Schmidt, B. et al. A natural history of botanical therapeutics. Metabolism 57, S3–S9 (2008).
Wright, G. D. Unlocking the potential of natural products in drug discovery. Microb. Biotechnol. 12, 55–57 (2019).
Schloss, P. D. & Handelsman, J. Metagenomics for studying unculturable microorganisms: cutting the Gordian knot. Genome Biol. 6, 229 (2005).
Han, M., Yang, P., Zhou, H., Li, H. & Ning, K. Metagenomics and Single-Cell Omics Data Analysis for Human Microbiome Research. in Translational Biomedical Informatics: A. Precision Medicine Perspective (eds Shen, B., Tang, H. & Jiang, X.) 117–137 https://doi.org/10.1007/978-981-10-1503-8_6. (Springer, Singapore, 2016).
Nowrotek, M., Jałowiecki, Ł, Harnisz, M. & Płaza, G. A. Culturomics and metagenomics: In understanding of environmental resistome. Front. Environ. Sci. Eng. 13, 40 (2019).
Keller, N. P., Turner, G. & Bennett, J. W. Fungal secondary metabolism — from biochemistry to genomics. Nat. Rev. Microbiol. 3, 937–947 (2005).
Bentley, S. D. et al. Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417, 141–147 (2002).
Ōmura, S. et al. Genome sequence of an industrial microorganism Streptomyces avermitilis: Deducing the ability of producing secondary metabolites. Proc. Natl. Acad. Sci. 98, 12215–12220 (2001).
Almeida, A. et al. A unified catalog of 204,938 reference genomes from the human gut microbiome. Nat. Biotechnol. 39, 105–114 (2021).
Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat. Biotechnol. 32, 834–841 (2014).
Drula, E. et al. The carbohydrate-active enzyme database: functions and literature. Nucleic Acids Res. 50, D571–D577 (2022).
Caspi, R. et al. The MetaCyc database of metabolic pathways and enzymes – a 2019 update. Nucleic Acids Res. 48, D445–D453 (2020).
Newman, D. J., Cragg, G. M. & Snader, K. M. The influence of natural products upon drug discovery. Nat. Prod. Rep. 17, 215–234 (2000).
Newman, D. J., Cragg, G. M., Holbeck, S. & Sausville, E. A. Natural products and derivatives as leads to cell cycle pathway targets in cancer chemotherapy. Curr. Cancer Drug Targets 2, 279–308.
Sparks, T. C., Sparks, J. M. & Duke, S. O. Natural product-based crop protection compounds─origins and future prospects. J. Agric. Food Chem. 71, 2259–2269 (2023).
Newman, D. J. & Cragg, G. M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod. 83, 770–803 (2020).
Katz, L. & Baltz, R. H. Natural product discovery: past, present, and future. J. Ind. Microbiol. Biotechnol. 43, 155–176 (2016).
Elshafie, H. S., Camele, I. & Mohamed, A. A. A Comprehensive review on the biological, agricultural and pharmaceutical properties of secondary metabolites based-plant origin. Int. J. Mol. Sci. 24, 3266 (2023).
Karnwal, A. et al. Microbial biosurfactant as an alternate to chemical surfactants for application in cosmetics industries in personal and skin care products: a critical review. BioMed. Res. Int. 2023, 2375223 (2023).
Dinglasan, J. L. N., Otani, H., Doering, D. T., Udwary, D. & Mouncey, N. J. Microbial secondary metabolites: advancements to accelerate discovery towards application. Nat. Rev. Microbiol. 23, 338–354 (2025).
Yuzawa, S., Keasling, J. D. & Katz, L. Bio-based production of fuels and industrial chemicals by repurposing antibiotic-producing type I modular polyketide synthases: opportunities and challenges. J. Antibiot. 70, 378–385 (2017).
Chen, X. & Li, B. Analysis of co-localized biosynthetic gene clusters identifies a membrane-permeabilizing natural product. J. Nat. Prod. 87, 1694–1703 (2024).
Kwon, M. J. et al. Beyond the biosynthetic gene cluster paradigm: genome-wide coexpression networks connect clustered and unclustered transcription factors to secondary metabolic pathways. Microbiol. Spectr. 9, e00898–21 (2021).
Medema, M. H. et al. Minimum Information about a Biosynthetic Gene cluster. Nat. Chem. Biol. 11, 625–631 (2015).
