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Cited by 83RNA and protein synthesis mechanismsBacterial Genetics and BiotechnologyRNA modifications and cancer

Deleterious mutations in small subunit ribosomal RNA identify functional sites and potential targets for antibiotics

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Yassin, Aymen, Fredrick, Kurt, Mankin, Alexander S.·2005·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.0508444102PMC PMC1283848
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Abstract

Many clinically useful antibiotics interfere with protein synthesis in bacterial pathogens by inhibiting ribosome function. The sites of action of known drugs are limited in number, are composed primarily of ribosomal RNA (rRNA), and coincide with functionally critical centers of the ribosome. Nucleotide alterations within such sites are often deleterious. To identify functional sites and potential sites of antibiotic action in the ribosome, we prepared a random mutant library of rRNA genes and selected dominant mutations in 16S rRNA that interfere with cell growth. Fifty-three 16S rRNA positions were identified whose mutation inhibits protein synthesis. Mutations were ranked according to the severity of the phenotype, and the detrimental effect of several mutations on translation was verified in a specialized ribosome system. Analysis of the polysome profiles of mutants suggests that the majority of the mutations directly interfered with ribosome function, whereas a smaller fraction of mutations affected assembly of the small ribosomal subunit. Twelve of the identified mutations mapped to sites targeted by known antibiotics, confirming that deleterious mutations can be used to identify antibiotic targets. About half of the mutations coincided with known functional sites in the ribosome, whereas the rest of the mutations affected ribosomal sites with less clear functional significance. Four clusters of deleterious mutations in otherwise unremarkable ribosomal sites were identified, suggesting their functional importance and potential as antibiotic targets.

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Authors
Yassin, A., Fredrick, K., & Mankin, A. S.
Affiliations
University of Illinois Chicago (US)
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2005-11-03
Volume
102
Issue
46
Pages
16620-16625
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.0508444102
PMC
PMC1283848
OpenAlex
W1992898925
Cited by
83
References
38
Citations by year
2026: 4 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 4 · 2021: 1 · 2020: 4 · 2019: 1 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 3 · 2013: 6 · 2012: 3
FWCI
2.14
Type
journal article
Language
en
Open access
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • University of California, Santa Cruz
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases (U19AI056575, U19 AI 56575)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
Keywords
16S rRNA, small subunit rRNA, deleterious mutations, antibiotic targets, random mutant library, protein synthesis inhibition, ribosome assembly, polysome profiles, bacterial ribosome
MeSH terms
Anti-Bacterial Agents, Base Sequence, Molecular Sequence Data, Mutation, Nucleic Acid Conformation, RNA, Ribosomal, DNA Primers

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