Microbial Bioactives

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Microbial Bioactives

Volume 7 Number 1 2025

Article Contents

REVIEWS   (Open Access)
Contents Vol 7 (1)

Developmental Control and Activation of Secondary Metabolism in Streptomyces: A Systematic Review and Meta-Analytical Perspective

Abstract 1. Introduction 2. Materials and Methods 3. Results 4. Discussion 5. Limitations 6. Conclusion References

Anwar Ullah 1*

+ Author Affiliations

Microbial Bioactives 7 (1) 1-8 https://doi.org/10.25163/microbbioacts.7110659

Submitted: 10 June 2025 Revised: 04 August 2025  Accepted: 12 August 2025  Published: 14 August 2025 

Abstract

The genus Streptomyces is renowned for producing structurally diverse and clinically important secondary metabolites, yet harnessing its full biosynthetic potential remains a challenge due to complex developmental regulation and largely silent biosynthetic gene clusters. This systematic review and meta-analysis aimed to integrate and quantitatively synthesize experimental evidence linking developmental control, morphological organization, and activation strategies to secondary metabolite production in Streptomyces. A comprehensive literature search was conducted across major biomedical databases to identify peer-reviewed studies published up to 2024. Eligible studies underwent standardized screening, data extraction, and quality assessment. Where appropriate, meta-analyses using random-effects models quantified effect sizes while accounting for inter-study heterogeneity, complemented by narrative synthesis for outcomes unsuitable for pooling. Findings reveal consistent trends across multiple outcomes, despite variability in experimental conditions, strain characteristics, and measurement approaches. Pooled estimates indicate statistically meaningful effects, and sensitivity analyses confirmed robustness. Heterogeneity analyses highlight the influence of morphology, developmental stage, and regulatory interventions on secondary metabolite yield. Most studies demonstrated moderate to high methodological quality, with minimal evidence of publication bias. Overall, this work consolidates fragmented knowledge, clarifies effective strategies for activating cryptic biosynthetic pathways, and emphasizes the critical interplay between developmental differentiation, morphological control, and regulatory modulation. By providing a robust, evidence-based framework, the study informs rational approaches to optimize metabolite production and guides future natural product discovery in Streptomyces.

Keywords: Streptomyces; secondary metabolism; systematic review; meta-analysis; developmental regulation; biosynthetic activation

References

Amoutzias, G. D., Chaliotis, A., & Mossialos, D. (2016). Discovery strategies of bioactive compounds synthesized by nonribosomal peptide synthetases and type-I polyketide synthases derived from marine microbiomes. Marine Drugs, 14(4), 80. https://doi.org/10.3390/md14040080

Bérdy, J. (2012). Thoughts and facts about antibiotics: Where we are now and where we are heading. Journal of Antibiotics, 65(8), 385–395. https://doi.org/10.1038/ja.2012.27

Blin, K., Shaw, S., Steinke, K., Villebro, R., Ziemert, N., Lee, S. Y., Medema, M. H., & Weber, T. (2019). antiSMASH 5.0: Updates to the secondary metabolite genome mining pipeline. Nucleic Acids Research, 47(W1), W81–W87. https://doi.org/10.1093/nar/gkz310

Blunt, J. W., Carroll, A. R., Copp, B. R., Davis, R. A., Keyzers, R. A., & Prinsep, M. R. (2018). Marine natural products. Natural Product Reports, 35(1), 8–53. https://doi.org/10.1039/C7NP00052A

Boddy, C. N. (2014). Bioinformatics tools for genome mining of polyketide and non-ribosomal peptides. Journal of Industrial Microbiology & Biotechnology, 41, 443–450. https://doi.org/10.1007/s10295-013-1349-5

Brakhage, A. A., & Schroeckh, V. (2011). Fungal secondary metabolites – Strategies to activate silent gene clusters. Fungal Genetics and Biology, 48(1), 15–22. https://doi.org/10.1016/j.fgb.2010.04.004

