Modeling the impact of drug interactions on therapeutic selectivity.

Nat Commun
Publication type
Journal Article
Authors
Keywords
Abstract

Combination therapies that produce synergistic growth inhibition are widely sought after for the pharmacotherapy of many pathological conditions. Therapeutic selectivity, however, depends on the difference between potency on disease-causing cells and potency on non-target cell types that cause toxic side effects. Here, we examine a model system of antimicrobial compound combinations applied to two highly diverged yeast species. We find that even though the drug interactions correlate between the two species, cell-type-specific differences in drug interactions are common and can dramatically alter the selectivity of compounds when applied in combination vs. single-drug activity-enhancing, diminishing, or inverting therapeutic windows. This study identifies drug combinations with enhanced cell-type-selectivity with a range of interaction types, which we experimentally validate using multiplexed drug-interaction assays for heterogeneous cell cultures. This analysis presents a model framework for evaluating drug combinations with increased efficacy and selectivity against pathogens or tumors.

Year of Publication
2018
Journal
Nat Commun
Volume
9
Issue
1
Pages
3452
Date Published
2018 08 27
ISSN
2041-1723
DOI
10.1038/s41467-018-05954-3
PubMed ID
30150706
PubMed Central ID
PMC6110842
Links
Grant list
U01 CA176152 / CA / NCI NIH HHS / United States
P50 GM107618 / GM / NIGMS NIH HHS / United States
DP2 AI131083 / AI / NIAID NIH HHS / United States
P50 HG004233 / HG / NHGRI NIH HHS / United States
T32 GM008541 / GM / NIGMS NIH HHS / United States