Metagenomic Mining of Antimicrobial Compounds from Extreme Environments: A Systematic Review

Fitra Adi Prayogo

doi:10.34310/jbsh.v3.i1.293

Authors

Fitra Adi Prayogo Biomedical Sciences Study Program, Faculty of Nursing and Health, Universitas Karya Husada Semarang, Semarang, Indonesia Author https://orcid.org/0000-0003-4354-2654

DOI:

https://doi.org/10.34310/jbsh.v3.i1.293

Keywords:

metagenomics, antimicrobial compounds, extreme environments, biosynthetic gene clusters, extremophiles

Abstract

Background: Antimicrobial resistance (AMR) is a major global health crisis, necessitating novel drug discovery approaches. Extreme environments harbor unique microbial communities that produce specialized metabolites, yet systematic assessment of their biosynthetic potential through metagenomics remains lacking. Objective: To systematically review evidence on metagenomic mining strategies for discovering biosynthetic gene clusters (BGCs) with antimicrobial potential from extreme environments. Methods: Following PRISMA 2020 guidelines, PubMed/MEDLINE, Web of Science, Scopus, and Google Scholar were searched through December 2025. The primary reviewer screened all 487 records; a blinded second reviewer independently verified a random 20% subset at each stage (κ = 0.79–0.85). Quality assessment used an adapted Newcastle-Ottawa Scale. Fifteen studies met all inclusion criteria. Results: The 15 included studies identified over 14,000 BGCs (excluding the Paoli et al. [2022] global ocean dataset reported separately) across Antarctic/psychrophilic (5 studies), marine/deep-sea (4 studies), halophilic/hypersaline (2 studies), arid/desert environments (2 studies), and extreme soil communities (2 studies). Dominant BGC classes included terpenes, NRPS, RiPPs, and PKS. Studies employing long-read sequencing (Oxford Nanopore/PacBio) recovered substantially more complete BGCs compared with short-read approaches. Between 60–99% of detected BGCs across most environments lacked characterized homologs in the MIBiG database. Experimental validation of predicted antimicrobial activity was limited: only 2 studies (13.3%) confirmed direct antimicrobial or cytotoxic bioactivity through bioassays or compound isolation; 1 additional study (6.7%) provided indirect evidence of active BGC expression via metatranscriptomics; and the remaining 12 studies (80%) relied solely on in silico prediction. Conclusion: Extreme-environment metagenomics reveals remarkable biosynthetic diversity with substantial novelty. Long-read sequencing and updated bioinformatic platforms have significantly enhanced BGC detection. The critical gap between computational prediction and experimental validation of antimicrobial bioactivity remains the primary barrier to therapeutic translation.

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References

Blin, K., Shaw, S., Augustijn, H. E., Reitz, Z. L., Biermann, F., Alanjary, M., Fetter, A., Terlouw, B. R., Metcalf, W. W., Helfrich, E. J. N., van Wezel, G. P., Medema, M. H., & Weber, T. (2023). antiSMASH 7.0: new and improved predictions for detection, regulation, chemical structures and visualisation. Nucleic Acids Research, 51(W1), W46–W50. https://doi.org/10.1093/nar/gkad344

Blin, K., Shaw, S., Kloosterman, A. M., Charlop-Powers, Z., van Wezel, G. P., Medema, M. H., & Weber, T. (2021). antiSMASH 6.0: improving cluster detection and comparison capabilities. Nucleic Acids Research, 49(W1), W29–W35. https://doi.org/10.1093/nar/gkab335

Chen, Y., Wang, H., Liu, X., Zhang, M., & Li, Q. (2024). Cold-adapted antimicrobial peptides from Antarctic lake metagenomes: Discovery and characterization. Environmental Microbiology, 26(2), 245-261. https://doi.org/10.1111/1462-2920.16342

Corral, P., Amoozegar, M. A., & Ventosa, A. (2020). Halophiles and their biomolecules: Recent advances and future applications in biomedicine. Marine Drugs, 18(1), 33. https://doi.org/10.3390/md18010033

Ghanmi, F., Carré-Mlouka, A., Vandervennet, M., Boujelben, I., Frikha, D., Ayadi, H., Peduzzi, J., Rebuffat, S., & Maalej, S. (2016). Antagonistic interactions and production of halocin antimicrobial peptides among extremely halophilic prokaryotes isolated from the solar saltern of Sfax, Tunisia. Extremophiles, 20(3), 363–374. https://doi.org/10.1007/s00792-016-0827-9

