{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T13:30:23Z","timestamp":1786368623295,"version":"build-2736575974"},"reference-count":82,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32560015"],"award-info":[{"award-number":["32560015"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["32560015"],"award-info":[{"award-number":["32560015"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004763","name":"Natural Science Foundation of Inner Mongolia Autonomous Region","doi-asserted-by":"publisher","award":["2025JQ023"],"award-info":[{"award-number":["2025JQ023"]}],"id":[{"id":"10.13039\/501100004763","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Microorganisms"],"abstract":"<jats:p>Natural products remain a major source of structurally diverse and biologically active small molecules, yet traditional activity-guided discovery is labor-intensive and prone to rediscovery, while untargeted genome mining often lacks efficient prioritization criteria for biosynthetic gene clusters (BGCs). Self-resistance-gene guided discovery has emerged as a powerful strategy to address this limitation. In producing organisms, toxic metabolites are typically accompanied by genetically encoded self-protection mechanisms, such as resistant target homologs, duplicated housekeeping genes, detoxification enzymes, repair systems, or transporters. When co-localized with BGCs, these determinants serve as functional markers for predicting bioactivity and, in some cases, molecular targets prior to compound isolation. Over the past decade, this concept has evolved into a target-directed genome mining framework supported by tools and databases including ARTS, FunARTS, antiSMASH, and MIBiG. This review summarizes the biological basis, workflow, representative advances, and limitations of this strategy. Self-resistance genes can thus be viewed as functional beacons for accelerating bioactive natural product discovery.<\/jats:p>","DOI":"10.3390\/microorganisms14081762","type":"journal-article","created":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:47:36Z","timestamp":1786366056000},"page":"1762","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Self-Resistance as a Functional Beacon: Target-Directed Microbial Genome Mining from Classical Discovery to Automated Pipelines"],"prefix":"10.3390","volume":"14","author":[{"given":"Jiaxin","family":"Wu","sequence":"first","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1695-0120","authenticated-orcid":false,"given":"Mengxu","family":"Qiao","sequence":"additional","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yayue","family":"Ma","sequence":"additional","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"},{"name":"Inner Mongolia Engineering Technology Research Center of Germplasm Resources Conservation and Utilization, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Wei","sequence":"additional","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"},{"name":"Inner Mongolia Engineering Technology Research Center of Germplasm Resources Conservation and Utilization, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-9781","authenticated-orcid":false,"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Laboratory of Microbial Resources and Synthetic Biology, School of Life Sciences, Inner Mongolia University, Hohhot 010010, China"},{"name":"Inner Mongolia Engineering Technology Research Center of Germplasm Resources Conservation and Utilization, Inner Mongolia University, Hohhot 010010, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1021\/acs.jnatprod.9b01285","article-title":"Natural Products as Sources of New Drugs over the Nearly Four Decades from 01\/1981 to 09\/2019","volume":"83","author":"Newman","year":"2020","journal-title":"J. Nat. Prod."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"23672","DOI":"10.1038\/s41598-025-08454-9","article-title":"Genomic Analysis for the Identification of Bioactive Compounds in Xenorhabdus stockiae Strain RT25.5","volume":"15","author":"Meesil","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrmicro3496","article-title":"Discovery of Microbial Natural Products by Activation of Silent Biosynthetic Gene Clusters","volume":"13","author":"Rutledge","year":"2015","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1362","DOI":"10.1039\/b817069j","article-title":"Genomic Basis for Natural Product Biosynthetic Diversity in the Actinomycetes","volume":"26","author":"Nett","year":"2009","journal-title":"Nat. Prod. