Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions

T. Bollenbach, S. Quan, R.P. Chait, R. Kishony, Cell 139 (2009) 707–718.

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Abstract
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.
Publishing Year
Date Published
2009-01-01
Journal Title
Cell
Volume
139
Issue
4
Page
707 - 718
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Bollenbach T, Quan S, Chait RP, Kishony R. Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions. Cell. 2009;139(4):707-718. doi:10.1016/j.cell.2009.10.025
Bollenbach, T., Quan, S., Chait, R. P., & Kishony, R. (2009). Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions. Cell, 139(4), 707–718. https://doi.org/10.1016/j.cell.2009.10.025
Bollenbach, Tobias, Selwyn Quan, Remy P Chait, and Roy Kishony. “Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions.” Cell 139, no. 4 (2009): 707–18. https://doi.org/10.1016/j.cell.2009.10.025.
T. Bollenbach, S. Quan, R. P. Chait, and R. Kishony, “Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions,” Cell, vol. 139, no. 4, pp. 707–718, 2009.
Bollenbach T, Quan S, Chait RP, Kishony R. 2009. Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions. Cell. 139(4), 707–718.
Bollenbach, Tobias, et al. “Nonoptimal Microbial Response to Antibiotics Underlies Suppressive Drug Interactions.” Cell, vol. 139, no. 4, Cell Press, 2009, pp. 707–18, doi:10.1016/j.cell.2009.10.025.

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