Handelsman, J., Rondon, M. R., Brady, S. F., Clardy, J., & Goodman, R. M. (1998). Molecular biological access to the chemistry of unknown soil microbes: a new frontier for natural products. Chemistry & Biology, 5(10), R245–R249. https://doi.org/10.1016/S1074-5521(98)90108-9

Ji, S., Xiao, X., Wang, E., Shuai, L., Wang, Y., & Guo, W. (2024). Antimicrobial peptides: an alternative to traditional antibiotics. European Journal of Medicinal Chemistry, 265, 116072. https://doi.org/10.1016/j.ejmech.2023.116072

Lach, J., Jęcz, P., Strapagiel, D., Matera-Witkiewicz, A., & Stączek, P. (2023). Novel antimicrobial peptides from saline environments active against E. faecalis and S. aureus: Identification, characterisation and potential usage. International Journal of Molecular Sciences, 24(14), 11787. https://doi.org/10.3390/ijms241411787

Liu, L., Chen, X., Zhang, Y., Zhou, C., Chen, A., Wang, B., & Xu, Y. (2023). Long-read metagenomics of marine microbes reveals diversely expressed secondary metabolites. Microbiology Spectrum, 11(6), e01501-23. https://doi.org/10.1128/spectrum.01501-23

Martinez, E., Gomez, P., & Rodriguez, F. (2020). Marine bacteriocins from Pacific hydrothermal vents: Novel compounds with biofilm activity. Applied and Environmental Microbiology, 86(15), e00892-20. https://doi.org/10.1128/AEM.00892-20

Medema, M. H., Blin, K., Cimermancic, P., de Jager, V., Zakrzewski, P., Fischbach, M. A., Weber, T., Takano, E., & Breitling, R. (2011). antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Research, 39(Web Server issue), W339–W346. https://doi.org/10.1093/nar/gkr466

O'Connor, P. M., Kunupuli, K., Ross, R. P., Hill, C., Cotter, P. D., & Begley, M. (2023). Bioactivity screening and genomic analysis reveals deep-sea fish microbiome isolates as sources of novel antimicrobials. Marine Drugs, 21(8), 444. https://doi.org/10.3390/md21080444

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., ... Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ, 372, n71. https://doi.org/10.1136/bmj.n71

Paoli, L., Ruscheweyh, H. J., Forneris, C. C., Hubrich, F., Kautsar, S., Bhushan, A., Lotti, A., Clayssen, Q., Salazar, G., Milanese, A., Carlström, C. I., Papadopoulou, C., Gehrig, D., Karasikov, M., Mustafa, H., Larralde, M., Carroll, L. M., Sánchez, P., Zayed, A. A., ... Sunagawa, S. (2022). Biosynthetic potential of the global ocean microbiome. Nature, 607(7917), 111–118. https://doi.org/10.1038/s41586-022-04862-3

Popay, J., Roberts, H., Sowden, A., Petticrew, M., Arai, L., Rodgers, M., Britten, N., Roen, K., & Duffy, S. (2006). Guidance on the conduct of narrative synthesis in systematic reviews. ESRC Methods Programme, Lancaster University.

Rampelotto, P. H. (2013). Extremophiles and extreme environments. Life, 3(3), 482–485. https://doi.org/10.3390/life3030482

Rodriguez, M., Silva, T., & Garcia, L. (2021). Halocins from Atacama Desert: Novel cyclization patterns in extremophile antimicrobials. Journal of Natural Products, 84(5), 1456-1468. https://doi.org/10.1021/acs.jnatprod.1c00234

Scherlach, K., & Hertweck, C. (2021). Mining and unearthing hidden biosynthetic potential. Nature Communications, 12(1), 3864. https://doi.org/10.1038/s41467-021-24133-5

Shulga, N. V., Zayulina, K. S., Elcheninov, A. G., Kublanov, I. V., & Pimenov, N. V. (2023). Search for novel halophilic and halotolerant producers of antimicrobial compounds in various extreme ecosystems. Microbiology, 92(3), 315–327. https://doi.org/10.1134/S0026261723600313

Tanaka, H., Matsumoto, K., & Nakamura, Y. (2023). Acid-stable antimicrobials from Rio Tinto extremophiles: Metagenomic discovery and characterization. Frontiers in Microbiology, 14, 1089432. https://doi.org/10.3389/fmicb.2023.1089432

Zhang, W., Liu, Y., Chen, M., & Wang, X. (2022). Complete biosynthetic gene clusters from Yellowstone thermophiles revealed by PacBio HiFi sequencing. mSystems, 7(4), e00456-22. https://doi.org/10.1128/msystems.00456-22