Crits-Christoph, A., Bhattacharya, N., Olm, M. R., Song, Y. S. & Banfield, J. F. Transporter genes in biosynthetic gene clusters predict metabolite characteristics and siderophore activity. Genome Res. 31, 239–250 (2021).
Medema, M. H. & Fischbach, M. A. Computational approaches to natural product discovery. Nat. Chem. Biol. 11, 639–648 (2015).
Atanasov, A. G., Zotchev, S. B., Dirsch, V. M. & Supuran, C. T. Natural products in drug discovery: advances and opportunities. Nat. Rev. Drug Discov. 20, 200–216 (2021).
Payne, D. J., Gwynn, M. N., Holmes, D. J. & Pompliano, D. L. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29–40 (2007).
Hoskisson, P. A. & Seipke, R. F. Cryptic or Silent? The Known Unknowns, Unknown Knowns, and Unknown Unknowns of Secondary Metabolism. mBio 11, https://doi.org/10.1128/mbio.02642-20 (2020).
Kerkhoven, E. J. Advances in constraint-based models: methods for improved predictive power based on resource allocation constraints. Curr. Opin. Microbiol. 68, 102168 (2022).
Rutledge, P. J. & Challis, G. L. Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nat. Rev. Microbiol. 13, 509–523 (2015).
Zhang, M. M. et al. CRISPR–Cas9 strategy for activation of silent Streptomyces biosynthetic gene clusters. Nat. Chem. Biol. 13, 607–609 (2017).
Poppeliers, J., Boon, M., De Mey, M., Masschelein, J. & Lavigne, R. Non-model bacteria as platforms for endogenous gene expression in synthetic biology. Nat. Rev. Bioeng. 1–15 https://doi.org/10.1038/s44222-025-00354-x (2025).
Kadjo, A. E. & Eustáquio, A. S. Bacterial natural product discovery by heterologous expression. J. Ind. Microbiol. Biotechnol. 50, kuad044 (2023).
Maeda, H. A. Evolutionary diversification of primary metabolism and its contribution to plant chemical diversity. Front. Plant Sci. 10, 881 (2019).
Sanchez, S. & Demain, A. L. Metabolic regulation and overproduction of primary metabolites. Microb. Biotechnol. 1, 283–319 (2008).
Ivanisevic, J. et al. Biochemical Trade-Offs: Evidence for Ecologically Linked Secondary Metabolism of the Sponge Oscarella balibaloi. PLOS ONE 6, e28059 (2011).
Brand, A. & Tissier, A. Control of resource allocation between primary and specialized metabolism in glandular trichomes. Curr. Opin. Plant Biol. 66, 102172 (2022).
Ribeiro Monteiro, S., Kerdel, Y., Gathot, J. & Rigali, S. The Transcriptional Architecture of Bacterial Biosynthetic Gene Clusters. J. Nat. Prod. 88, 1772–1780 (2025).
Bruggeman, F. J., Planqué, R., Molenaar, D. & Teusink, B. Searching for principles of microbial physiology. FEMS Microbiol. Rev. 44, 821–844 (2020).
Galm, U. & Shen, B. Expression of biosynthetic gene clusters in heterologous hosts for natural product production and combinatorial biosynthesis. Expert Opin. Drug Discov. 1, 409–437 (2006).
Covington, B. C., Xu, F. & Seyedsayamdost, M. R. A natural product chemist’s guide to unlocking silent biosynthetic gene clusters. Annu. Rev. Biochem. 90, 763–788 (2021).
Cawood, G. L. & Ton, J. Decoding resilience: ecology, regulation, and evolution of biosynthetic gene clusters. Trends Plant Sci. 30, 185–198 (2025).
Rigali, S., Anderssen, S., Naômé, A. & van Wezel, G. P. Cracking the regulatory code of biosynthetic gene clusters as a strategy for natural product discovery. Biochem. Pharmacol. 153, 24–34 (2018).
Kang, H.-S. & Kim, E.-S. Recent advances in heterologous expression of natural product biosynthetic gene clusters in Streptomyces hosts. Curr. Opin. Biotechnol. 69, 118–127 (2021).
Fernández-Moreno, M. A., Caballero, J., Hopwood, D. A. & Malpartida, F. The act cluster contains regulatory and antibiotic export genes, direct targets for translational control by the bldA tRNA gene of streptomyces. Cell 66, 769–780 (1991).
Arias, P., Fernández-Moreno, M. A. & Malpartida, F. Characterization of the Pathway-Specific Positive Transcriptional Regulator for Actinorhodin Biosynthesis inStreptomyces coelicolor A3(2) as a DNA-Binding Protein. J. Bacteriol. 181, 6958–6968 (1999).
