as a lead for developing new antibiotics.
SN  - 0028-0836
SN  - 1476-4687
ER  -