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Systems-level antimicrobial drug and drug synergy discovery
Abstract
Here, we review the 'target-centric' genomic strategy to antimicrobial discovery and share our perspective on identification, validation and prioritization of potential antimicrobial drug targets in the context of emerging chemical biology, genomics and phenotypic screening strategies. We propose that coupling the dual processes of antimicrobial small-molecule screening and target identification in a whole-cell context is essential to empirically annotate 'druggable' targets and advance early stage antimicrobial discovery. We also advocate a systems-level approach to annotating synthetic-lethal genetic interactions comprehensively within yeast and bacteria models. The resulting genetic interaction networks provide a landscape to rationally predict and exploit drug synergy between cognate inhibitors. We posit that synergistic combination agents provide an important and largely unexploited strategy to 'repurpose' existing chemical space and simultaneously address issues of potency, spectrum, toxicity and drug resistance in early stages of antimicrobial drug discovery.
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“Synthetic lethal interactions are of particular interest as they can be harnessed to identify new antibiotic or cancer therapeutic targets (6, 7).”
From A global genetic interaction network maps a wiring diagram of cellular function (2016) · cites this paper as [6]
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Metadata
- Authors
- Roemer, T., & Boone, C.
- Affiliations
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Toronto (CA)
- Corresponding author
- Roemer, Terry
- Boone, Charles
- ORCID
- Boone, Charles
- Venue
- Nature Chemical Biology
- Published
- 2013-03-18
- Volume
- 9
- Issue
- 4
- Pages
- 222-231
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- OpenAlex
- W2085719025
- Semantic Scholar
- a4baefb4f35813be6ec8cc6c076833402fcc8f24
- Cited by
- 159
- References
- 126
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 9 · 2023: 8 · 2022: 13 · 2021: 8 · 2020: 15 · 2019: 9 · 2018: 10 · 2017: 18 · 2016: 19 · 2015: 19 · 2014: 16 · 2013: 7
- FWCI
- 22.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-57830)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Immunology and Microbiology › Applied Microbiology and Biotechnology › Microbial Natural Products and Biosynthesis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Bacterial Genetics and Biotechnology
- Keywords
- antimicrobial drug discovery, drug synergy, synthetic lethality, genetic interaction networks, drug resistance, yeast model, druggable targets
- MeSH terms
- Anti-Bacterial Agents, Antifungal Agents, Bacteria, Drug Synergism, Genotype, Humans, Phenotype, Yeasts, Genomics, Small Molecule Libraries, Validation Studies as Topic, Drug Discovery, High-Throughput Screening Assays, Molecular Targeted Therapy
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