Retzlaff, L. & Distler, J. The regulator of streptomycin gene expression, StrR, of Streptomyces griseus is a DNA binding activator protein with multiple recognition sites. Mol. Microbiol. 18, 151–162 (1995).
Lim, F. Y. et al. Fungal Isocyanide Synthases and Xanthocillin Biosynthesis in Aspergillus fumigatus. mBio 9, https://doi.org/10.1128/mbio.00785-18 (2018).
Hoskisson, P. A. & Fernández-Martínez, L. T. Regulation of specialised metabolites in Actinobacteria – expanding the paradigms. Environ. Microbiol. Rep. 10, 231–238 (2018).
Cuthbertson, L. & Nodwell, J. R. The TetR family of regulators. Microbiol. Mol. Biol. Rev. MMBR 77, 440–475 (2013).
Takano, E. γ-Butyrolactones: Streptomyces signalling molecules regulating antibiotic production and differentiation. Curr. Opin. Microbiol. 9, 287–294 (2006).
Takano, E. et al. A bacterial hormone (the SCB1) directly controls the expression of a pathway-specific regulatory gene in the cryptic type I polyketide biosynthetic gene cluster of Streptomyces coelicolor. Mol. Microbiol. 56, 465–479 (2005).
Seipke, R. F., Patrick, E. & Hutchings, M. I. Regulation of antimycin biosynthesis by the orphan ECF RNA polymerase sigma factor σAntA. PeerJ 2, e253 (2014).
Foulston, L. & Bibb, M. Feed-forward regulation of microbisporicin biosynthesis in Microbispora corallina ▿. J. Bacteriol. 193, 3064–3071 (2011).
Lyu, H.-N., Liu, H.-W., P. Keller, N. & Yin, W.-B. Harnessing diverse transcriptional regulators for natural product discovery in fungi. Nat. Prod. Rep. 37, 6–16 (2020).
Anderssen, S. et al. AURTHO: Autoregulation of transcription factors as facilitator of cis-acting element discovery. Biochim. Biophys. Acta BBA – Gene Regul. Mech. 1865, 194847 (2022).
Martín, J.-F. & Liras, P. Engineering of regulatory cascades and networks controlling antibiotic biosynthesis in Streptomyces. Curr. Opin. Microbiol. 13, 263–273 (2010).
Romero-Rodríguez, A. et al. Interplay between carbon, nitrogen and phosphate utilization in the control of secondary metabolite production in Streptomyces. Antonie Van. Leeuwenhoek 111, 761–781 (2018).
Lu, W., Alanzi, A. R., Abugrain, M. E., Ito, T. & Mahmud, T. Global and pathway-specific transcriptional regulations of pactamycin biosynthesis in Streptomyces pactum. Appl. Microbiol. Biotechnol. 102, 10589–10601 (2018).
Martín, J. F. et al. Cross-talk of global nutritional regulators in the control of primary and secondary metabolism in Streptomyces. Microb. Biotechnol. 4, 165–174 (2011).
Apel, A. K., Sola-Landa, A., Rodríguez-García, A. & Martín, J. F. Phosphate control of phoA, phoC and phoD gene expression in Streptomyces coelicolor reveals significant differences in binding of PhoP to their promoter regions. Microbiology 153, 3527–3537 (2007).
Atsushi, M., Soon-Kwang, H., Hiroshi, I., Sueharu, H. & Teruhiko, B. Phosphorylation of the AfsR protein involved in secondary metabolism in Streptomyces species by a eukaryotic-type protein kinase. Gene 146, 47–56 (1994).
Santos-Beneit, F., Rodríguez-García, A. & Martín, J. F. Complex transcriptional control of the antibiotic regulator afsS in Streptomyces: PhoP and AfsR are overlapping, competitive activators▿. J. Bacteriol. 193, 2242–2251 (2011).
He, J.-M. et al. Direct involvement of the master nitrogen metabolism regulator glnr in antibiotic biosynthesis in Streptomyces*. J. Biol. Chem. 291, 26443–26454 (2016).
Shu, D. et al. afsQ1-Q2-sigQ is a pleiotropic but conditionally required signal transduction system for both secondary metabolism and morphological development in Streptomyces coelicolor. Appl. Microbiol. Biotechnol. 81, 1149–1160 (2009).
