October 1, 2017
m inhibitory concentration for each drug is given in Table 1. Assays were performed in clear, flat-bottom 384-well microplates by dispensing nanoliter volumes of drugs using a digital drug dispenser (D300e Digital Dispenser, HP). Dispense locations were randomized within each plate using the software to minimize the plate position effect. Mid-log phase cultures were diluted to an optical density (
Combinations of three or more drugs are used to treat many diseases, including tuberculosis. Thus, it is important to understand how synergistic or antagonistic drug interactions affect the efficacy of combination therapies. However, our understanding of high-order drug interactions is limited because of the lack of both efficient measurement methods and theoretical framework for analysis and interpretation. We developed an efficient experimental sampling and scoring method [diagonal measurement of n-way drug interactions (DiaMOND)] to measure drug interactions for combinations of any number of drugs. DiaMOND provides an efficient alternative to checkerboard assays, which are commonly used to measure drug interactions. We established a geometric framework to factorize high-order drug interactions into lower-order components, thereby establishing a road map of how to use lower-order measurements to predict high-order interactions. Our framework is a generalized Loewe additivity model for high-order drug interactions. Using DiaMOND, we identified and analyzed synergistic and antagonistic antibiotic combinations against Mycobacteriumtuberculosis. Efficient measurement and factorization of high-order drug interactions by DiaMOND are broadly applicable to other cell types and disease models.
Cokol, M; Kuru, N; Bicak, E; Larkins-Ford, J; Aldridge, BB;
Journal: Sci Adv Pages: e1701881