Brakhage, A. A., et al. (2008). Activation of fungal silent gene clusters: A new avenue to drug discovery. Progress in Drug Research, 66, 1–12. https://doi.org/10.1007/978-3-7643-8678-8_1

Calteau, A., et al. (2014). Phylum-wide comparative genomics unravel the diversity of secondary metabolism in cyanobacteria. BMC Genomics, 15, 977. https://doi.org/10.1186/1471-2164-15-977

Cimermancic, P., Medema, M. H., Claesen, J., Kurita, K., Wieland Brown, L. C., Mavrommatis, K., … Fischbach, M. A. (2014). Insights into secondary metabolism from a global analysis of prokaryotic biosynthetic gene clusters. Cell, 158(2), 412–421. https://doi.org/10.1016/j.cell.2014.06.034

Donadio, S., Monciardini, P., & Sosio, M. (2007). Polyketide synthases and nonribosomal peptide synthetases: The emerging view from bacterial genomics. Natural Product Reports, 24(5), 1073–1109. https://doi.org/10.1039/B514050D

Egger, M., Davey Smith, G., Schneider, M., & Minder, C. (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315(7109), 629–634. https://doi.org/10.1136/bmj.315.7109.629

Fenical, W., & Jensen, P. R. (2006). Developing a new resource for drug discovery: Marine actinomycete bacteria. Nature Chemical Biology, 2(12), 666–673. https://doi.org/10.1038/nchembio841

Gross, H. (2009). Strategies to unravel the function of orphan biosynthesis pathways: Recent examples and future prospects. Applied Microbiology and Biotechnology, 84(2), 211–222. https://doi.org/10.1007/s00253-009-2046-0

Harvey, A. L., Edrada-Ebel, R., & Quinn, R. J. (2015). The re-emergence of natural products for drug discovery in the genomics era. Nature Reviews Drug Discovery, 14(2), 111–129. https://doi.org/10.1038/nrd4510

Hentschel, U., et al. (2012). Genomic insights into marine sponge microbiome. Nature Reviews Microbiology, 10, 641–654. https://doi.org/10.1038/nrmicro2839

Hertweck, C. (2015). Decoding and reprogramming complex polyketide assembly lines: Prospects for synthetic biology. Trends in Biochemical Sciences, 40(4), 189–199. https://doi.org/10.1016/j.tibs.2015.02.001

Jenke-Kodama, H., & Dittmann, E. (2009). Evolution of metabolic diversity: Insights from microbial PKS. Phytochemistry, 70, 1858–1866. https://doi.org/10.1016/j.phytochem.2009.07.019

Keller, N. P. (2019). Fungal secondary metabolism: Regulation, function and drug discovery. Nature Reviews Microbiology, 17(3), 167–180. https://doi.org/10.1038/s41579-018-0121-1

Leal, M. C., Sheridan, C., Osinga, R., Dionísio, G., Rocha, R. J. M., Silva, B., … Calado, R. (2016). Marine microorganism-inspired drugs: Status, challenges and prospects. Marine Drugs, 14(8), 149. https://doi.org/10.3390/md14080149

Medema, M. H., Cimermancic, P., Sali, A., Takano, E., & Fischbach, M. A. (2015). A systematic computational analysis of biosynthetic gene cluster evolution. PLoS Computational Biology, 10(12), e1004016. https://doi.org/10.1371/journal.pcbi.1004016

Molinski, T. F., Dalisay, D. S., Lievens, S. L., & Saludes, J. P. (2009). Drug development from marine natural products. Nature Reviews Drug Discovery, 8(1), 69–85. https://doi.org/10.1038/nrd2487

Nagarajan, M., Rajesh Kumar, R., Meenakshi Sundaram, K., & Sundaram, M. (2015). Marine biotechnology: Potentials of marine microbes and algae. Plant Biology and Biotechnology, 685–723. https://doi.org/10.1007/978-81-322-2283-5_27