Martín, J. F. & Liras, P. The balance metabolism safety net: integration of stress signals by interacting transcriptional factors in Streptomyces and related actinobacteria. Front. Microbiol. 10, 3120 (2020).
Pullan, S. T., Chandra, G., Bibb, M. J. & Merrick, M. Genome-wide analysis of the role of GlnR in Streptomyces venezuelae provides new insights into global nitrogen regulation in actinomycetes. BMC Genomics 12, 175 (2011).
Romero-Rodríguez, A., Ruiz-Villafán, B., Tierrafría, V. H., Rodríguez-Sanoja, R. & Sánchez, S. Carbon catabolite regulation of secondary metabolite formation and morphological differentiation in Streptomyces coelicolor. Appl. Biochem. Biotechnol. 180, 1152–1166 (2016).
Rigali, S. et al. Feast or famine: the global regulator DasR links nutrient stress to antibiotic production by Streptomyces. EMBO Rep. 9, 670–675 (2008).
Rodríguez-García, A., Sola-Landa, A., Apel, K., Santos-Beneit, F. & Martín, J. F. Phosphate control over nitrogen metabolism in Streptomyces coelicolor: direct and indirect negative control of glnR, glnA, glnII and amtB expression by the response regulator PhoP. Nucleic Acids Res. 37, 3230–3242 (2009).
Díaz, M., Esteban, A., Fernández-Abalos, J. M. & Santamaría, R. I. The high-affinity phosphate-binding protein PstS is accumulated under high fructose concentrations and mutation of the corresponding gene affects differentiation in Streptomyces lividans. Microbiology 151, 2583–2592 (2005).
Cuervo, L., Malmierca, M. G. & Olano, C. An overview of Lsr2 repressor effect in streptomyces spp. secondary metabolism. Microorganisms 12, 2317 (2024).
Marui, J. et al. Kojic acid biosynthesis in Aspergillus oryzae is regulated by a Zn(II)2Cys6 transcriptional activator and induced by kojic acid at the transcriptional level. J. Biosci. Bioeng. 112, 40–43 (2011).
Bok, J. W. et al. GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus Virulence. Infect. Immun. 74, 6761–6768 (2006).
Gramajo, H. C., Takano, E. & Bibb, M. J. Stationary-phase production of the antibiotic actinorhodin in Streptomyces coelicolor A3(2) is transcriptionally regulated. Mol. Microbiol. 7, 837–845 (1993).
Augustijn, H. E. et al. Genome mining based on transcriptional regulatory networks uncovers a novel locus involved in desferrioxamine biosynthesis. PLOS Biol. 23, e3003183 (2025).
Dorman, C. J. Function of Nucleoid-Associated Proteins in Chromosome Structuring and Transcriptional Regulation. J. Mol. Microbiol. Biotechnol. 24, 316–331 (2015).
Dillon, S. C. & Dorman, C. J. Bacterial nucleoid-associated proteins, nucleoid structure and gene expression. Nat. Rev. Microbiol. 8, 185–195 (2010).
Gehrke, E. J. et al. Silencing cryptic specialized metabolism in Streptomyces by the nucleoid-associated protein Lsr2. eLife 8, e47691 (2019).
Palmer, J. M. & Keller, N. P. Secondary metabolism in fungi: does chromosomal location matter? Curr. Opin. Microbiol. 13, 431–436 (2010).
Collemare, J. & Seidl, M. F. Chromatin-dependent regulation of secondary metabolite biosynthesis in fungi: is the picture complete? FEMS Microbiol. Rev. 43, 591–607 (2019).
Strauss, J. & Reyes-Dominguez, Y. Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet. Biol. 48, 62–69 (2011).
Connolly, L. R., Smith, K. M. & Freitag, M. The Fusarium graminearum Histone H3 K27 Methyltransferase KMT6 Regulates Development and Expression of Secondary Metabolite Gene Clusters. PLOS Genet. 9, e1003916 (2013).
Gacek, A. & Strauss, J. The chromatin code of fungal secondary metabolite gene clusters. Appl. Microbiol. Biotechnol. 95, 1389–1404 (2012).
Jamieson, K., Rountree, M. R., Lewis, Z. A., Stajich, J. E. & Selker, E. U. Regional control of histone H3 lysine 27 methylation in Neurospora. Proc. Natl. Acad. Sci. 110, 6027–6032 (2013).
