{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T05:18:26Z","timestamp":1788326306784,"version":"build-2803163510"},"reference-count":41,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T00:00:00Z","timestamp":1784160000000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM118101"],"award-info":[{"award-number":["R35GM118101"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM147894"],"award-info":[{"award-number":["R35GM147894"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R35GM159915"],"award-info":[{"award-number":["R35GM159915"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["T32GM007544"],"award-info":[{"award-number":["T32GM007544"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["5F31AI186432"],"award-info":[{"award-number":["5F31AI186432"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Bafilomycin and concanamycin analogs (1-3) are microbial natural products with potent V-ATPase inhibitory activity. Despite their promising therapeutic potential, limited access to these plecomacrolide scaffolds has constrained their broader bioactivity evaluation. Here, we report an integrative approach combining genome mining, strain engineering, and molecular networking to expand the chemical diversity of natural concanamycin analogs. Genome analysis identified a concanamycin-like biosynthetic gene cluster in Streptomyces humidus with a unique genetic architecture, suggesting that it may encode previously uncharacterized analogs. Coupling strain engineering, untargeted metabolomics, and feature-based molecular networking of the engineered S. humidus strain expedited dereplication and visualization of an underexplored subnetwork of concanamycin-like metabolites. This prioritization strategy enabled the isolation of five known analogs (4-7, 9) and three new analogs that we termed tanamycin E, X, and F (10-12). Optimization of cultivation conditions for the engineered S. humidus strain facilitated the isolation of 93.0 mg of TAN-1323 D (9) and 24.7 mg of the newly identified compound 10, per liter of culture. Collectively, this work provides scalable strategies for accessing and prioritizing new derivatives, overcoming traditional limitations in the production and discovery of bioactive natural products.<\/jats:p>","DOI":"10.1021\/acs.jnatprod.6c00590","type":"journal-article","created":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T01:38:38Z","timestamp":1784252318000},"page":"2347-2358","source":"Crossref","is-referenced-by-count":0,"title":["Regulator-Guided\nStrain Prioritization and Genome\nEngineering Uncovers Concanamycin Analogs"],"prefix":"10.1021","volume":"89","author":[{"given":"Linnea","family":"Verhey-Henke","sequence":"first","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine L.","family":"Lev","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"McCauley","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5801-2483","authenticated-orcid":true,"given":"Nirmal K.","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia R.","family":"Harris","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salika","family":"Safar","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson R.","family":"Rapala","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8901-0154","authenticated-orcid":true,"given":"Teresa R.","family":"O\u2019Meara","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8334-3647","authenticated-orcid":true,"given":"David H.","family":"Sherman","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0557-8480","authenticated-orcid":true,"given":"Filipa","family":"Pereira","sequence":"additional","affiliation":[{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]},{"name":"University of Michigan , , , ,","place":["Ann Arbor, Michigan, United States, 48109"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,16]]},"reference":[{"key":"2026090200084031600_cit1","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.ymben.2023.12.007","article-title":"Building a Highly Efficient Streptomyces Super-Chassis\nfor Secondary Metabolite Production by Reprogramming Naturally-Evolved\nMultifaceted Shifts","volume":"81","author":"Qiu","year":"2024","journal-title":"Metab. Eng."