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1039\/C6NP00025H","article-title":"The Evolution of Genome Mining in Microbes\u2014A Review","volume":"33","author":"Ziemert","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.biotechadv.2017.03.007","article-title":"New Strategies and Approaches for Engineering Biosynthetic Gene Clusters of Microbial Natural Products","volume":"35","author":"Li","year":"2017","journal-title":"Biotechnol. Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"6639","DOI":"10.1002\/anie.202015442","article-title":"Self-Resistance in the Biosynthesis of Fungal Macrolides Involving Cycles of Extracellular Oxidative Activation and Intracellular Reductive Inactivation","volume":"60","author":"Zhang","year":"2021","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"14688","DOI":"10.1074\/jbc.M112.448415","article-title":"The Fish Pathogen Yersinia ruckeri Produces Holomycin and Uses an RNA Methyltransferase for Self-Resistance","volume":"288","author":"Qin","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1021\/acs.orglett.4c04656","article-title":"Biosynthesis of the Antifungal Polyhydroxy-Polyketide Acrophialocinol","volume":"27","author":"Wieder","year":"2025","journal-title":"Org. Lett."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"W546","DOI":"10.1093\/nar\/gkaa374","article-title":"ARTS 2.0: Feature Updates and Expansion of the Antibiotic Resistant Target Seeker for Comparative Genome Mining","volume":"48","author":"Mungan","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"W191","DOI":"10.1093\/nar\/gkad386","article-title":"FunARTS, the Fungal BioActive Compound Resistant Target Seeker, an Exploration Engine for Target-Directed Genome Mining in Fungi","volume":"51","author":"Yilmaz","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"D678","DOI":"10.1093\/nar\/gkae1115","article-title":"MIBiG 4.0: Advancing Biosynthetic Gene Cluster Curation through Global Collaboration","volume":"53","author":"Zdouc","year":"2025","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"W36","DOI":"10.1093\/nar\/gkx319","article-title":"antiSMASH 4.0\u2014Improvements in Chemistry Prediction and Gene Cluster Boundary Identification","volume":"45","author":"Blin","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1039\/C9NP00050J","article-title":"Recent Developments in Self-Resistance Gene Directed Natural Product Discovery","volume":"37","author":"Yan","year":"2020","journal-title":"Nat. Prod. Rep."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1021\/acschembio.1c00799","article-title":"Dual-Mechanism Confers Self-Resistance to the Antituberculosis Antibiotic Capreomycin","volume":"17","author":"Pan","year":"2022","journal-title":"ACS Chem. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"26883","DOI":"10.1021\/jacs.3c09600","article-title":"Uncommon Arrangement of Self-Resistance Allows Biosynthesis of de novo Purine Biosynthesis Inhibitor That Acts as an Immunosuppressor","volume":"145","author":"Sato","year":"2023","journal-title":"J. Am. Chem. Soc."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Dong, H., and Ming, D. (2023). A Comprehensive Self-Resistance Gene Database for Natural-Product Discovery with an Application to Marine Bacterial Genome Mining. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241512446"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Chen, X.R., Pan, H.X., and Tang, G.L. (2022). Newly Discovered Mechanisms of Antibiotic Self-Resistance with Multiple Enzymes Acting at Different Locations and Stages. Antibiotics, 12.","DOI":"10.3390\/antibiotics12010035"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Martin, J.F., Alvarez-Alvarez, R., and Liras, P. (2022). Penicillin-Binding Proteins, \u03b2-Lactamases, and \u03b2-Lactamase Inhibitors in \u03b2-Lactam-Producing Actinobacteria: Self-Resistance Mechanisms. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105662"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e0282621","DOI":"10.1128\/mbio.02826-21","article-title":"The Odilorhabdin Antibiotic Biosynthetic Cluster and Acetyltransferase Self-Resistance Locus Are Niche and Species Specific","volume":"13","author":"Pantel","year":"2022","journal-title":"mBio"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"24032","DOI":"10.1021\/jacs.5c07625","article-title":"Self-Resistance Guided Discovery of a Hybrid Polyketide-Peptide Antibiotic from Vibrio ruber","volume":"147","author":"Kishore","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e202416648","DOI":"10.1002\/anie.202414941","article-title":"Self-Resistance Gene-Guided Discovery of the Molecular Basis for Biosynthesis of the Fatty Acid Synthase Inhibitor Cerulenin","volume":"64","author":"Shang","year":"2025","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1039\/D1NP00064K","article-title":"From Solo to Duet, Intersections of Natural Product Assembly with Self-Resistance","volume":"39","author":"Wu","year":"2022","journal-title":"Nat. Prod. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1021\/acscentsci.5c02019","article-title":"An Antifungal with a Novel Mechanism of Action Discovered via Resistance Gene-Guided Genome Mining","volume":"12","author":"Perlatti","year":"2026","journal-title":"ACS Cent. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1021\/acs.jnatprod.5b01055","article-title":"Natural Products as Sources of New Drugs from 1981 to 2014","volume":"79","author":"Newman","year":"2016","journal-title":"J. Nat. Prod."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.mib.2006.04.002","article-title":"Microbial Genomics for the Improvement of Natural Product Discovery","volume":"9","author":"Shen","year":"2006","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e46854","DOI":"10.15252\/embr.201846824","article-title":"The Impact and Prospect of Natural Product Discovery in Agriculture: New Technologies to Explore the Diversity of Secondary Metabolites in Plants and Microorganisms for Applications in Agriculture","volume":"19","author":"Yan","year":"2018","journal-title":"EMBO Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3801","DOI":"10.1021\/cr990097b","article-title":"Mycophenolic Acid: A One Hundred Year Odyssey from Antibiotic to Immunosuppressant","volume":"100","author":"Bentley","year":"2000","journal-title":"Chem. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1111\/j.1365-2958.1993.tb01728.x","article-title":"The Interaction between Coumarin Drugs and DNA Gyrase","volume":"9","author":"Maxwell","year":"1993","journal-title":"Mol. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/nrd4510","article-title":"The Re-Emergence of Natural Products for Drug Discovery in the Genomics Era","volume":"14","author":"Harvey","year":"2015","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00372-19","DOI":"10.1128\/mSystems.00085-19","article-title":"Resistance Gene-Directed Genome Mining of 50 Aspergillus Species","volume":"4","author":"Kjaerbolling","year":"2019","journal-title":"mSystems"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"0046","DOI":"10.34133\/bdr.0046","article-title":"Structural Bases of Dihydroxy Acid Dehydratase Inhibition and Biodesign for Self-Resistance","volume":"6","author":"Zang","year":"2024","journal-title":"Biodesign Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2275","DOI":"10.1021\/acschembio.6b00213","article-title":"Resistance Gene-Guided Genome Mining: Serial Promoter Exchanges in Aspergillus nidulans Reveal the Biosynthetic Pathway for Fellutamide B, a Proteasome Inhibitor","volume":"11","author":"Yeh","year":"2016","journal-title":"ACS Chem. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"6043","DOI":"10.1021\/jacs.1c01516","article-title":"Targeted Genome Mining Reveals the Biosynthetic Gene Clusters of Natural Product CYP51 Inhibitors","volume":"143","author":"Liu","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Yuan, Y., Huang, C., Singh, N., Xun, G., and Zhao, H. (2023). Automated, Self-Resistance Gene-Guided, and High-Throughput Genome Mining of Bioactive Natural Products from Streptomyces. bioRxiv.","DOI":"10.1101\/2023.10.26.564101"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"101237","DOI":"10.1016\/j.cels.2025.101237","article-title":"Self-Resistance-Gene-Guided, High-Throughput Automated Genome Mining of Bioactive Natural Products from Streptomyces","volume":"16","author":"Yuan","year":"2025","journal-title":"Cell Syst."