Nett, M., Ikeda, H., & Moore, B. S. (2009). Genomic basis for natural product biosynthetic diversity in the actinomycetes. Natural Product Reports, 26(11), 1362–1384. https://doi.org/10.1039/B817069J

Newman, D. J., & Cragg, G. M. (2020). Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. Journal of Natural Products, 83(3), 770–803. https://doi.org/10.1021/acs.jnatprod.9b01285

Nikolouli, K., & Mossialos, D. (2012). Bioactive compounds synthesized by non-ribosomal synthetases and type-I polyketide synthases discovered through genome-mining and metagenomics. Biotechnology Letters, 34(8), 1393–1403. https://doi.org/10.1007/s10529-012-0933-4

Penesyan, A., Kjelleberg, S., & Egan, S. (2010). Development of novel drugs from marine surface associated microorganisms. Marine Drugs, 8(3), 438–459. https://doi.org/10.3390/md8030438

Pettit, R. K. (2011). Culturability and secondary metabolite diversity of extreme microbes: Expanding contribution of deep sea and deep-sea vent microbes. Marine Biotechnology, 13(1), 1–11. https://doi.org/10.1007/s10126-010-9294-4

Rutledge, P. J., & Challis, G. L. (2015). Discovery of microbial natural products by activation of silent biosynthetic gene clusters. Nature Reviews Microbiology, 13(8), 509–523. https://doi.org/10.1038/nrmicro3496

Schroeckh, V., Scherlach, K., Nutzmann, H. W., Shelest, E., Schmidt-Heck, W., Schuemann, J., … Brakhage, A. A. (2009). Intimate bacterial–fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proceedings of the National Academy of Sciences, 106(34), 14558–14563. https://doi.org/10.1073/pnas.0901870106

Simon, C., & Daniel, R. (2009). Achievements and new knowledge unraveled by metagenomics. Applied Microbiology and Biotechnology, 85, 265–276. https://doi.org/10.1007/s00253-009-2233-2

Strieker, M., Tanovic, A., & Marahiel, M. A. (2010). Nonribosomal peptide synthetases: Structures and dynamics. Current Opinion in Structural Biology, 20(2), 234–240. https://doi.org/10.1016/j.sbi.2010.01.009

Thomas, T., Rusch, D., DeMaere, M. Z., Yung, P. Y., Lewis, M., Halpern, A., … Cavicchioli, R. (2010). Functional genomic signatures of sponge bacteria reveal unique and shared features of symbiosis. ISME Journal, 4(12), 1557–1567. https://doi.org/10.1038/ismej.2010.74

Trindade, M., van Zyl, L. J., Navarro-Fernández, J., & Abd Elrazak, A. (2015). Targeted metagenomics as a tool to tap into marine natural product diversity. Frontiers in Microbiology, 6, 890. https://doi.org/10.3389/fmicb.2015.00890

Vartoukian, S., Palmer, R., & Wade, W. (2010). Strategies for culture of “unculturable” bacteria. FEMS Microbiology Letters, 309(1), 1–7. https://doi.org/10.1111/j.1574-6968.2010.02023.x

Walsh, C. T., & Fischbach, M. A. (2010). Natural products version 2.0: Connecting genes to molecules. Journal of the American Chemical Society, 132(8), 2469–2493. https://doi.org/10.1021/ja909118a

Weber, T., et al. (2015). antiSMASH 3.0—A comprehensive resource for genome mining of biosynthetic gene clusters. Nucleic Acids Research, 43(W1), W237–W243. https://doi.org/10.1093/nar/gkv437

Ziemert, N., et al. (2014). Diversity and evolution of secondary metabolism in the marine actinomycete genus Salinispora. Proceedings of the National Academy of Sciences, 111(11), 1130–1139. https://doi.org/10.1073/pnas.1315166111


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