Microbial Bioactives
Microbial Bioactives | Online ISSN 2209-2161
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Unlocking Aromatic Polyketides to Combat Antimicrobial Resistance: A Systematic Review and Meta-Analytic Perspective on Biosynthetic Potential and Synthetic Biology Strategies
Bahareh Nowruzi 1*
Microbial Bioactives 9 (1) 1-8 https://doi.org/10.25163/microbbioacts.9110607
Submitted: 06 October 2025 Revised: 04 January 2026 Accepted: 10 January 2026 Published: 12 January 2026
Abstract
Antimicrobial resistance (AMR) continues to erode the foundations of modern medicine, threatening once-manageable infections and complicating routine clinical care. In response to this escalating crisis, renewed attention has turned toward microbial natural products—particularly aromatic polyketides—as a source of structurally diverse and biologically potent antimicrobial scaffolds. This systematic review and meta-analysis synthesize current evidence on the antimicrobial efficacy and biosynthetic potential of aromatic polyketides, while contextualizing their discovery within advances in genome mining, metabologenomics, and synthetic biology. Across diverse microbial systems, especially actinomycetes from marine, desert, and other underexplored environments, aromatic polyketides consistently demonstrated strong antimicrobial activity, frequently at low minimum inhibitory concentrations. Meta-analytic pooling under random-effects models confirmed a significant overall effect, despite expected heterogeneity driven by ecological origin, compound structure, and assay variability. Subgroup analyses revealed that rare and environmentally specialized strains often yielded compounds with enhanced potency, reinforcing the importance of ecological novelty in natural product discovery. Beyond bioactivity, this review highlights the expanding toolkit enabling scalable production and rational optimization. Advances in heterologous expression, pathway refactoring, and computational protein modeling are helping to unlock cryptic biosynthetic gene clusters and improve yields, thereby addressing longstanding translational bottlenecks. Collectively, the integrated evidence underscores aromatic polyketides as a renewable and adaptable chemical reservoir with genuine promise for next-generation antimicrobial development. Bridging ecological exploration with genome-enabled engineering strategies may prove essential for revitalizing antibiotic pipelines in the era of global resistance.
Keywords: Aromatic polyketides; antimicrobial resistance; polyketide synthases; genome mining; metabolic engineering; synthetic biology; natural products; systematic review; meta-analysis
References
Alam, K., Hao, J., Zhong, L., Fan, G., Ouyang, Q., Islam, M. M., Islam, S., Sun, H., Zhang, Y., Li, R., et al. (2022). Complete genome sequencing and in silico genome mining reveal the promising metabolic potential in Streptomyces strain CS 7. Frontiers in Microbiology, 13, 939919. https://doi.org/10.3389/fmicb.2022.939919
Aslam, B., Wang, W., Arshad, M. I., Khurshid, M., Muzammil, S., Rasool, M. H., Nisar, M. A., Alvi, R. F., Aslam, M. A., Qamar, M. U., et al. (2018). Antibiotic resistance: A rundown of a global crisis. Infectious Drug Resistance, 11, 1645–1658. https://doi.org/10.2147/IDR.S173867
Baek, M., DiMaio, F., Anishchenko, I., Dauparas, J., Ovchinnikov, S., Lee, G. R., Wang, J., Cong, Q., Kinch, L. N., Schaeffer, R. D., & Kim, H. S. (2021). Accurate prediction of protein structures and interactions using a three-track neural network. Science, 373, 871–876. https://doi.org/10.1126/science.abj8754
