Dresden 2009 – scientific programme

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BP: Fachverband Biologische Physik

BP 18: Regulation and Signaling

BP 18.9: Talk

Thursday, March 26, 2009, 12:15–12:30, HÜL 186

Non-optimal microbial response to antibiotics underlies drug interactions — •Tobias Bollenbach and Roy Kishony — Harvard Medical School, Boston, MA, USA

Bacterial cells respond to antibiotic stress by regulating gene expression. Of key importance for survival and growth is the regulation of ribosomal genes, which control the overall cellular translation rate. While ribosome production is known to be tuned to different nutrient conditions to maximize growth, much less is known about the optimality of ribosome production under antibiotic stress. Inhibition of translation by drugs can relieve the inhibitory effect of antibiotics that target DNA synthesis, suggesting a greater-than-optimal expression of ribosomal genes when under DNA stress. Here we test this hypothesis by measuring and manipulating gene expression in Escherichia coli under various antibiotic stresses. We find that cells down-regulate ribosomal gene expression in response to antibiotics that inhibit DNA replication. The hallmark of non-optimality is the possibility for improvement: using strains with genetically manipulated ribosomal gene expression, we show that decreased ribosomal expression can increase survival and growth under DNA stress. Further, we find that genetically optimizing ribosomal expression removes the suppression between DNA and protein synthesis inhibitors, demonstrating that these drug interactions result from non-optimal gene regulation. We present a mathematical model which shows how optimal growth rate-dependent regulation of ribosome synthesis can lead to (1) non-optimal regulation in response to antibiotics and (2) suppressive drug interactions.