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Cell. 2009 Nov 13;139(4):707-18. doi: 10.1016/j.cell.2009.10.025.

Nonoptimal microbial response to antibiotics underlies suppressive drug interactions.

Author information

1
Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.

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.

PMID:
19914165
PMCID:
PMC2838386
DOI:
10.1016/j.cell.2009.10.025
[Indexed for MEDLINE]
Free PMC Article

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