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3277","DOI":"10.1007\/s00253-019-09708-z","article-title":"Detecting and Prioritizing Biosynthetic Gene Clusters for Bioactive Compounds in Bacteria and Fungi","volume":"103","author":"Tran","year":"2019","journal-title":"Appl. Microbiol. Biotechnol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"e202514683","DOI":"10.1002\/anie.202514683","article-title":"Discovery of Antivirulence ClpP Inhibitors by Self-Resistance Gene-Guided Mining Coupled with Dual Functional Screening","volume":"64","author":"Wang","year":"2025","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e0049322","DOI":"10.1128\/spectrum.00493-22","article-title":"Mycothiol Peroxidase Activity as a Part of the Self-Resistance Mechanisms against the Antitumor Antibiotic Cosmomycin D","volume":"10","author":"Garrido","year":"2022","journal-title":"Microbiol. Spectr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13524","DOI":"10.1021\/acs.jafc.1c05206","article-title":"Monooxygenase LaPhzX Is Involved in Self-Resistance Mechanisms during the Biosynthesis of N-Oxide Phenazine Myxin","volume":"69","author":"Liu","year":"2021","journal-title":"J. Agric. Food Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1038\/s41586-025-08678-9","article-title":"A Polyene Macrolide Targeting Phospholipids in the Fungal Cell Membrane","volume":"640","author":"Deng","year":"2025","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9259","DOI":"10.1038\/s41467-024-53695-3","article-title":"Alligamycin A, an Antifungal \u03b2-Lactone Spiroketal Macrolide from Streptomyces iranensis","volume":"15","author":"Yang","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"W237","DOI":"10.1093\/nar\/gkv437","article-title":"antiSMASH 3.0\u2014A Comprehensive Resource for the Genome Mining of Biosynthetic Gene Clusters","volume":"43","author":"Weber","year":"2015","journal-title":"Nucleic Acids Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/nchembio.1890","article-title":"Minimum Information about a Biosynthetic Gene Cluster","volume":"11","author":"Medema","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"W42","DOI":"10.1093\/nar\/gkx360","article-title":"The Antibiotic Resistant Target Seeker (ARTS), an Exploration Engine for Antibiotic Cluster Prioritization and Novel Drug Target Discovery","volume":"45","author":"Alanjary","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"D736","DOI":"10.1093\/nar\/gkab940","article-title":"ARTS-DB: A Database for Antibiotic Resistant Targets","volume":"50","author":"Mungan","year":"2022","journal-title":"Nucleic Acids Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1038\/s41586-018-0319-4","article-title":"Resistance-Gene-Directed Discovery of a Natural-Product Herbicide with a New Mode of Action","volume":"559","author":"Yan","year":"2018","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1038\/s41589-019-0400-9","article-title":"A Computational Framework to Explore Large-Scale Biosynthetic Diversity","volume":"16","author":"Mullowney","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"13710","DOI":"10.1074\/jbc.M115.646414","article-title":"The Biosynthesis of Capuramycin-Type Antibiotics","volume":"290","author":"Cai","year":"2015","journal-title":"J. Biol. Chem."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6361","DOI":"10.1038\/s41467-022-34150-7","article-title":"A Fungal NRPS-PKS Enzyme Catalyses the Formation of the Flavonoid Naringenin","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/mmi.13711","article-title":"A Cryptic Pigment Biosynthetic Pathway Uncovered by Heterologous Expression Is Essential for Conidial Development","volume":"105","author":"Zhang","year":"2017","journal-title":"Mol. Microbiol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Zeng, G.H., Zhang, P., Zhang, Q.Q., Zhao, H., Li, Z., Zhang, X., Wang, C., Yin, W.-B., and Fang, W. (2018). Duplication of a Gene Cluster and Subsequent Functional Diversification Facilitate Environmental Adaptation in Species. PLoS Genet., 14.","DOI":"10.1371\/journal.pgen.1007472"},{"key":"ref_53","first-page":"6789","article-title":"Identification and Characterization of a Cryptic Bifunctional Type I Diterpene Synthase Involved in Talaronoid Biosynthesis from a Marine-Derived Fungus","volume":"24","author":"Zhang","year":"2022","journal-title":"Org. Lett."