Wiemann, P. et al. Deciphering the cryptic genome: genome-wide analyses of the rice pathogen Fusarium fujikuroi reveal complex regulation of secondary metabolism and novel metabolites. PLOS Pathog. 9, e1003475 (2013).
Bok, J. W. & Keller, N. P. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3, 527–535 (2004).
Van Assche, E., Van Puyvelde, S., Vanderleyden, J. & Steenackers, H. P. RNA-binding proteins involved in post-transcriptional regulation in bacteria. Front. Microbiol. 6, 141 (2015).
Romeo, T., Vakulskas, C. A. & Babitzke, P. Post-transcriptional regulation on a global scale: form and function of Csr/Rsm systems. Environ. Microbiol. 15, 313–324 (2013).
Mukherjee, A., Cui, Y., Liu, Y., Dumenyo, C. K. & Chatterjee, A. K. Global regulation in Erwinia species by Erwinia carotovora rsmA, a homologue of Escherichia coli csrA: repression of secondary metabolites, pathogenicity and hypersensitive reaction. Microbiology 142, 427–434 (1996).
Swiercz, J. P. et al. Small non-coding RNAs in Streptomyces coelicolor. Nucleic Acids Res. 36, 7240–7251 (2008).
Mellin, J. R. & Cossart, P. Unexpected versatility in bacterial riboswitches. Trends Genet. 31, 150–156 (2015).
Tucker, B. J. & Breaker, R. R. Riboswitches as versatile gene control elements. Curr. Opin. Struct. Biol. 15, 342–348 (2005).
Balasubramanian, D. & Vanderpool, C. K. New developments in post-transcriptional regulation of operons by small RNAs. RNA Biol. 10, 337–341 (2013).
Deng, J. et al. A transcription factor-mediated regulatory network controls fungal pathogen colonization of insect body cavities. mBio 15, e03504-23 (2024).
Lozada-Chávez, I., Janga, S. C. & Collado-Vides, J. Bacterial regulatory networks are extremely flexible in evolution. Nucleic Acids Res. 34, 3434–3445 (2006).
Seshasayee, A. S., Bertone, P., Fraser, G. M. & Luscombe, N. M. Transcriptional regulatory networks in bacteria: from input signals to output responses. Curr. Opin. Microbiol. 9, 511–519 (2006).
Augustijn, H. E., Roseboom, A. M., Medema, M. H. & van Wezel, G. P. Harnessing regulatory networks in Actinobacteria for natural product discovery. J. Ind. Microbiol. Biotechnol. 51, kuae011 (2024).
Hwang, S. et al. System-level analysis of transcriptional and translational regulatory elements in Streptomyces griseus. Front. Bioeng. Biotechnol. 10, 844200 (2022).
Hecker, M., Lambeck, S., Toepfer, S., van Someren, E. & Guthke, R. Gene regulatory network inference: Data integration in dynamic models—A review. Biosystems 96, 86–103 (2009).
Thieffry, D., Huerta, A. M., Pérez-Rueda, E. & Collado-Vides, J. From specific gene regulation to genomic networks: a global analysis of transcriptional regulation in Escherichia coli. BioEssays 20, 433–440 (1998).
Badia-i-Mompel, P. et al. Gene regulatory network inference in the era of single-cell multi-omics. Nat. Rev. Genet. 24, 739–754 (2023).
Yuan, Q. & Duren, Z. Inferring gene regulatory networks from single-cell multiome data using atlas-scale external data. Nat. Biotechnol. 43, 247–257 (2025).
Lyu, M. et al. AccR, a TetR family transcriptional repressor, coordinates short-chain acyl coenzyme A homeostasis in Streptomyces avermitilis. Appl. Environ. Microbiol. 86, e00508–e00520 (2020).
Alam, M. T. et al. Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor. BMC Genomics 11, 202 (2010).
Nielsen, J. Cell factory engineering for improved production of natural products. Nat. Prod. Rep. 36, 1233–1236 (2019).
Bode, H. B., Bethe, B., Höfs, R. & Zeeck, A. Big effects from small changes: possible ways to explore nature’s chemical diversity. ChemBioChem 3, 619–627 (2002).
Chiang, Y.-M., Chang, S.-L., Oakley, B. R. & Wang, C. C. Recent advances in awakening silent biosynthetic gene clusters and linking orphan clusters to natural products in microorganisms. Curr. Opin. Chem. Biol. 15, 137–143 (2011).
Zhang, Y.-Q., Brock, M. & Keller, N. P. Connection of Propionyl-CoA metabolism to polyketide biosynthesis in Aspergillus nidulans. Genetics 168, 785–794 (2004).
