SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets

Zheng, Shuyu; Wang, W; Aldahdooh, Jehad; Malyutina, Alina; Pessia, Alberto; Tang, Jing

doi:10.1101/2021.06.01.446564

Cited by 23 publications

(8 citation statements)

References 55 publications

(78 reference statements)

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“…Miniature checkerboard assays were prepared in CAMHB medium in 4x4 well format using 1/8 -1/2 the MIC for each antimicrobial. Replicate checkerboard data was processed and interpreted with SynergyFinder2 (http://www.synergyfinder.org/#!/) (98,99). Strong antagonistic interactions were noted when the Loewe Additivity and Bliss Independence scores were below -10.…”

Section: Antimicrobial Susceptibility Testing and Interaction Assaysmentioning

confidence: 99%

Cell envelope structural and functional contributions to antibiotic resistance inBurkholderia cenocepacia

Hogan,

Motnenko,

Rahman

et al. 2024

Preprint

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Antibiotic activity is limited by the physical construction of the Gram-negative cell envelope. Species of theBurkholderia cepaciacomplex (Bcc) are known as intrinsically multidrug-resistant opportunistic pathogens with low permeability cell envelopes. Here, we re-examined a previously performed chemical-genetic screen of barcoded transposon mutants inB. cenocepaciaK56-2 with a focus on cell envelope structural and functional processes. We identified structures mechanistically important for resistance to singular and multiple antibiotic classes. For example, the polymeric O-antigen was specifically important for resistance to cationic antibiotics, while defects in peptidoglycan precursor synthesis specifically increased susceptibility to cycloserine and revealed a new putative amino acid racemase. Susceptibility to novobiocin, avibactam, and the LpxC inhibitor, PF-04753299, was linked to the BpeAB-OprB efflux pump, suggesting these drugs are substrates for this pump inB. cenocepacia. Additionally, disruption of the periplasmic disulfide bond formation system caused pleiotropic defects on outer membrane integrity and β-lactamase activity. Our findings highlight the layering of resistance mechanisms in the structure and function of the cell envelope. Consequently, we point out processes which can be targeted for the development of antibiotic potentiators.

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Section: Antimicrobial Susceptibility Testing and Interaction Assaysmentioning

confidence: 99%

Cell envelope structural and functional contributions to antibiotic resistance inBurkholderia cenocepacia

Hogan,

Motnenko,

Rahman

et al. 2024

Preprint

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“…Each experiment was repeated in triplicate and the mean value was recorded. The data generated from the varied ratio MIC assay was entered into SynergyFinder 2.0, a web application for interactive analysis and visualization [47]. A log logistic model was applied to the varied ratio MIC findings in order to generate dose-response curves for the essential oils in each combination.…”

Section: Preparation Of Culturesmentioning

confidence: 99%

Optimizing the Antimicrobial Synergism of Melaleuca alternifolia (Tea Tree) Essential Oil Combinations for Application against Respiratory Related Pathogens

2023

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Antimicrobial research into the use of Melaleuca alternifolia essential oil has demonstrated broad-spectrum activity; however, much of the research published focuses on identifying the potential of this essential oil individually, rather than in combination for an enhanced antimicrobial effect. This study aimed to determine the antimicrobial activity of four essential oil combinations, all inclusive of M. alternifolia, against nine pathogens associated with the respiratory tract. The minimum inhibitory concentration assay was used to determine the antimicrobial activity of four essential oil combinations, M. alternifolia in combination with Cupressus sempervirens, Origanum majorana, Myrtus communis, and Origanum vulgare essential oils. The interactions between essential oil combinations were analyzed using isobolograms and SynergyFinder 2.0 software to visualize the synergistic potential at varied ratios. The antimicrobial activity of the different combinations of essential oils all demonstrated the ability to produce an enhanced antimicrobial effect compared to the essential oils when investigated independently. The findings of this study determined that isobolograms provide a more in-depth analysis of an essential oil combination interaction; however, the value of that interaction should be further quantified using computational modelling such as SynergyFinder. This study further supports the need for more studies where varied ratios of essential oils are investigated for antimicrobial potential.