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1039\/D5NP00036J","article-title":"Streptomyces as a Versatile Host Platform for Heterologous Production of Microbial Natural Products","volume":"43","author":"Lasch","year":"2026","journal-title":"Nat. Prod. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1038\/nprot.2008.5","article-title":"Selective Isolation of Genomic Loci from Complex Genomes by Transformation-Associated Recombination Cloning in Yeast","volume":"3","author":"Kouprina","year":"2008","journal-title":"Nat. Protoc."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e208","DOI":"10.1002\/cpz1.207","article-title":"Highly Selective, CRISPR\/Cas9-Mediated Isolation of Genes and Genomic Loci from Complex Genomes by TAR Cloning in Yeast","volume":"1","author":"Kouprina","year":"2021","journal-title":"Curr. Protoc."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"e70058","DOI":"10.1111\/1751-7915.70067","article-title":"An Improved Transformation-Associated Recombination Cloning Approach for Direct Capturing of Natural Product Biosynthetic Gene Clusters","volume":"17","author":"Kurylenko","year":"2024","journal-title":"Microb. Biotechnol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"4898","DOI":"10.1039\/C8SC01325J","article-title":"Self-Resistance Guided Genome Mining Uncovers New Topoisomerase Inhibitors from Myxobacteria","volume":"9","author":"Panter","year":"2018","journal-title":"Chem. Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1038\/s41429-020-0295-4","article-title":"Induction of Secondary Metabolite Production by Hygromycin B and Identification of the 1233A Biosynthetic Gene Cluster with a Self-Resistance Gene","volume":"73","author":"Kato","year":"2020","journal-title":"J. Antibiot."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"24801","DOI":"10.1021\/jacs.5c06894","article-title":"Structure and Biosynthesis of Aridomycins Reveal a Glycosylated Prodrug Strategy for Self-Resistance","volume":"147","author":"Liu","year":"2025","journal-title":"J. Am. Chem. Soc."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3035","DOI":"10.1128\/AEM.03015-10","article-title":"Molecular Basis for Mycophenolic Acid Biosynthesis in Penicillium brevicompactum","volume":"77","author":"Regueira","year":"2011","journal-title":"Appl. Environ. Microbiol."},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Choi, B.K., Jo, S.H., Choi, D.K., Trinh, P.T.H., Lee, H.-S., Cao, V.A., Van, T.T.T., and Shin, H.J. (2020). Anti-Neuroinflammatory Agent, Restricticin B, from the Marine-Derived Fungus and Its Inhibitory Activity on the NO Production in BV-2 Microglia Cells. Mar. Drugs, 18.","DOI":"10.3390\/md18090465"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"6179","DOI":"10.1021\/bi060419n","article-title":"A Gene Cluster for Biosynthesis of the Sesquiterpenoid Antibiotic Pentalenolactone in Streptomyces avermitilis","volume":"45","author":"Tetzlaff","year":"2006","journal-title":"Biochemistry"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1506","DOI":"10.1080\/09168451.2018.1549934","article-title":"Identification of a Gene Cluster for Biosynthesis of the Sesquiterpene Antibiotic, Heptelidic Acid, in Aspergillus oryzae","volume":"83","author":"Shinohara","year":"2019","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"11904","DOI":"10.1021\/jacs.5b07816","article-title":"Efficient Biosynthesis of Fungal Polyketides Containing the Dioxabicyclo-octane Ring System","volume":"137","author":"Mao","year":"2015","journal-title":"J. Am. Chem. Soc."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1366","DOI":"10.1021\/acs.orglett.6b00299","article-title":"Biosynthetic Pathway of the Reduced Polyketide Product Citreoviridin in Aspergillus terreus var. aureus Revealed by Heterologous Expression in Aspergillus nidulans","volume":"18","author":"Lin","year":"2016","journal-title":"Org. Lett."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"37","DOI":"10.7164\/antibiotics.49.37","article-title":"FR901483, a Novel Immunosuppressant Isolated from Cladobotryum sp. No 11231\u2014Taxonomy of the Producing Organism, Fermentation, Isolation, Physico-Chemical Properties and Biological Activities","volume":"49","author":"Sakamoto","year":"1996","journal-title":"J. Antibiot."