Barka, E. A., Vatsa, P., Sanchez, L., Gaveau Vaillant, N., Jacquard, C., Klenk, H.-P., Clément, C., Ouhdouch, Y., & van Wezel, G. P. (2016). Taxonomy, physiology, and natural products of Actinobacteria. Microbiology and Molecular Biology Reviews, 80, 1–43. https://doi.org/10.1128/MMBR.00019-15
Bises, C., Dehnert, I., Aeby, G., Dennis, M., Gobbato, J., Hodge, J., Staiger, M., Siena, F., Galli, P., & Montano, S. (2024). Widespread occurrence of coral growth anomalies in the Republic of Maldives. Diversity, 16, 15. https://doi.org/10.3390/d16010015
Bräuer, A., Zhou, Q., Grammbitter, G. L. C., Schmalhofer, M., Rühl, M., Kaila, V. R. I., Bode, H. B., & Groll, M. (2020). Structural snapshots of the minimal PKS system responsible for octaketide biosynthesis. Nature Chemistry, 12, 755–763. https://doi.org/10.1038/s41557-020-0491-7
Contardi, M., Fadda, M., Isa, V., Louis, Y. D., Madaschi, A., Vencato, S., Montalbetti, E., Bertolacci, L., Ceseracciu, L., Seveso, D., et al. (2023). Biodegradable zein-based biocomposite films for underwater delivery of curcumin reduce thermal stress effects in corals. ACS Applied Materials & Interfaces, 15, 33916–33931. https://doi.org/10.1021/acsami.3c01166
Dat, T. T. H., Steinert, G., Cuc, N. T. K., Cuong, P. V., Smidt, H., & Sipkema, D. (2023). Diversity of bacterial secondary metabolite biosynthetic gene clusters in three Vietnamese sponges. Marine Drugs, 21, 29. https://doi.org/10.3390/md21010029
Dehnert, I., Galli, P., & Montano, S. (2023). Ecological impacts of coral gardening outplanting in the Maldives. Restoration Ecology, 31, e13783. https://doi.org/10.1111/rec.13783
Dehnert, I., Saponari, L., Isa, V., Seveso, D., Galli, P., & Montano, S. (2022). Exploring the performance of mid-water lagoon nurseries for coral restoration in the Maldives. Restoration Ecology, 30, e13600. https://doi.org/10.1111/rec.13600
Du, D., Katsuyama, Y., Horiuchi, M., Fushinobu, S., Chen, A., Davis, T. D., Burkart, M. D., & Ohnishi, Y. (2020). Structural basis for selectivity in a highly reducing type II polyketide synthase. Nature Chemical Biology, 16, 776–782. https://doi.org/10.1038/s41589-020-0530-0
Eze, O. C., et al. (2023). Therapeutic potential of marine probiotics: A survey on the anticancer and antibacterial effects of Pseudoalteromonas spp. Pharmaceuticals, 16(8), 1091. https://doi.org/10.3390/ph16081091
Fenical, W., & Jensen, P. R. (2006). Developing a new resource for drug discovery: Marine actinomycete bacteria. Nature Chemical Biology, 2, 666–673. https://doi.org/10.1038/nchembio841
Grammbitter, G. L. C., Schmalhofer, M., Karimi, K., Shi, Y. M., Schoner, T. A., Tobias, N. J., Morgner, N., Groll, M., & Bode, H. B. (2019). An uncommon type II PKS catalyzes biosynthesis of aryl polyene pigments. Journal of the American Chemical Society, 141, 16615–16623. https://doi.org/10.1021/jacs.8b10776
Hertweck, C., Luzhetskyy, A., Rebets, Y., & Bechthold, A. (2007). Type II polyketide synthases: Gaining a deeper insight into enzymatic teamwork. Natural Product Reports, 24, 162–190. https://doi.org/10.1039/B507395M
Hodapp, D., Roca, I. T., Fiorentino, D., Garilao, C., Kaschner, K., Kesner-Reyes, K., Schneider, B., Segschneider, J., Kocsis, A. T., Kiessling, W., et al. (2023). Climate change disrupts core habitats of marine species. Global Change Biology, 29, 3304–3317. https://doi.org/10.1111/gcb.16612
Hoskisson, P. A., & Seipke, R. F. (2020). Cryptic or silent? The known unknowns, unknown knowns, and unknown unknowns of secondary metabolism. mBio, 11, e02642-20. https://doi.org/10.1128/mBio.02642-20
Hulst, M. B., Grocholski, T., Neefjes, J. J. C., van Wezel, G. P., & Metsa-Ketela, M. (2022). Anthracyclines: Biosynthesis, engineering and clinical applications. Natural Product Reports, 39, 814–841. https://doi.org/10.1039/D1NP00059D
