Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome
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Significance: The identification of negamycin’s binding site within helix 34 of the small subunit head domain and the elucidation of its mechanism of action during messenger RNA decoding provide a physical framework for exploring structure–activity relationships of this largely unexplored antibiotic class. These findings lay the foundation for the rational design of improved negamycin analogs that may one day serve as potent antibacterial agents in the clinic.
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Negamycin is a natural bactericidal antibiotic active against a broad spectrum of Gram-negative pathogens, including Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii.
“Negamycin is a natural bactericidal antibiotic that displays activity against a broad spectrum of Gram-negative pathogens, including Klebsiella pneumoniae , Pseudomonas aeruginosa , and Acinetobacter baumannii (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
The MIC value of tetracycline for the U1052G mutant was fourfold lower than that of the wild-type ribosome.
“The MIC value of tetracycline for the U1052G mutant was fourfold lower than that of the wild-type ribosome (12) (Table 1).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
In the T. thermophilus structure with a bound tRNA molecule, the phosphate oxygens of nucleotides U1052 and G1053 indirectly interact with negamycin and the tRNA molecule through a coordinated Mg2+ ion.
“In the T. thermophilus structure with a bound tRNA molecule, the phosphate oxygens of nucleotides U1052 and G1053 indirectly interact with negamycin and the tRNA molecule through a coordinated Mg 2 + ion (Fig. 1 E and Fig. S1).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
The phosphate group of A1197 engages negamycin through a bound Mg2+ ion.
“The phosphate group of A1197 also engages negamycin through a bound Mg 2 + ion.”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
Negamycin's impact on miscoding is significantly suppressed by the U1052G resistance mutation.
“Negamycin ' s impact on miscoding is, however, significantly suppressed by the U1052G resistance mutation (12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
In the negamycin-bound structure of the wild-type 70S E. coli ribosome, the phosphate oxygen of nucleotide G1053 is within 4.3 Å of the methyl group on N8 of negamycin.
“The negamycin-bound structure of the wild-type 70S E. coli ribosome shows that the phosphate oxygen of nucleotide G1053 is within 4.3 Å of the methyl group on N8 of negamycin (12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
Two previously identified negamycin resistance mutations, U1052G and U1060A, localize to the head domain of the 30S subunit positioned within helix 34 (h34) and are in close proximity to the negamycin binding site.
“Two previously identified negamycin resistance mutations, U1052G and U1060A, localize to the head domain of the 30S subunit positioned within helix 34 (h34) and are in close proximity to the negamycin binding site (Fig. 1 A and B ) (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
The mechanism of action for both negamycin and tetracycline is to interfere with tRNA binding to the aminoacyl-tRNA (aa-tRNA) site of the small 30S ribosomal subunit.
“The mechanism of action for both antibiotics is to interfere with tRNA binding to the aminoacyltRNA (aa-tRNA) site of the small 30S ribosomal subunit (11, 12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
Negamycin has no detectable impact on the selection of cognate aa-tRNA but compromises the ribosome's ability to reject near-cognate aa-tRNA.
“Previous investigations have shown that negamycin has no detectable impact on the selection of cognate aa-tRNA but instead, compromises the ribosome ' s ability to reject those that are near-cognate (12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
These findings provide additional evidence that conformational rearrangements between the head and body regions of the small subunit play a role in the tRNA selection process.
“These findings provide additional evidence that conformational rearrangements between the head and body regions of the small subunit play a role in the tRNA selection process (12).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
Negamycin and tetracycline possess chemically distinct features that form different sets of electrostatic and van der Waals interactions, specifically with h31 and h34.
“Despite the overlapping binding sites, negamycin and tetracycline possess chemically distinct features (Fig. 2 B ) that form different sets of electrostatic and van der Waals interactions, specifically with h31 and h34 (11, 12, 17).”
From Resistance mutations generate divergent antibiotic susceptibility profiles against translation inhibitors (2016) · cites this paper as [12]
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Self-citation
- Authors
- Olivier, N. B., Altman, R. B., Noeske, J., Basarab, G. S., Code, E., Ferguson, A. D., Gao, N., Huang, J., Juette, M. F., Livchak, S., Miller, M. D., Prince, D. B., Cate, J. H. D., Buurman, E. T., & Blanchard, S. C.
- Affiliations
- AstraZeneca (United States) (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- QB3 (US)
- Departments of dChemistry and
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-11-03
- Volume
- 111
- Issue
- 46
- Pages
- 16274-16279
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC4246262
- OpenAlex
- W2036199133
- Cited by
- 48
- References
- 66
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 9 · 2023: 2 · 2022: 2 · 2021: 6 · 2020: 3 · 2019: 1 · 2018: 5 · 2017: 3 · 2016: 5 · 2015: 6
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- AstraZeneca
- Deutscher Akademischer Austauschdienst
- Pharmaron
- National Institutes of Health
- Weill Cornell Medical College
- National Institute of General Medical Sciences (GM079238, R01GM079238, GM098859, GM65050, R01GM065050, R01GM098859)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- negamycin, ribosome, 16S rRNA, A-site, antibiotic resistance, Escherichia coli, protein synthesis inhibition
- MeSH terms
- Tigecycline, Amino Acids, Diamino, Anti-Bacterial Agents, Binding Sites, Binding, Competitive, Escherichia coli, Minocycline, Models, Molecular, Nucleic Acid Conformation, Ribosomes, RNA, Bacterial, RNA, Ribosomal, 16S, RNA, Transfer, Tetracycline Resistance, Tetracyclines, Protein Biosynthesis, Point Mutation, Crystallography, X-Ray, Base Pairing, Drug Resistance, Multiple, Bacterial
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