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1021\/jacs.0c12352","article-title":"Biosynthesis of the Immunosuppressant [-]-FR901483","volume":"143","author":"Zhang","year":"2021","journal-title":"J. Am. Chem. Soc."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"6543","DOI":"10.1073\/pnas.0708957105","article-title":"Investigations of Valanimycin Biosynthesis: Elucidation of the Role of Seryl-tRNA","volume":"105","author":"Garg","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1038\/s41467-018-08093-x","article-title":"Aminoacyl Sulfonamide Assembly in SB-203208 Biosynthesis","volume":"10","author":"Hu","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1039\/c3np20126k","article-title":"From Epoxomicin to Carfilzomib: Chemistry, Biology, and Medical Outcomes","volume":"30","author":"Kim","year":"2013","journal-title":"Nat. Prod. Rep."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"26066","DOI":"10.1074\/jbc.M402989200","article-title":"Identification and Characterization of the First Class of Potent Bacterial Acetyl-CoA Carboxylase Inhibitors with Antibacterial Activity","volume":"279","author":"Freiberg","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"10660","DOI":"10.1021\/ja063194c","article-title":"A Biosynthetic Gene Cluster for the Acetyl-CoA Carboxylase Inhibitor Andrimid","volume":"128","author":"Jin","year":"2006","journal-title":"J. Am. Chem. Soc."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/0167-4838(92)90431-C","article-title":"Koningic Acid (Heptelidic Acid) Inhibition of Glyceraldehyde-3-Phosphate Dehydrogenases from Various Sources","volume":"1120","author":"Kato","year":"1992","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6913","DOI":"10.1073\/pnas.93.18.9420","article-title":"The Structure of Bovine F1-ATPase Complexed with the Antibiotic Inhibitor Aurovertin B","volume":"93","author":"Abrahams","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4182","DOI":"10.1002\/aic.16324","article-title":"Identification of the Pyranonigrin A Biosynthetic Gene Cluster by Genome Mining in Penicillium thymicola IBT 5891","volume":"64","author":"Tang","year":"2018","journal-title":"AIChE J."},{"key":"ref_77","first-page":"474","article-title":"Resistance-gene directed discovery of bioactive natural products","volume":"5","author":"Song","year":"2024","journal-title":"Synth. Biol. J."},{"key":"ref_78","first-page":"1473","article-title":"Studies in Relation to Biosynthesis. 38. A Preliminary Study of Fumagillin","volume":"11","author":"Birch","year":"1969","journal-title":"J. Chem. Soc. Perkin 1"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1126\/science.282.5392.1324","article-title":"Structure of Human Methionine Aminopeptidase-2 Complexed with Fumagillin","volume":"282","author":"Liu","year":"1998","journal-title":"Science"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4426","DOI":"10.1021\/ja500881e","article-title":"Generation of Complexity in Fungal Terpene Biosynthesis: Discovery of a Multifunctional Cytochrome P450 in the Fumagillin Pathway","volume":"136","author":"Lin","year":"2014","journal-title":"J. Am. Chem. Soc."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.addr.2016.04.026","article-title":"New Agents for the Treatment of Drug-Resistant Mycobacterium tuberculosis","volume":"102","author":"Hoagland","year":"2016","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_82","first-page":"244","article-title":"Self-resistant Gene-Directed Genome Mining in Microorganisms and Its Application in the Discovery of Natural Products","volume":"47","author":"Xie","year":"2023","journal-title":"Prog. Pharm. Sci."}],"container-title":["Microorganisms"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1762\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T12:51:55Z","timestamp":1786366315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-2607\/14\/8\/1762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,10]]},"references-count":82,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["microorganisms14081762"],"URL":"https:\/\/doi.org\/10.3390\/microorganisms14081762","relation":{},"ISSN":["2076-2607"],"issn-type":[{"value":"2076-2607","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,10]]}}}