Editorial: Microbial host and metabolic engineering for natural product discovery and production

Natural products have a well-documented role in providing scaffolds that are important to society such as those that can be developed into pharmaceuticals.¹ However, main challenges of natural product discovery and development include limited supply and structural diversification to improve drug-like properties.^2–4 Microbial engineering has the potential to help address these challenges.

This Themed Collection contains articles on topics that are enabling microbial natural product discovery, supply and engineering. Relating to discovery and supply, a Viewpoint article by Philmus and colleagues (https://doi.org/10.1039/D5NP00016E) discusses challenges and opportunities for natural product discovery from cyanobacteria. A Highlight by Del Carratore & Breitling (https://doi.org/10.1039/D5NP00038F) covers the engineering of microbial communities to discover natural products. As an alternative to working with native producers, Reviews by Lasch, Myronovskyi & Luzhetskyy (https://doi.org/10.1039/D5NP00036J) and by Heard & Eustaquio (https://doi.org/10.1039/D5NP00024F) outline bacterial hosts developed for the heterologous expression of natural product biosynthetic gene clusters.

Relating to structure diversification, a Review by Bozkurt and colleagues (https://doi.org/10.1039/D4NP00031E) discusses enzyme discovery to enable biocatalysis. Moreover, a Review by Chen and colleagues (https://doi.org/10.1039/D5NP00041F) outlines platforms to engineer the biosynthesis of polyketides and nonribosomal peptides.

It is clear from the collected articles that microbial engineering is poised to help solve supply and structural diversification challenges. Genetics and heterologous expression tools have been developed for more established bacterial phyla such as Actinomycetota (https://doi.org/10.1039/D5NP00036J) but also increasingly to emerging sources of natural products such as bacteria from the Cyanobacteriota (https://doi.org/10.1039/D5NP00016E) and Pseudomonadota (https://doi.org/10.1039/D5NP00024F) phyla. Moreover, engineering microbial communities (https://doi.org/10.1039/D5NP00038F) rather than isolated strains has been demonstrated to enhance natural product production as distributing metabolic tasks among different community members reduces the burden on individual organisms.

In terms of structural diversification, biocatalysis plays an important role not only in natural product structural modification but also in making synthetic routes to drugs more sustainable by improving selectivity and specificity, and reducing environmental impact. Thus, accelerating enzyme discovery and engineering to enable biocatalysis is important (https://doi.org/10.1039/D4NP00031E). Finally, the apparently modular architecture of large polyketide synthases and nonribosomal peptide synthetases has inspired efforts to engineer them for decades, with limited success. Recent advances in structural biology, computational modelling and synthetic biology as detailed in this collection (https://doi.org/10.1039/D5NP00041F) are bringing us closer to the goal of tailor-made polyketides and nonribosomal peptides.

We hope you will enjoy the articles in this Themed Collection!

References

1. D. J. Newman and G. M. Cragg, Natural Products as Sources of New Drugs over the Nearly Four Decades from 01/1981 to 09/2019, J. Nat. Prod., 2020, 83, 770–803,  DOI:10.1021/acs.jnatprod.9b01285.
2. A. G. Atanasov, S. B. Zotchev, V. M. Dirsch, C. T. Supuran and International Natural Product Sciences Taskforce, Natural products in drug discovery: advances and opportunities, Nat. Rev. Drug Discovery, 2021, 20, 200–216,  DOI:10.1038/s41573-020-00114-z.
3. G. D. Wright, Opportunities for natural products in 21^st century antibiotic discovery, Nat. Prod. Rep., 2017, 34, 694–701,  10.1039/c7np00019g.
4. G. T. Carter, Natural products and Pharma 2011: strategic changes spur new opportunities, Nat. Prod. Rep., 2011, 28, 1783–1789,  10.1039/c1np00033k.

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