Gómez, C. et al. Amino Acid precursor supply in the biosynthesis of the RNA polymerase inhibitor Streptolydigin by Streptomyces lydicus. J. Bacteriol. 193, 4214–4223 (2011).
Choi, J. W. & Da Silva, N. A. Improving polyketide and fatty acid synthesis by engineering of the yeast acetyl-CoA carboxylase. J. Biotechnol. 187, 56–59 (2014).
Butler, M. J. et al. Engineering of primary carbon metabolism for improved antibiotic production in Streptomyces lividans. Appl. Environ. Microbiol. 68, 4731–4739 (2002).
Rokem, J. S., Lantz, A. E. & Nielsen, J. Systems biology of antibiotic production by microorganisms. Nat. Prod. Rep. 24, 1262–1287 (2007).
Borodina, I. et al. Antibiotic Overproduction in Streptomyces coelicolor A3(2) Mediated by Phosphofructokinase Deletion*. J. Biol. Chem. 283, 25186–25199 (2008).
Hui, S. et al. Quantitative proteomic analysis reveals a simple strategy of global resource allocation in bacteria. Mol. Syst. Biol. 11, MSB145697 (2015).
Snoeck, S., Guidi, C. & De Mey, M. Metabolic burden” explained: stress symptoms and its related responses induced by (over)expression of (heterologous) proteins in Escherichia coli. Microb. Cell Fact. 23, 96 (2024).
Ruiz-Villafán, B. et al. Carbon catabolite regulation of secondary metabolite formation, an old but not well-established regulatory system. Microb. Biotechnol. 15, 1058–1072 (2022).
Sola-Landa, A., Moura, R. S. & Martín, J. F. The two-component PhoR-PhoP system controls both primary metabolism and secondary metabolite biosynthesis in Streptomyces lividans. Proc. Natl. Acad. Sci. 100, 6133–6138 (2003).
Tudzynski, B. Nitrogen regulation of fungal secondary metabolism in fungi. Front. Microbiol. 5, 656 (2014).
Li, R. & Townsend, C. A. Rational strain improvement for enhanced clavulanic acid production by genetic engineering of the glycolytic pathway in Streptomyces clavuligerus. Metab. Eng. 8, 240–252 (2006).
Wang, J. et al. Structural basis for the biosynthesis of lovastatin. Nat. Commun. 12, 867 (2021).
Hendrickson, L. et al. Lovastatin biosynthesis in Aspergillus terreus: Characterization of blocked mutants, enzyme activities and a multifunctional polyketide synthase gene. Chem. Biol. 6, 429–439 (1999).
S. Moore, B. & Hertweck, C. Biosynthesis and attachment of novel bacterial polyketide synthase starter units. https://doi.org/10.1039/B003939J (2002).
Shende, V. V., Bauman, K. D. & Moore, B. S. The shikimate pathway: gateway to metabolic diversity. Nat. Prod. Rep. 41, 604–648 (2024).
Li, Y., Liang, S., Wang, J., Ma, D. & Wen, J. Enhancing the production of tacrolimus by engineering target genes identified in important primary and secondary metabolic pathways and feeding exogenous precursors. Bioprocess Biosyst. Eng. 42, 1081–1098 (2019).
Schulz, S. et al. Optimization of the precursor supply for an enhanced FK506 production in Streptomyces tsukubaensis. Front. Bioeng. Biotechnol. 10, 1067467 (2022).
Liras, P. & Rodríguez-García, A. Clavulanic acid, a β-lactamase inhibitor: biosynthesis and molecular genetics. Appl. Microbiol. Biotechnol. 54, 467–475 (2000).
Zhang, J. J., Tang, X. & Moore, B. S. Genetic platforms for heterologous expression of microbial natural products. Nat. Prod. Rep. 36, 1313–1332 (2019).
Wang, C., Cao, Y., Wang, Y., Sun, L. & Song, H. Enhancing surfactin production by using systematic CRISPRi repression to screen amino acid biosynthesis genes in Bacillus subtilis. Microb. Cell Factories 18, 90 (2019).
Shao, M., Xu, F., Ke, X., Huang, M. & Chu, J. Enhancing erythromycin production in Saccharopolyspora erythraea through rational engineering and fermentation refinement: A Design-Build-Test-Learn approach. Biotechnol. J. 19, 2400039 (2024).
