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by Andreas Angermayr

Detail Summary
Date 13 August 2018
Time 11:00 - 12:00

Institute for Biological Physics

University of Cologne, Germany

 

A growth-mediated negative feedback loop lowers the sensitivity to antibiotics.”

 

summary

Understanding how pathogens respond to antibiotics is relevant for establishing effective disease treatments and for fighting drug resistance evolution. The environment affects the growth of bacteria and their susceptibility to antibiotics. Using a set of six different antibiotics—representing the main modes of action—we tested how growth rate influences their efficacy. For trimethoprim—an antibiotic used widely to treat urinary tract infections—we have found a reduction of susceptibility for slow growing Escherichia coli cultures. The folate-synthesis inhibitor trimethoprim shows a consistently observed very shallow dose-response curve. Using four different means of growth limitation—each encompassing a broad range of growth rates—we can change the steepness of the dose-response curve for trimethoprim. Combining these results, we have established a general growth-mediated negative feedback loop that controls the dose-sensitivity for trimethoprim. Next, we asked for the molecular mechanism governing antibiotic susceptibility and dose-sensitivity. Lowered growth rate leads to an increased drug target-expression level which in turn lowers the dose-sensitivity to the drug. The growth-mediated negative feedback offers an explanation for the shallow dose-response curve for trimethoprim. These results have implications for antibiotic efficacy in clearing infections and for resistance evolution. Negative growth-mediated feedback offers an opportunity for slowing the evolution of drug resistance.

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