Efficient Measurement of Drug Interactions with DiaMOND (Diagonal Measurement of N-Way Drug Interactions).

Abstract:

Treatment of tuberculosis necessitates combination therapy. Therefore, development of new tuberculosis therapies should consider multidrug effects because specific combinations may improve or reduce treatment efficacy through synergistic or antagonistic drug interactions, respectively. The standard assay of drug interactions is a checkerboard assay, wherein the drug-dose combinations are well-sampled across broad dose ranges. However, measuring three or more drugs in combination with a checkerboard assay is impractical due to the high number of measurements. We describe a protocol for efficient and quantitative measurement of drug interactions called diagonal measurement of n-way drug interactions (DiaMOND). DiaMOND is a geometric optimization of the checkerboard assay, using only the diagonal and axes of the checkerboard. This protocol describes how to perform DiaMOND experiments and analysis for Mycobacterium tuberculosis growth inhibition in standard growth conditions. As a guide on how to customize the DiaMOND assay, this protocol includes notes to modify the procedures for other growth conditions and outcome measures.