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A Minimal Biophysical Model of Combined Antibiotic Action

View ORCID ProfileBor Kavčič, View ORCID ProfileGašper Tkačik, View ORCID ProfileTobias Bollenbach
doi: https://doi.org/10.1101/2020.04.18.047886
Bor Kavčič
1Institute of Science and Technology Austria, Klosterneuburg, Austria
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Gašper Tkačik
1Institute of Science and Technology Austria, Klosterneuburg, Austria
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Tobias Bollenbach
2University of Cologne, Cologne, Germany
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  • For correspondence: t.bollenbach@uni-koeln.de
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Abstract

Combining drugs can improve the efficacy of treatments. However, predicting the effect of drug combinations is still challenging. The combined potency of drugs determines the drug interaction, which is classified as synergistic, additive, antagonistic, or suppressive. While probabilistic, non-mechanistic models exist, there is currently no biophysical model that can predict antibiotic interactions. Here, we present a physiologically relevant model of the combined action of antibiotics that inhibit protein synthesis by targeting the ribosome. This model captures the kinetics of antibiotic binding and transport, and uses bacterial growth laws to predict growth in the presence of antibiotic combinations. We find that this biophysical model can produce all drug interaction types except suppression. We show analytically that antibiotics which cannot bind to the ribosome simultaneously generally act as substitutes for one another, leading to additive drug interactions. Previously proposed null expectations for higher-order drug interactions follow as a limiting case of our model. We further extend the model to include the effects of direct physical or allosteric interactions between individual drugs on the ribosome. Notably, such direct interactions profoundly change the combined drug effect, depending on the kinetic parameters of the drugs used. The model makes additional predictions for the effects of resistance genes on drug interactions and for interactions between ribosome-targeting antibiotics and antibiotics with other targets. These findings enhance our understanding of the interplay between drug action and cell physiology and are a key step toward a general framework for predicting drug interactions.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted April 18, 2020.
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A Minimal Biophysical Model of Combined Antibiotic Action
Bor Kavčič, Gašper Tkačik, Tobias Bollenbach
bioRxiv 2020.04.18.047886; doi: https://doi.org/10.1101/2020.04.18.047886
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A Minimal Biophysical Model of Combined Antibiotic Action
Bor Kavčič, Gašper Tkačik, Tobias Bollenbach
bioRxiv 2020.04.18.047886; doi: https://doi.org/10.1101/2020.04.18.047886

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