Zha, W., Rubin-Pitel, S. B., Shao, Z. & Zhao, H. Improving cellular malonyl-CoA level in Escherichia coli via metabolic engineering. Metab. Eng. 11, 192–198 (2009).
Duban, M., Cociancich, S. & Leclère, V. Nonribosomal Peptide Synthesis Definitely Working Out of the Rules. Microorganisms 10, 577 (2022).
Kastberg, L. L. B., Ard, R., Jensen, M. K. & Workman, C. T. Burden imposed by heterologous protein production in two major industrial yeast cell factories: identifying sources and mitigation strategies. Front. Fungal Biol. 3, 827704 (2022).
Onaka, H., Mori, Y., Igarashi, Y. & Furumai, T. Mycolic acid-containing bacteria induce natural-product biosynthesis in streptomyces species. Appl. Environ. Microbiol. 77, 400–406 (2011).
Liu, C. & Kakeya, H. Cryptic chemical communication: secondary metabolic responses revealed by microbial co-culture. Chem. – Asian J. 15, 327–337 (2020).
Feng, G. H. & Leonard, T. J. Culture conditions control expression of the genes for Aflatoxin and Sterigmatocystin biosynthesis in Aspergillus parasiticus and A. nidulans. Appl. Environ. Microbiol. 64, 2275–2277 (1998).
Santamaria, G. et al. Evolution and regulation of microbial secondary metabolism. eLife 11, e76119 (2022).
Schniete, J. K. et al. Expanding primary metabolism helps generate the metabolic robustness to facilitate antibiotic biosynthesis in Streptomyces. mBio 9, https://doi.org/10.1128/mbio.02283-17 (2018).
Mao, D., Yoshimura, A., Wang, R. & Seyedsayamdost, M. R. Reporter-guided transposon mutant selection for activation of silent gene clusters in Burkholderia thailandensis. ChemBioChem 21, 1826–1831 (2020).
Yoshimura, A. et al. Unlocking cryptic metabolites with mass spectrometry-guided transposon mutant selection. ACS Chem. Biol. 15, 2766–2774 (2020).
Fedashchin, A. et al. Random transposon mutagenesis of the Saccharopolyspora erythraea genome reveals additional genes influencing erythromycin biosynthesis. FEMS Microbiol. Lett. 362, fnv180 (2015).
Guzmán-Chávez, F., Zwahlen, R. D., Bovenberg, R. A. L. & Driessen, A. J. M. Engineering of the Filamentous Fungus Penicillium chrysogenum as Cell Factory for Natural Products. Front. Microbiol. 9, 2768 (2018).
McCarty, N. S., Graham, A. E., Studená, L. & Ledesma-Amaro, R. Multiplexed CRISPR technologies for gene editing and transcriptional regulation. Nat. Commun. 11, 1281 (2020).
Zhao, Y. et al. CRISPR/dCas9-mediated multiplex gene repression in Streptomyces. Biotechnol. J. 13, 1800121 (2018).
Baral, B., Akhgari, A. & Metsä-Ketelä, M. Activation of microbial secondary metabolic pathways: Avenues and challenges. Synth. Syst. Biotechnol. 3, 163–178 (2018).
Sharp, P. M. & Li, W.-H. The codon adaptation index-a measure of directional synonymous codon usage bias, and its potential applications. Nucleic Acids Res 15, 1281–1295 (1987).
Liu, Y. A code within the genetic code: codon usage regulates co-translational protein folding. Cell Commun. Signal. 18, 145 (2020).
Nah, H.-J., Pyeon, H.-R., Kang, S.-H., Choi, S.-S. & Kim, E.-S. Cloning and heterologous expression of a large-sized natural product biosynthetic gene cluster in Streptomyces species. Front. Microbiol. 8, 394 (2017).
Bekiesch, P., Basitta, P. & Apel, A. K. Challenges in the heterologous production of antibiotics in Streptomyces. Arch. Pharm. 349, 594–601 (2016).
Teijaro, C. N., Adhikari, A. & Shen, B. Challenges and opportunities for natural product discovery, production, and engineering in native producers versus heterologous hosts. J. Ind. Microbiol. Biotechnol. 46, 433–444 (2019).
Sharma, R., Evans, P. A. & Bhavsar, V. C. Regulatory link mapping between organisms. BMC Syst. Biol. 5, S4 (2011).
Blin, K. et al. antiSMASH 8.0: extended gene cluster detection capabilities and analyses of chemistry, enzymology, and regulation. Nucleic Acids Res. 53, W32–W38 (2025).
