Antimicrobial resistance threatens a resurgence of life-threatening bacterial infections and the potential demise of many aspects of modern medicine. Despite intensive drug discovery efforts, no new ...classes of antibiotics have been developed into new medicines for decades, in large part owing to the stringent chemical, biological and pharmacological requisites for effective antibiotic drugs. Combinations of antibiotics and of antibiotics with non-antibiotic activity-enhancing compounds offer a productive strategy to address the widespread emergence of antibiotic-resistant strains. In this Review, we outline a theoretical and practical framework for the development of effective antibiotic combinations.
The BioGRID (Biological General Repository for Interaction Datasets, thebiogrid.org) is an open‐access database resource that houses manually curated protein and genetic interactions from multiple ...species including yeast, worm, fly, mouse, and human. The ~1.93 million curated interactions in BioGRID can be used to build complex networks to facilitate biomedical discoveries, particularly as related to human health and disease. All BioGRID content is curated from primary experimental evidence in the biomedical literature, and includes both focused low‐throughput studies and large high‐throughput datasets. BioGRID also captures protein post‐translational modifications and protein or gene interactions with bioactive small molecules including many known drugs. A built‐in network visualization tool combines all annotations and allows users to generate network graphs of protein, genetic and chemical interactions. In addition to general curation across species, BioGRID undertakes themed curation projects in specific aspects of cellular regulation, for example the ubiquitin‐proteasome system, as well as specific disease areas, such as for the SARS‐CoV‐2 virus that causes COVID‐19 severe acute respiratory syndrome. A recent extension of BioGRID, named the Open Repository of CRISPR Screens (ORCS, orcs.thebiogrid.org), captures single mutant phenotypes and genetic interactions from published high throughput genome‐wide CRISPR/Cas9‐based genetic screens. BioGRID‐ORCS contains datasets for over 1,042 CRISPR screens carried out to date in human, mouse and fly cell lines. The biomedical research community can freely access all BioGRID data through the web interface, standardized file downloads, or via model organism databases and partner meta‐databases.
Abstract
The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the curation and archival storage of protein, genetic and ...chemical interactions for all major model organism species and humans. As of September 2018 (build 3.4.164), BioGRID contains records for 1 598 688 biological interactions manually annotated from 55 809 publications for 71 species, as classified by an updated set of controlled vocabularies for experimental detection methods. BioGRID also houses records for >700 000 post-translational modification sites. BioGRID now captures chemical interaction data, including chemical–protein interactions for human drug targets drawn from the DrugBank database and manually curated bioactive compounds reported in the literature. A new dedicated aspect of BioGRID annotates genome-wide CRISPR/Cas9-based screens that report gene–phenotype and gene–gene relationships. An extension of the BioGRID resource called the Open Repository for CRISPR Screens (ORCS) database (https://orcs.thebiogrid.org) currently contains over 500 genome-wide screens carried out in human or mouse cell lines. All data in BioGRID is made freely available without restriction, is directly downloadable in standard formats and can be readily incorporated into existing applications via our web service platforms. BioGRID data are also freely distributed through partner model organism databases and meta-databases.
The Biological General Repository for Interaction Datasets (BioGRID: https://thebiogrid.org) is an open access database dedicated to the annotation and archival of protein, genetic and chemical ...interactions for all major model organism species and humans. As of September 2016 (build 3.4.140), the BioGRID contains 1 072 173 genetic and protein interactions, and 38 559 post-translational modifications, as manually annotated from 48 114 publications. This dataset represents interaction records for 66 model organisms and represents a 30% increase compared to the previous 2015 BioGRID update. BioGRID curates the biomedical literature for major model organism species, including humans, with a recent emphasis on central biological processes and specific human diseases. To facilitate network-based approaches to drug discovery, BioGRID now incorporates 27 501 chemical-protein interactions for human drug targets, as drawn from the DrugBank database. A new dynamic interaction network viewer allows the easy navigation and filtering of all genetic and protein interaction data, as well as for bioactive compounds and their established targets. BioGRID data are directly downloadable without restriction in a variety of standardized formats and are freely distributed through partner model organism databases and meta-databases.
Polo-like kinase 1 (PLK1) is a serine/threonine kinase required for mitosis and cytokinesis. As cancer cells are often hypersensitive to partial PLK1 inactivation, chemical inhibitors of PLK1 have ...been developed and tested in clinical trials. However, these small molecule inhibitors alone are not completely effective. PLK1 promotes numerous molecular and cellular events in the cell division cycle and it is unclear which of these events most crucially depend on PLK1 activity. We used a CRISPR-based genome-wide screening strategy to identify genes whose inactivation enhances cell proliferation defects upon partial chemical inhibition of PLK1. Genes identified encode proteins that are functionally linked to PLK1 in multiple ways, most notably factors that promote centromere and kinetochore function. Loss of the kinesin KIF18A or the outer kinetochore protein SKA1 in PLK1-compromised cells resulted in mitotic defects, activation of the spindle assembly checkpoint and nuclear reassembly defects. We also show that PLK1-dependent CENP-A loading at centromeres is extremely sensitive to partial PLK1 inhibition. Our results suggest that partial inhibition of PLK1 compromises the integrity and function of the centromere/kinetochore complex, rendering cells hypersensitive to different kinetochore perturbations. We propose that KIF18A is a promising target for combinatorial therapies with PLK1 inhibitors.