},{"issue":"5937","key":"2026090200084031600_cit2","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1126\/science.1168243","article-title":"Drug Discovery and\nNatural Products: End of an Era\nor an Endless Frontier?","volume":"325","author":"Li","year":"2009","journal-title":"Science"},{"issue":"14","key":"2026090200084031600_cit3","doi-asserted-by":"publisher","first-page":"4615","DOI":"10.1039\/D0CS00155D","article-title":"Tools and Strategies of Systems Metabolic\nEngineering for the Development of Microbial Cell Factories for Chemical\nProduction","volume":"49","author":"Ko","year":"2020","journal-title":"Chem. Soc. Rev."},{"key":"2026090200084031600_cit4","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.01404","article-title":"A Review of the\nMicrobial Production of Bioactive Natural Products and Biologics","volume":"10","author":"Pham","year":"2019","journal-title":"Front. Microbiol."},{"issue":"W1","key":"2026090200084031600_cit5","doi-asserted-by":"publisher","first-page":"W32","DOI":"10.1093\/nar\/gkaf334","article-title":"antiSMASH 8.0: Extended Gene Cluster\nDetection Capabilities and Analyses of Chemistry, Enzymology, and\nRegulation","volume":"53","author":"Blin","year":"2025","journal-title":"Nucleic Acids Res."},{"issue":"12","key":"2026090200084031600_cit6","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001026","article-title":"Expansion of RiPP Biosynthetic Space through Integration\nof Pan-Genomics and Machine Learning Uncovers a Novel Class of Lanthipeptides","volume":"18","author":"Kloosterman","year":"2020","journal-title":"PLOS Biol."},{"issue":"14","key":"2026090200084031600_cit7","doi-asserted-by":"publisher","first-page":"3761","DOI":"10.1016\/j.cell.2024.05.013","article-title":"Discovery of Antimicrobial\nPeptides\nin the Global Microbiome with Machine Learning","volume":"187","author":"Santos-Ju\u0301nior","year":"2024","journal-title":"Cell"},{"key":"2026090200084031600_cit8","doi-asserted-by":"crossref","unstructured":"Kalkreuter, E.; Kautsar, S. A.; Yang, D.; Bader, C. D.; Teijaro, C. N.; Fluegel, L. L.; Davis, C. M.; Simpson, J. R.; Lauterbach, L.; Steele, A. D.; Gui, C.; Meng, S.; Li, G.; Viehrig, K.; Ye, F.; Su, P.; Kiefer, A. F.; Nichols, A.; Cepeda, A. J.; Yan, W.; Fan, B.; Jiang, Y.; Adhikari, A.; Zheng, C.-J.; Schuster, L.; Cowan, T. M.; Smanski, M. J.; Chevrette, M. G.; de Carvalho, L. P. S.; Shen, B.\n          The Natural Products\nDiscovery Center:\nRelease of the First 8490 Sequenced Strains for Exploring Actinobacteria\nBiosynthetic Diversity.  bioRxiv2024, 2023.12.14.57175910.1101\/2023.12.14.571759.","DOI":"10.1101\/2023.12.14.571759"},{"issue":"43","key":"2026090200084031600_cit9","doi-asserted-by":"publisher","first-page":"40544","DOI":"10.1074\/jbc.M207345200","article-title":"Concanamycin A, the Specific Inhibitor of V-ATPases,\nBinds to the Vo Subunit C*","volume":"277","author":"Huss","year":"2002","journal-title":"J. Biol. 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Antibiot."},{"key":"2026090200084031600_cit17","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.ymben.2024.11.008","article-title":"Optimized\nProduction of Concanamycins Using a Rational Metabolic Engineering\nStrategy","volume":"88","author":"Pereira","year":"2025","journal-title":"Metab. Eng."},{"issue":"6","key":"2026090200084031600_cit18","doi-asserted-by":"publisher","first-page":"4483","DOI":"10.1021\/acs.jmedchem.3c01574","article-title":"Structure\u2013Activity\nRelationships of Natural and Semisynthetic Plecomacrolides Suggest\nDistinct Pathways for HIV-1 Immune Evasion and Vacuolar ATPase-Dependent\nLysosomal Acidification","volume":"67","author":"McCauley","year":"2024","journal-title":"J. Med. Chem."