Abstract
Since the earliest days of using natural remedies, combining therapies for disease treatment has been standard practice. Combination treatments exhibit synergistic effects, broadly defined as a greater-than-additive effect of two or more therapeutic agents. Clinicians often use their experience and expertise to tailor such combinations to maximize the therapeutic effect. Although understanding and predicting biophysical underpinnings of synergy have benefitted from high-throughput screening and computational studies, one challenge is how to best design and analyze the results of synergy studies, especially because the number of possible combinations to test quickly becomes unmanageable. Nevertheless, the benefits of such studies are clear-by combining multiple drugs in the treatment of infectious disease and cancer, for instance, one can lessen host toxicity and simultaneously reduce the likelihood of resistance to treatment. This study introduces a new approach to characterize drug synergy, in which we extend the widely validated chemogenomic HIP-HOP assay to drug combinations; this assay involves parallel screening of comprehensive collections of barcoded deletion mutants. We identify a class of "combination-specific sensitive strains" that introduces mechanisms for the synergies we observe and further suggest focused follow-up studies.
Highlights
Drugs and drug-like molecules are powerful molecular tools that can act by rapid and reversible inhibition of a specific protein or other biomolecule in cells
Following up on how drug–drug interactions predict drug– gene interactions – to predict synergy using chemogenomic data, we examined 18 datasets and assessed if the known drug-targets listed in Table 1 were sensitive in any of the treatments based on the log2 ratio of control over treatment
Visualization of HaploInsufficiency Profiling (HIP)–HOmozygous Profiling (HOP) Screens To facilitate the visualization of the single agent and combination screens, we provide a custom shiny app to (1) upload excel or text files, (2) visualize each screen as a scatterplot (HIP and HOP plots side-by-side), (3) rapidly identify combination specific strains, significantly sensitive strains, and non-significantly sensitive strains, and (4) the significant strains are detailed below the plots with hyperlinks
Summary
Drugs and drug-like molecules are powerful molecular tools that can act by rapid and reversible inhibition of a specific protein or other biomolecule in cells. Such chemical perturbations, while similar to genetic manipulations, have several experimental advantages: they are tunable, fast-acting, often reversible, and applicable across large evolutionary distances, e.g., from yeast to human. The clinical success of chemical combination therapies has motivated our empirical study of synergistic chemical interactions. These data can be assessed to predict how two drugs might interact in a biological system. To study the potential interactions, several mathematical models of drug
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