Chapter 30
Efficient Measurement of Drug Interactions with DiaMOND
(Diagonal Measurement of N-Way Drug Interactions)
Nhi Van, Yonatan N. Degefu, and Bree B. Aldridge
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.
Key words DiaMOND, Antibiotics, Drug interaction, Combination therapy
1 Introduction
Tuberculosis and other mycobacterial diseases require multidrug
treatment to improve efficacy and treat an infection with variable
lesion types. The design of new therapeutic regimens should therefore consider the effects of drug combinations rather than the
activities of single drugs alone [1]. Antibiotics in combination
may be more or less effective than expected based on the efficacies
of single drugs in a phenomenon called a drug interaction. Drug
interactions can be classified as synergistic (improved effect), antagonistic (reduced effect), or additive (no interaction) [2, 3].
The standard assay for drug interactions is systematic measurement of drug-dose combinations across a broad range of doses
followed by calculation of the shape of the isobole (contour) in
this “checkerboard” where growth inhibition is the same [3]. For
Tanya Parish and Anuradha Kumar (eds.), Mycobacteria Protocols, Methods in Molecular Biology, vol. 2314,
https://doi.org/10.1007/978-1-0716-1460-0_30, © Springer Science+Business Media, LLC, part of Springer Nature 2021
703
Efficient Measurement of Drug Interactions with DiaMOND
(Diagonal Measurement of N-Way Drug Interactions)
Nhi Van, Yonatan N. Degefu, and Bree B. Aldridge
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.
Key words DiaMOND, Antibiotics, Drug interaction, Combination therapy
1 Introduction
Tuberculosis and other mycobacterial diseases require multidrug
treatment to improve efficacy and treat an infection with variable
lesion types. The design of new therapeutic regimens should therefore consider the effects of drug combinations rather than the
activities of single drugs alone [1]. Antibiotics in combination
may be more or less effective than expected based on the efficacies
of single drugs in a phenomenon called a drug interaction. Drug
interactions can be classified as synergistic (improved effect), antagonistic (reduced effect), or additive (no interaction) [2, 3].
The standard assay for drug interactions is systematic measurement of drug-dose combinations across a broad range of doses
followed by calculation of the shape of the isobole (contour) in
this “checkerboard” where growth inhibition is the same [3]. For
Tanya Parish and Anuradha Kumar (eds.), Mycobacteria Protocols, Methods in Molecular Biology, vol. 2314,
https://doi.org/10.1007/978-1-0716-1460-0_30, © Springer Science+Business Media, LLC, part of Springer Nature 2021
703