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Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions
Open accessAbstract
Suppressive drug interactions, in which one antibiotic can actually help bacterial cells to grow faster in the presence of another, occur between protein and DNA synthesis inhibitors. Here, we show that this suppression results from nonoptimal regulation of ribosomal genes in the presence of DNA stress. Using GFP-tagged transcription reporters in Escherichia coli, we find that ribosomal genes are not directly regulated by DNA stress, leading to an imbalance between cellular DNA and protein content. To test whether ribosomal gene expression under DNA stress is nonoptimal for growth rate, we sequentially deleted up to six of the seven ribosomal RNA operons. These synthetic manipulations of ribosomal gene expression correct the protein-DNA imbalance, lead to improved survival and growth, and completely remove the suppressive drug interaction. A simple mathematical model explains the nonoptimal regulation in different nutrient environments. These results reveal the genetic mechanism underlying an important class of suppressive drug interactions.
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“This difference is important to consider when performing experiments that depend on the number of cellular divisions or cells present, such as cellular communication [12, 13] and antibiotic susceptibility [14–17] and biofilms [18].”
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Metadata
- Authors
- Bollenbach, T., Quan, S., Chait, R., & Kishony, R.
- Affiliations
- Harvard University (US)
- Stanford University (US)
- Corresponding author
- Kishony, Roy
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2009-11
- Volume
- 139
- Issue
- 4
- Pages
- 707-718
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC2838386
- OpenAlex
- W2145744900
- Cited by
- 227
- References
- 79
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 11 · 2023: 9 · 2022: 12 · 2021: 8 · 2020: 19 · 2019: 12 · 2018: 14 · 2017: 15 · 2016: 16 · 2015: 19 · 2014: 16 · 2013: 19 · 2012: 10
- FWCI
- 6.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1390 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences (R01GM081617)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- antibiotic synergy, ribosomal RNA operon, growth rate, Escherichia coli, transcriptional regulation, protein synthesis inhibitors, DNA synthesis inhibitors
- MeSH terms
- Anti-Infective Agents, DNA, Drug Interactions, Escherichia coli, Ribosomes, Protein Biosynthesis, Nucleic Acid Synthesis Inhibitors
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