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.

• PMID: 30150706
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Journal Article | Research Support, N.I.H., Extramural | Research Support, U.S. Gov't, Non-P.H.S.

Authors

Weinstein ZB, Kuru N, Kiriakov S, Palmer AC, Khalil AS, Clemons PA, Zaman MH, Roth FP, Cokol M

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