Isa, V., Seveso, D., Diamante, L., Montalbetti, E., Montano, S., Gobbato, J., Lavorano, S., Galli, P., & Louis, Y. D. (2024). Physical and cellular impact of environmentally relevant microplastic exposure on thermally challenged Pocillopora damicornis (Cnidaria, Scleractinia). Science of the Total Environment, 918, 170651. https://doi.org/10.1016/j.scitotenv.2024.170651
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Zidek, A., Potapenko, A., et al. (2021). Highly accurate protein structure prediction with AlphaFold. Nature, 596, 583–589. https://doi.org/10.1038/s41586-021-03819-2
Katz, L., & Baltz, R. H. (2016). Natural product discovery: Past, present, and future. Journal of Industrial Microbiology & Biotechnology, 43, 155–176. https://doi.org/10.1007/s10295-015-1723-5
LaJeunesse, T. C., Parkinson, J. E., Gabrielson, P. W., Jeong, H. J., Reimer, J. D., Voolstra, C. R., & Santos, S. R. (2018). Systematic revision of Symbiodiniaceae highlights the antiquity and diversity of coral endosymbionts. Current Biology, 28, 2570–2580.e6. https://doi.org/10.1016/j.cub.2018.07.008
Litaudon, M., et al. (2015). Secondary metabolites from the genus Beilschmiedia: A review of their phytochemistry and pharmacology. Biomolecules, 5(2), 910–941. https://doi.org/10.3390/biom5020910
Liu, Y., Tu, X., Xu, Q., Bai, C., Kong, C., Liu, Q., Yu, J., Peng, Q., Zhou, X., & Zhang, Y. (2018). Engineered monoculture and co-culture of methylotrophic yeast for de novo production of monacolin J and lovastatin from methanol. Metabolic Engineering, 45, 189–199. https://doi.org/10.1016/j.ymben.2017.12.009
Malit, J. J. L., Leung, H. Y. C., & Qian, P.-Y. (2022). Targeted large-scale genome mining and candidate prioritization for natural product discovery. Marine Drugs, 20, 398. https://doi.org/10.3390/md20060398
Millán Aguiñaga, N., Soldatou, S., Brozio, S., Munnoch, J. T., Howe, J. A., Hoskisson, P. A., & Duncan, K. R. (2019). Awakening ancient polar Actinobacteria: Diversity, evolution and specialized metabolite potential. Microbiology, 165, 1169–1180. https://doi.org/10.1099/mic.0.000845
Montalbetti, E., Fallati, L., Casartelli, M., Maggioni, D., Montano, S., Galli, P., & Seveso, D. (2022). Reef complexity influences distribution and habitat choice of the corallivorous seastar Culcita schmideliana in the Maldives. Coral Reefs, 41, 253–264. https://doi.org/10.1007/s00338-022-02230-1
Nothias, L. F., Petras, D., Schmid, R., Dührkop, K., Rainer, J., Sarvepalli, A., Protsyuk, I., Ernst, M., Tsugawa, H., Fleischauer, M., et al. (2020). Feature-based molecular networking in the GNPS analysis environment. Nature Methods, 17, 905–908. https://doi.org/10.1038/s41592-020-0933-6
Palma Esposito, F., López-Mobilia, A., Tangherlini, M., Casella, V., Coppola, A., Varola, G., … & Galasso, C. (2025). Novel insights and genomic characterization of coral-associated microorganisms from Maldives displaying antimicrobial, antioxidant, and UV-protectant activities. Biology, 14(4), 401. https://doi.org/10.3390/biology14040401
Pfeifer, B. A., Admiraal, S. J., Gramajo, H., Cane, D. E., & Khosla, C. (2001). Biosynthesis of complex polyketides in a metabolically engineered strain of E. coli. Science, 291, 1790–1792. https://doi.org/10.1126/science.1058092
Raffaelli, S., Abreo, E., Altier, N., Vázquez, Á., & Alborés, S. (2022). Bioprospecting the antibiofilm and antimicrobial activity of soil and insect gut bacteria. Molecules, 27(6), 2002. https://doi.org/10.3390/molecules27062002
Rizzi, C., Seveso, D., De Grandis, C., Montalbetti, E., Lancini, S., Galli, P., & Villa, S. (2023). Bioconcentration and cellular effects of emerging contaminants in sponges from Maldivian coral reefs: A managing tool for sustainable tourism. Marine Pollution Bulletin, 192, 115084. https://doi.org/10.1016/j.marpolbul.2023.115084
