Abstract
Bacteria provide a rich source of natural products with potential therapeutic applications, such as novel antibiotic classes or anticancer drugs. Bioactivity-guided screening of bacterial extracts and characterization of biosynthetic pathways for drug discovery is now complemented by the availability of large (meta)genomic collections, placing researchers into the postgenomic, big-data era. The progress in next-generation sequencing and the rise of powerful computational tools provide unprecedented insights into unexplored taxa, ecological niches and ‘biosynthetic dark matter’, revealing diverse and chemically distinct natural products in previously unstudied bacteria. In this Review, we discuss such sources of new chemical entities and the implications for drug discovery with a particular focus on the strategies that have emerged in recent years to identify and access novelty.
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Acknowledgements
J.P. acknowledges funding by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement No. 742739), the Gordon and Betty Moore Foundation (#9204, https://doi.org/10.37807/GBMF9204), the Swiss National Science Foundation (205320_185077 and NRP 72 ‘Antimicrobial resistance’, 407240_167051), the Helmut Horten Foundation and the Promedica Foundation.
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Glossary
- Dereplication
-
The process of recognizing already known biosynthetic gene clusters (BGCs) or compounds and eliminating them from downstream analysis.
- Biosynthetic gene clusters
-
(BGCs). Gene loci encoding proteins involved in natural product (NP) biosynthesis, resistance and regulation.
- Congeners
-
Structurally related compounds with overall high similarity.
- Metagenomics
-
Methods that explore mixed communities at the DNA level.
- Maturases
-
Enzymes modifying ribosomally synthesized and post-translationally modified peptide (RiPP) precursors or proteins.
- Siderophores
-
Compounds able to complex iron with high affinity.
- Mutualists
-
Members of a beneficial symbiosis.
- Microbial dark matter
-
The large and as yet poorly explored portion of microbial diversity that has eluded laboratory cultivation.
- Contigs
-
Sets of overlapping DNA sequencing reads from the same genomic source.
- Binning
-
The computational grouping of contigs with shared DNA properties, such as sequence coverage or oligonucleotide frequency, after metagenome sequencing.
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Hemmerling, F., Piel, J. Strategies to access biosynthetic novelty in bacterial genomes for drug discovery. Nat Rev Drug Discov 21, 359–378 (2022). https://doi.org/10.1038/s41573-022-00414-6
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DOI: https://doi.org/10.1038/s41573-022-00414-6
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