Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA 02111, USA.
Laboratory of Systems Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
Sci Adv. 2017 Oct 11;3(10):e1701881. doi: 10.1126/sciadv.1701881. eCollection 2017 Oct.
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 -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 . Efficient measurement and factorization of high-order drug interactions by DiaMOND are broadly applicable to other cell types and disease models.
三联或更多种药物的联合应用被用于治疗多种疾病，包括结核病。因此，了解药物相互作用的协同或拮抗作用如何影响联合治疗的疗效非常重要。然而，由于缺乏有效的测量方法和用于分析和解释的理论框架，我们对高阶药物相互作用的了解受到限制。我们开发了一种有效的实验采样和评分方法[三向药物相互作用的对角线测量（DiaMOND）]，以测量任意数量药物组合的药物相互作用。DiaMOND 为棋盘检测提供了一种有效的替代方法，棋盘检测常用于测量药物相互作用。我们建立了一个几何框架，将高阶药物相互作用分解为较低阶的组成部分，从而为如何使用较低阶测量来预测高阶相互作用建立了一个路线图。我们的框架是一个用于高阶药物相互作用的广义 Loewe 加性模型。使用 DiaMOND，我们鉴定和分析了针对 的协同和拮抗抗生素组合。DiaMOND 对高阶药物相互作用的高效测量和分解广泛适用于其他细胞类型和疾病模型。