Hannigan, G. D. et al. A deep learning genome-mining strategy for biosynthetic gene cluster prediction. Nucleic Acids Res. 47, e110 (2019).
Rios-Martinez, C., Bhattacharya, N., Amini, A. P., Crawford, L. & Yang, K. K. Deep self-supervised learning for biosynthetic gene cluster detection and product classification. PLOS Comput. Biol. 19, e1011162 (2023).
Lai, Q. et al. Deciphering the biosynthetic potential of microbial genomes using a BGC language processing neural network model. Nucleic Acids Res. 53, gkaf305 (2025).
Blin, K. et al. antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation. Nucleic Acids Res. 51, W46–W50 (2023).
Ribeiro Monteiro, S. & Rigali, S. Enhanced prediction of expression control in bacterial biosynthetic gene clusters via genomic and functional data integration. Microb. Genomics 11, 001512 (2025).
Spohn, M., Wohlleben, W. & Stegmann, E. Elucidation of the zinc-dependent regulation in Amycolatopsis japonicum enabled the identification of the ethylenediamine-disuccinate ([S,S]-EDDS) genes. Environ. Microbiol. 18, 1249–1263 (2016).
Bajpe, H. et al. The transcriptional regulatory network of the Escherichia coli MG1655 reference strain. Nucleic Acids Res. 54, gkag059 (2026).
Rajput, A. et al. Machine learning from Pseudomonas aeruginosa transcriptomes identifies independently modulated sets of genes associated with known transcriptional regulators. Nucleic Acids Res. 50, 3658–3672 (2022).
Rychel, K. et al. iModulonDB: a knowledgebase of microbial transcriptional regulation derived from machine learning. Nucleic Acids Res. 49, D112–D120 (2021).
Breitling, R., Achcar, F. & Takano, E. Modeling challenges in the synthetic biology of secondary metabolism. ACS Synth. Biol. 2, 373–378 (2013).
Kim, H. U., Charusanti, P., Lee, S. Y. & Weber, T. Metabolic engineering with systems biology tools to optimize production of prokaryotic secondary metabolites. Nat. Prod. Rep. 33, 933–941 (2016).
Sulheim, S., Fossheim, F. A., Wentzel, A. & Almaas, E. Automatic reconstruction of metabolic pathways from identified biosynthetic gene clusters. BMC Bioinforma. 22, 81 (2021).
Hemphill, C. F. P. et al. OSMAC approach leads to new fusarielin metabolites from Fusarium tricinctum. J. Antibiot. 70, 726–732 (2017).
Schroeckh, V. et al. Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc. Natl. Acad. Sci. 106, 14558–14563 (2009).
Shima, J., Hesketh, A., Okamoto, S., Kawamoto, S. & Ochi, K. Induction of actinorhodin production by rpsL (encoding ribosomal protein S12) mutations that confer streptomycin resistance in Streptomyces lividans and Streptomyces coelicolor A3(2). J. Bacteriol. 178, 7276–7284 (1996).
Ding, Z. et al. Overexpression of global regulator Talae1 leads to the discovery of new antifungal polyketides from endophytic fungus Trichoderma afroharzianum. Front. Microbiol. 11, 622785 (2020).
Shwab, E. K. et al. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 6, 1656–1664 (2007).
Bergmann, S. et al. Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem. Biol. 3, 213–217 (2007).
Guo, F. et al. Targeted activation of silent natural product biosynthesis pathways by reporter-guided mutant selection. Metab. Eng. 28, 134–142 (2015).
Olano, C. et al. Activation and identification of five clusters for secondary metabolites in Streptomyces albus J1074. Microb. Biotechnol. 7, 242–256 (2014).
Tay, D. W. P. et al. Exploring a general multi-pronged activation strategy for natural product discovery in Actinomycetes. Commun. Biol. 7, 50 (2024).
Wang, X. et al. Discovery of recombinases enables genome mining of cryptic biosynthetic gene clusters in Burkholderiales species. Proc. Natl. Acad. Sci. 115, E4255–E4263 (2018).
Wang, G. et al. CRAGE enables rapid activation of biosynthetic gene clusters in undomesticated bacteria. Nat. Microbiol. 4, 2498–2510 (2019).
Siebels, I. et al. Cell-Free Synthesis of Natural Compounds from Genomic DNA of Biosynthetic Gene Clusters. ACS Synth. Biol. 9, 2418–2426 (2020).