Dosage and Dose Schedule Screening of Drug Combinations in Agent-Based Models Reveals Hidden Synergies
Authored by Clemens Kuehn, Lisa C Barros de Andrade e Sousa, Katarzyna M Tyc, Edda Klipp
Date Published: 2016
DOI: 10.3389/fphys.2015.00398
Sponsors:
European Union
Platforms:
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Model Documentation:
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Abstract
The fungus Candida alb/cans is the most common causative agent of human
fungal infections and better drugs or drug combination strategies are
urgently needed. Here, we present an agent-based model of the interplay
of C. albicans with the host immune system and with the microflora of
the host. We took into account the morphological change of C. albicans
from the yeast to hyphae form and its dynamics during infection. The
model allowed us to follow the dynamics of fungal growth and morphology, of the immune cells and of microflora in different perturbing
situations. We specifically focused on the consequences of microflora
reduction following antibiotic treatment. Using the agent-based model, different drug types have been tested for their effectiveness, namely
drugs that inhibit cell division and drugs that constrain the
yeast-to-hyphae transition. Applied individually, the division drug
turned out to successfully decrease hyphae while the transition drug
leads to a burst in hyphae after the end of the treatment. To evaluate
the effect of different drug combinations, doses, and schedules, we
introduced a measure for the return to a healthy state, the infection
score. Using this measure, we found that the addition of a transition
drug to a division drug treatment can improve the treatment reliability
while minimizing treatment duration and drug dosage. In this work we
present a theoretical study. Although our model has not been calibrated
to quantitative experimental data, the technique of computationally
identifying synergistic treatment combinations in an agent based model
exemplifies the importance of computational techniques in translational
research.
Tags
Infection
systems biology
Multiscale
Expression
Defense
Candida-albicans
Macrophages
Epithelial-cells
Tissue-damage
Fluconazole