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BP: Fachverband Biologische Physik
BP 1: Statistical Physics in Biological Systems I (joint DY, BP)
BP 1.6: Talk
Monday, March 14, 2011, 12:00–12:15, ZEU 250
Resolution of gene regulatory conflicts caused by combinations of antibiotics — •Tobias Bollenbach1,2 and Roy Kishony1 — 1Harvard Medical School, Boston, MA, USA — 2IST Austria, Klosterneuburg, Austria
Regulatory conflicts occur when two signals, which individually trigger opposite cellular responses, are present simultaneously. Here, we investigate how such gene regulation conflicts are resolved in the bacterial response to antibiotic combinations. We use an Escherichia coli promoter-GFP reporter library to study the genome-wide transcriptional response to either additive or antagonistic drug pairs at fine two-dimensional resolution of drug concentration. Using principal component analysis (PCA), we find that this complete dataset can be almost fully characterized as a surprisingly simple linear sum of only two components. The first component, accounting for over 70% of the variance in the data set, represents the response to the net effectiveness of the drug combination in inhibiting growth. The second component describes how regulatory conflicts are resolved for genes that respond differently to each of the individual drugs. We find that for the non-interacting drug pair, conflicts are resolved by linearly interpolating the two single drug responses, while for the antagonistic drug pair, the drug that has the stronger impact on growth dominates the transcriptional response. Importantly, for a given drug pair, the same strategy of conflict resolution is used for almost all genes. These results provide a recipe for predicting gene expression responses to drug combinations, which may lead to a more rational design of combination treatments.