In:
Nature Communications, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2018-08-27)
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.
Type of Medium:
Online Resource
ISSN:
2041-1723
DOI:
10.1038/s41467-018-05954-3
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2018
detail.hit.zdb_id:
2553671-0
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