OBIF: an omics-based interaction framework to reveal molecular drivers of synergy

Abstract

Bioactive molecule library screening may empirically identify effective combination therapies, but molecular mechanisms underlying favorable drug–drug interactions often remain unclear, precluding further rational design. In the absence of an accepted systems theory to interrogate synergistic responses, we introduce Omics-Based Interaction Framework (OBIF) to reveal molecular drivers of synergy through integration of statistical and biological interactions in synergistic biological responses. OBIF performs full factorial analysis of feature expression data from single versus dual exposures to identify molecular clusters that reveal synergy-mediating pathways, functions and regulators. As a practical demonstration, OBIF analyzed transcriptomic and proteomic data of a dyad of immunostimulatory molecules that induces synergistic protection against influenza A and revealed unanticipated NF-κB/AP-1 cooperation that is required for antiviral protection. To demonstrate generalizability, OBIF analyzed data from a diverse array of Omics platforms and experimental conditions, successfully identifying the molecular clusters driving their synergistic responses. Hence, unlike existing synergy quantification and prediction methods, OBIF is a phenotype-driven systems model that supports multiplatform interrogation of synergy mechanisms.

Defective synaptic plasticity in a model of Coffin–Lowry syndrome is rescued by simultaneously targeting PKA and MAPK pathways

“…A number of methods have been introduced to quantitatively assess synergism. We applied the method of Slinker (1998) , which has been adopted by multiple groups ( Coss et al 2007 ; Thackray et al 2010 ; Binatti et al 2021 ; Ewing et al 2021 ; Pantaleon Garcia et al 2022 ; Zwolak and Wnuk 2022 ). With this approach, synergism is assessed by testing the interaction effect in a two-way ANOVA, where the two factors (A and B) are the two drugs of interest, subdivided based on whether the drug is present (+) or absent (−), yielding four groups (A − B − , A + B − , A − B + , and A + B + ).…”

“…To evaluate synergistic effects of dual-drug treatments on LTF and RSK activation, we used a two-way ANOVA to assess the interaction between two treatment factors ( Coss et al 2007 ; Thackray et al 2010 ; Binatti et al 2021 ; Ewing et al 2021 ; Pantaleon Garcia et al 2022 ; Zwolak and Wnuk 2022 ). The significance of the combined-drug interaction was used to evaluate the null hypothesis that the combined effect of two drugs is merely additive ( Figs.…”

Antimicrobial mitochondrial reactive oxygen species induction by lung epithelial immunometabolic modulation

“…AMP-activated kinase (AMPK) is a cellular energy sensor that is activated when cytosolic AMP levels rise due to ATP consumption [33,34], in turn activating catabolic pathways to promote ATP production, including acetyl-CoA carboxylase (ACC) [35,36]. Congruent with the observations that ODN alters cellular ATP/ADP/AMP stores (Figs 2 and 3), reverse phase protein array analysis of HBEC3-KT cells treated with ODN [37] revealed AMPK and ACC to be among the most activated signaling pathways following ODN exposure (Fig 4A). We confirmed time-dependent ODN-induced phosphorylation of AMPKα1, AMPKα2 and ACC in vitro (Figs 4B and S10).…”

Omics-based profiles and biomarkers of respiratory infections: are we there yet?

“…[ 10 ] are primarily descriptive, and the authors are appropriately cautious about asserting potential metabolic reprogramming mechanisms of neutrophils or predictive biomarker functions of their proteome profiles. However, descriptive omics-based clinical research are valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies [ 20 , 21 , 24 – 27 ].…”