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“…To determine the synergy between CPSF6 depletion and Sorafenib, cytotoxicity, cell cycle analysis and Western blotting were performed in Hep3B cells exposed to si-CPSF6 and/or Sorafenib. Combination index between CPSF6 depletion and Sorafenib was analyzed by the Compusyn software (ComboSyn, Inc., New York, NY, USA) and SynergyFinder [31,32]..…”

Section: Cam (Chick Chorioallantoic Membrane) Assaymentioning

confidence: 99%

CPSF6 promotes the Warburg effect and angiogenesis leading to tumor progression via c-Myc/ FBW7/ VEGF/ PD-L1 signaling axis with its siRNA synergistic potential with Sorafenib as a therapeutic target for liver cancer therapy.

Sim

Lee

Ahn

et al. 2023

Preprint

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Background Though CPSF6 was known to act as an oncoprotein via glycolysis in several cancers, the oncogenic mechanism of CPSF6 was not explored in association with the Warburg effect and angiogenesis in hepatocellular carcinoma (HCC) to date. Methods MTT assay, colony formation assay, cell cycle analysis and microarray were conducted in CPSF6 depleted HCC cells. Expression of CPSF6 was evaluated in HCC tissues, cell lines and by The Cancer Genome Atlas (TCGA) analysis, while molecular mechanism of CPSF6 was assessed by Western blotting, Immunofluorescence and Immunoprecipitation. The growth of Hep3B cells was monitored in BALB/c orthotopic and xenograft tumor models with Immunohistochemistry analysis. Also, tube formation assay, CAM assay and ELISA were performed for angiogenesis by CPSF6. Results CPSF6 was overexpressed in HCC tissues with poor survival rates compared to normal tissues. Hence, CPSF6 depletion suppressed the viability and colonies, induced apoptosis via PARP cleavages and increased sub-G1 population in Hep3B and Huh7 cells. Also, CPSF6 enhanced the stability of c-Myc via their binding through nuclear colocalization as an upstream of c-Myc, mainly in nucleoplasm. Furthermore, CPSF6 depletion activated phosphorylation of c-Myc (T58) for c-Myc degradation and inactivated c-Myc (S62), which was disturbed by FBW7 depletion or proteosomal inhibitor MG132. Additionally, CPSF6 depletion suppressed the Warburg effect by inhibition of glucose, HK2, PKM2, LDH and lactate, showed synergistic effect with Sorafenib in Hep3B cells and also inhibited angiogenesis by tube formation and CAM assays along with decreased expression and production of VEGF. Notably, CPSF6 depletion attenuated PD-L1 along with the increase of CD4/CD8 cell percentage in the splenocytes of BALB/c nude mice bearing Hep3B cells. Consistently, CPSF6 depletion reduced the growth of Hep3B cells in BALB/c mice in orthotopic and xenograft tumor models with inhibition of tumor microenvironment associated proteins by immunohistochemistry. Conclusions These findings suggest that CPSF6 enhances the Warburg effect for immune escape and angiogenesis, leading to cancer progression via c-Myc/ FBW-7/ VEGF/PD-L1 signaling axis with its siRNA synergistic effect with Sorafenib as a molecular target of liver cancer therapy. Trial registration: retrospectively registered

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SynergyFinder Plus: Toward Better Interpretation and Annotation of Drug Combination Screening Datasets

Cited by 23 publications

References 55 publications

Cell envelope structural and functional contributions to antibiotic resistance inBurkholderia cenocepacia

Cell envelope structural and functional contributions to antibiotic resistance inBurkholderia cenocepacia

Optimizing the Antimicrobial Synergism of Melaleuca alternifolia (Tea Tree) Essential Oil Combinations for Application against Respiratory Related Pathogens

CPSF6 promotes the Warburg effect and angiogenesis leading to tumor progression via c-Myc/ FBW7/ VEGF/ PD-L1 signaling axis with its siRNA synergistic potential with Sorafenib as a therapeutic target for liver cancer therapy.

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