Scherlach, K., & Hertweck, C. (2021). Mining and unearthing hidden biosynthetic potential. Nature Communications, 12, 3864. https://doi.org/10.1038/s41467-021-24012-z
Soldatou, S., Eldjarn, G. H., Huerta-Uribe, A., Rogers, S., & Duncan, K. R. (2019). Linking biosynthetic and chemical space to accelerate microbial secondary metabolite discovery. FEMS Microbiology Letters, 366, fenz142. https://doi.org/10.1093/femsle/fenz142
Soldatou, S., Eldjárn, G. H., Ramsay, A., van der Hooft, J. J. J., Hughes, A. H., Rogers, S., & Duncan, K. R. (2021). Comparative metabologenomics analysis of polar actinomycetes. Marine Drugs, 19, 103. https://doi.org/10.3390/md19020103
Strona, G., Lafferty, K. D., Fattorini, S., Beck, P. S. A., Guilhaumon, F., Arrigoni, R., Montano, S., Seveso, D., Galli, P., Planes, S., et al. (2021). Global tropical reef fish richness could decline by around half if corals are lost. Proceedings of the Royal Society B: Biological Sciences, 288, 20210274. https://doi.org/10.1098/rspb.2021.0274
Subramani, R., & Aalbersberg, W. (2012). Marine actinomycetes: An ongoing source of novel bioactive metabolites. Microbiological Research, 167, 571–580. https://doi.org/10.1016/j.micres.2012.06.007
Sweet, M. J., & Bulling, M. T. (2017). On the importance of the microbiome and pathobiome in coral health and disease. Frontiers in Marine Science, 4, 9. https://doi.org/10.3389/fmars.2017.00009
Van Bergeijk, D. A., Terlouw, B. R., Medema, M. H., & van Wezel, G. P. (2020). Ecology and genomics of Actinobacteria: New concepts for natural product discovery. Nature Reviews Microbiology, 18, 546–558. https://doi.org/10.1038/s41579-020-0371-y
Vrancken, K., & Anné, J. (2009). Secretory production of recombinant proteins by Streptomyces. Future Microbiology, 4, 181–188. https://doi.org/10.2217/17460913.4.2.181
Wang, M., Carver, J. J., Phelan, V. V., Sanchez, L. M., Garg, N., Peng, Y., Nguyen, D. D., Watrous, J., Kapono, C. A., Luzzatto-Knaan, T., et al. (2016). Sharing and community curation of mass spectrometry data with Global Natural Products Social Molecular Networking. Nature Biotechnology, 34, 828–837. https://doi.org/10.1038/nbt.3597
Weber, T., Blin, K., Duddela, S., Krug, D., Kim, H. U., Bruccoleri, R., Lee, S. Y., Fischbach, M. A., Müller, R., Wohlleben, W., et al. (2015). antiSMASH 3.0—a comprehensive resource for the genome mining of biosynthetic gene clusters. Nucleic Acids Research, 43, W237–W243. https://doi.org/10.1093/nar/gkv437
Wen, Y., Zhang, G., Bahadur, A., Xu, Y., Liu, Y., Tian, M., Ding, W., Chen, T., Zhang, W., & Liu, G. (2022). Genomic investigation of desert Streptomyces huasconensis D23 reveals its environmental adaptability and antimicrobial activity. Microorganisms, 10(12), 2408. https://doi.org/10.3390/microorganisms10122408
Xue, Y., Zhou, Z., Feng, F., Zhao, H., Tan, S., Li, J., Wu, S., Ju, Z., He, S., & Ding, L. (2024). Genomic analysis of Kitasatospora setae to explore its biosynthetic potential regarding secondary metabolites. Antibiotics, 13, 459. https://doi.org/10.3390/antibiotics13050459
Yang, D., Eun, H., & Prabowo, C. P. S. (2023). Metabolic engineering and synthetic biology approaches for the heterologous production of aromatic polyketides. International Journal of Molecular Sciences, 24, 8923. https://doi.org/10.3390/ijms24108923
Ziko, L., Adel, M., Malash, M. N., & Siam, R. (2019). Insights into Red Sea brine pool specialized metabolism gene clusters encoding potential metabolites for biotechnological applications and extremophile survival. Marine Drugs, 17, 273. https://doi.org/10.3390/md17050273
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