},{"issue":"7","key":"2026090200084031600_cit19","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.7164\/antibiotics.45.1108","article-title":"Isolation,\nCharacterization and Biological Activities of Concanamycins as Inhibitors\nof Lysosomal Acidification","volume":"45","author":"Woo","year":"1992","journal-title":"J. Antibiot."},{"issue":"10","key":"2026090200084031600_cit20","doi-asserted-by":"publisher","first-page":"3161","DOI":"10.1099\/mic.0.28194-0","article-title":"Organization\nof the Biosynthetic Gene Cluster for the\nMacrolide Concanamycin A in Streptomyces neyagawaensis ATCC 27449","volume":"151","author":"Haydock","year":"2005","journal-title":"Microbiology."},{"issue":"4","key":"2026090200084031600_cit21","doi-asserted-by":"publisher","DOI":"10.1177\/17475198221109161","article-title":"Concanamycin\nH from the Soil Actinomycete Streptomyces Sp. R1706\u20138","volume":"46","author":"Li","year":"2022","journal-title":"J. Chem. Res."},{"issue":"12","key":"2026090200084031600_cit22","doi-asserted-by":"publisher","first-page":"1783","DOI":"10.7164\/antibiotics.36.1783","article-title":"THE STRUCTURE\nOF VIRUSTOMYCIN A","volume":"36","author":"Omura","year":"1983","journal-title":"J. Antibiot."},{"issue":"1","key":"2026090200084031600_cit23","doi-asserted-by":"publisher","first-page":"12","DOI":"10.7164\/antibiotics.48.12","article-title":"TAN-1323 C\nand D, New Concanamycin-Group Antibiotics; Detection of the Angiostatic\nActivity with a Wide Range of Macrolide Antibiotics","volume":"48","author":"Ishii","year":"1995","journal-title":"J. Antibiot."},{"issue":"5","key":"2026090200084031600_cit24","doi-asserted-by":"publisher","first-page":"1708","DOI":"10.1021\/jo001377q","article-title":"The First Total Synthesis of Concanamycin\nF (Concanolide\nA)","volume":"66","author":"Toshima","year":"2001","journal-title":"J. Org. Chem."},{"key":"2026090200084031600_cit25","doi-asserted-by":"crossref","unstructured":"Bindseil, K. U.; Zeeck, A.\n          Metabolic Products\nof Microorganisms. Part 265. Prelactones C and B, oligoketides from Streptomyces producing concanamycins and bafilomycins.  HCA1993, 76, 150\u2013157.10.1002\/hlca.19930760109.","DOI":"10.1002\/hlca.19930760109"},{"issue":"10","key":"2026090200084031600_cit26","doi-asserted-by":"publisher","first-page":"655","DOI":"10.7164\/antibiotics.57.655","article-title":"Biosynthetic Investigations of the V-Type ATPase Inhibitors Bafilomycin\nA1, B1, and Concanamycin A","volume":"57","author":"Schuhmann","year":"2004","journal-title":"J. Antibiot."},{"issue":"14","key":"2026090200084031600_cit27","doi-asserted-by":"publisher","first-page":"4484","DOI":"10.1128\/AEM.00985-13","article-title":"An Engineered\nStrong Promoter for Streptomycetes","volume":"79","author":"Wang","year":"2013","journal-title":"Appl. Environ. Microbiol."},{"issue":"11","key":"2026090200084031600_cit28","doi-asserted-by":"publisher","DOI":"10.1111\/mpp.70175","article-title":"Concanamycins\nAre Key Contributors to the Virulence\nof the Potato Common Scab Pathogen Streptomyces Scabiei","volume":"26","author":"Vincent","year":"2025","journal-title":"Mol. Plant Pathol."},{"issue":"13","key":"2026090200084031600_cit29","doi-asserted-by":"publisher","first-page":"2877","DOI":"10.1021\/acs.biochem.4c00711","article-title":"Regulatory Genes as Beacons for Discovery and Prioritization\nof Biosynthetic Gene Clusters in Streptomyces","volume":"64","author":"Augustijn","year":"2025","journal-title":"Biochemistry"},{"issue":"3","key":"2026090200084031600_cit30","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1016\/s0022-2836(05)80360-2","article-title":"Basic Local\nAlignment Search Tool","volume":"215","author":"AltschuP","year":"1990","journal-title":"J. Mol. 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