A minimal biophysical model of combined antibiotic action

B. Kavcic, G. Tkačik, T. Bollenbach, BioRxiv (2020).

Preprint | Published | English
Department
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.
Publishing Year
Date Published
2020-04-18
Journal Title
bioRxiv
Page
20
IST-REx-ID

Cite this

Kavcic B, Tkačik G, Bollenbach T. A minimal biophysical model of combined antibiotic action. bioRxiv. 2020.
Kavcic, B., Tkačik, G., & Bollenbach, T. (2020). A minimal biophysical model of combined antibiotic action. BioRxiv. Cold Spring Harbor Laboratory.
Kavcic, Bor, Gašper Tkačik, and Tobias Bollenbach. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv. Cold Spring Harbor Laboratory, 2020.
B. Kavcic, G. Tkačik, and T. Bollenbach, “A minimal biophysical model of combined antibiotic action,” bioRxiv. Cold Spring Harbor Laboratory, 2020.
Kavcic B, Tkačik G, Bollenbach T. 2020. A minimal biophysical model of combined antibiotic action. bioRxiv.
Kavcic, Bor, et al. “A Minimal Biophysical Model of Combined Antibiotic Action.” BioRxiv, Cold Spring Harbor Laboratory, 2020.
All files available under the following license(s):
Copyright Statement:
This Item is protected by copyright and/or related rights. [...]

Link(s) to Main File(s)
Access Level
OA Open Access
Material in IST:
Dissertation containing IST record

Export

Marked Publications

Open Data IST Research Explorer

Search this title in

Google Scholar