The Biological General Repository for Interaction Datasets (BioGRID: http://thebiogrid.org) is an open access database that houses genetic and protein interactions curated from the primary biomedical ...literature for all major model organism species and humans. As of September 2014, the BioGRID contains 749,912 interactions as drawn from 43,149 publications that represent 30 model organisms. This interaction count represents a 50% increase compared to our previous 2013 BioGRID update. BioGRID data are freely distributed through partner model organism databases and meta-databases and are directly downloadable in a variety of formats. In addition to general curation of the published literature for the major model species, BioGRID undertakes themed curation projects in areas of particular relevance for biomedical sciences, such as the ubiquitin-proteasome system and various human disease-associated interaction networks. BioGRID curation is coordinated through an Interaction Management System (IMS) that facilitates the compilation interaction records through structured evidence codes, phenotype ontologies, and gene annotation. The BioGRID architecture has been improved in order to support a broader range of interaction and post-translational modification types, to allow the representation of more complex multi-gene/protein interactions, to account for cellular phenotypes through structured ontologies, to expedite curation through semi-automated text-mining approaches, and to enhance curation quality control.
To identify therapeutic targets in acute myeloid leukemia (AML), we chemically interrogated 200 sequenced primary specimens. Mubritinib, a known ERBB2 inhibitor, elicited strong anti-leukemic effects ...in vitro and in vivo. In the context of AML, mubritinib functions through ubiquinone-dependent inhibition of electron transport chain (ETC) complex I activity. Resistance to mubritinib characterized normal CD34+ hematopoietic cells and chemotherapy-sensitive AMLs, which displayed transcriptomic hallmarks of hypoxia. Conversely, sensitivity correlated with mitochondrial function-related gene expression levels and characterized a large subset of chemotherapy-resistant AMLs with oxidative phosphorylation (OXPHOS) hyperactivity. Altogether, our work thus identifies an ETC complex I inhibitor and reveals the genetic landscape of OXPHOS dependency in AML.
•Mubritinib exhibits strong in vitro and in vivo anti-AML activity•It is selectively toxic against a distinct and large subset of poor outcome AMLs•Mubritinib is a ubiquinone-dependent NADH dehydrogenase inhibitor•Mubritinib-sensitive primary leukemias exhibit OXPHOS hyperactivity
Through a chemical screen in sequenced primary AML specimens, Baccelli et al. identify mubritinib, a known ERBB2 inhibitor, to be selectively toxic against a large subset of poor outcome AML specimens that exhibit oxidative phosphorylation hyperactivity by inhibiting the electron transport chain complex I.
The Biological General Repository for Interaction Datasets (BioGRID: http//thebiogrid.org) is an open access archive of genetic and protein interactions that are curated from the primary biomedical ...literature for all major model organism species. As of September 2012, BioGRID houses more than 500 000 manually annotated interactions from more than 30 model organisms. BioGRID maintains complete curation coverage of the literature for the budding yeast Saccharomyces cerevisiae, the fission yeast Schizosaccharomyces pombe and the model plant Arabidopsis thaliana. A number of themed curation projects in areas of biomedical importance are also supported. BioGRID has established collaborations and/or shares data records for the annotation of interactions and phenotypes with most major model organism databases, including Saccharomyces Genome Database, PomBase, WormBase, FlyBase and The Arabidopsis Information Resource. BioGRID also actively engages with the text-mining community to benchmark and deploy automated tools to expedite curation workflows. BioGRID data are freely accessible through both a user-defined interactive interface and in batch downloads in a wide variety of formats, including PSI-MI2.5 and tab-delimited files. BioGRID records can also be interrogated and analyzed with a series of new bioinformatics tools, which include a post-translational modification viewer, a graphical viewer, a REST service and a Cytoscape plugin.
We present 'significance analysis of interactome' (SAINT), a computational tool that assigns confidence scores to protein-protein interaction data generated using affinity purification-mass ...spectrometry (AP-MS). The method uses label-free quantitative data and constructs separate distributions for true and false interactions to derive the probability of a bona fide protein-protein interaction. We show that SAINT is applicable to data of different scales and protein connectivity and allows transparent analysis of AP-MS data.
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