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Bacteria as genetically programmable producers of bioactive natural products

Abstract

Next to plants, bacteria account for most of the biomass on Earth. They are found everywhere, although certain species thrive only in specific ecological niches. These microorganisms biosynthesize a plethora of both primary and secondary metabolites, defined, respectively, as those required for the growth and maintenance of cellular functions and those not required for survival but offering a selective advantage for the producer under certain conditions. As a result, bacterial fermentation has long been used to manufacture valuable natural products of nutritional, agrochemical and pharmaceutical interest. The interactions of secondary metabolites with their biological targets have been optimized by millions of years of evolution and they are, thus, considered to be privileged chemical structures, not only for drug discovery. During the last two decades, functional genomics has allowed for an in-depth understanding of the underlying biosynthetic logic of secondary metabolites. This has, in turn, paved the way for the unprecedented use of bacteria as programmable biochemical workhorses. In this Review, we discuss the multifaceted use of bacteria as biological factories in diverse applications and highlight recent advances in targeted genetic engineering of bacteria for the production of valuable bioactive compounds. Emphasis is on current advances to access nature’s abundance of natural products.

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Fig. 1: Bacteria as living biofactories.
Fig. 2: Chemical space of natural products.
Fig. 3: Reprogramming bacteria and activating biosynthetic dark matter.
Fig. 4: Heterologous expression workflow.
Fig. 5: Mutasynthesis and mutagenesis.
Fig. 6: Biosynthetic pathway reorganization.
Fig. 7: Engineering de novo biosynthetic pathways.
Fig. 8: Directed evolution of biosynthetic pathways.

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Acknowledgements

We would like to acknowledge B. Schnell, D. Pogorevc and J. Dastbaz for their helpful comments on this manuscript. Research in R.M.’s laboratory is funded by the Deutsche Forschungsgemeinschaft (DFG), the Bundesministerium für Bildung und Forschung (BMBF) and the Deutsches Zentrum für Infektionsforschung Standort Hannover-Braunschweig. Joachim J. Hug acknowledges funding by a PhD fellowship of the Boehringer Ingelheim Fonds.

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J.J.H., D.K. and R.M. wrote, edited and reviewed the manuscript. All authors contributed to the discussion of the content.

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Glossary

Promoter

Genetic region that initiates the transcription of a particular gene by binding RNA polymerase and transcription factors. Constitutive promoters are always active, while inducible promoters are regulated through molecules, temperature and light.

Isostere

Isosteres are molecules or ions with similar chemical scaffold. This means the same number and arrangement of atoms and comparable electronic properties.

Heterologous expression

The production of non-native biomolecules through the transfer of biosynthetic genes into a foreign host.

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Hug, J.J., Krug, D. & Müller, R. Bacteria as genetically programmable producers of bioactive natural products. Nat Rev Chem 4, 172–193 (2020). https://doi.org/10.1038/s41570-020-0176-1

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