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Here, we report the discovery of crossiguanipyrazines A\u2010I, a rare family of potent anti\u2010TB alkylpyrazines from the underexplored actinobacterium\n                    <jats:italic>Crossiella cryophila<\/jats:italic>\n                    DSM 44230. Crossiguanipyrazines (CGPs) feature an unusual 3\u2010methoxyl\u20102,5,6\u2010trialkyl\u2010pyrazine scaffold with variable hydroxylation and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010prenylation. The stereochemistry of CGPs A\u2010G was determined by Mosher's analysis and electronic circular dichroism spectroscopy. Stable isotope\u2010labeling revealed a unique biosynthetic origin from arginine and acetate. Inhibition with a cytochrome P450 inhibitor suppressed hydroxylation, while feeding experiments with stable isotope\u2010labeled CGP I demonstrated its role as a precursor for other CGPs, implicating P450 enzymes in CGP diversification. CGPs C and H exhibited potent anti\u2010TB activity in the low micromolar range without mammalian cell cytotoxicity, unlike previously reported cytotoxic trialkylpyrazine\u2010type natural products. Structure\u2010activity relationship (SAR) studies highlighted the critical roles of hydroxylation and\n                    <jats:italic>N<\/jats:italic>\n                    \u2010prenylation in modulating biological activity. Furthermore, we achieved the first total synthesis of CGP I, which validated the chemical structure and provided a foundation for further optimization of this compound class. These findings suggest that CGPs can serve as useful starting points for anti\u2010TB drug development.\n                  <\/jats:p>","DOI":"10.1002\/anie.202513977","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:19:28Z","timestamp":1762780768000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Discovery and Total Synthesis of Crossiguanipyrazines with Potent Activity Against\n                    <i>Mycobacterium tuberculosis<\/i>"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-4479-9581","authenticated-orcid":false,"given":"Haowen","family":"Zhao","sequence":"first","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8.1 Saarbr\u00fccken 66123 Germany"},{"name":"Helmholtz International Lab for Anti\u2010Infectives Helmholtz Centre for Infection Research Braunschweig 38124 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etienne","family":"Bickel","sequence":"additional","affiliation":[{"name":"Organic Chemistry I Saarland University  Campus C4.2 Saarbr\u00fccken 66123 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Liu","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8.1 Saarbr\u00fccken 66123 Germany"},{"name":"Helmholtz International Lab for Anti\u2010Infectives Helmholtz Centre for Infection Research Braunschweig 38124 Germany"},{"name":"Helmholtz International Lab for Anti\u2010infectives Shandong University\u2010Helmholtz Institute of Biotechnology State Key Laboratory of Microbial Technology Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Yang","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8.1 Saarbr\u00fccken 66123 Germany"},{"name":"Helmholtz International Lab for Anti\u2010Infectives Helmholtz Centre for Infection Research Braunschweig 38124 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Dal Molin","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine Division of Infectious Diseases Medical Faculty and University Hospital Cologne University of Cologne  Cologne 50937 Germany"},{"name":"Faculty of Medicine Center for Molecular Medicine Cologne (CMMC) University of Cologne  50937 Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Chhen","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine Division of Infectious Diseases Medical Faculty and University Hospital Cologne University of Cologne  Cologne 50937 Germany"},{"name":"Faculty of Medicine Center for Molecular Medicine Cologne (CMMC) University of Cologne  50937 Cologne Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqin","family":"Liu","sequence":"additional","affiliation":[{"name":"Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) Helmholtz Centre for Infection Research (HZI)  Campus E8.1 Saarbr\u00fccken 66123 Germany"},{"name":"Helmholtz International Lab for Anti\u2010Infectives Helmholtz Centre for Infection Research Braunschweig 38124 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyan","family":"Sui","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti\u2010infectives Shandong University\u2010Helmholtz Institute of Biotechnology State Key Laboratory of Microbial Technology Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Bian","sequence":"additional","affiliation":[{"name":"Helmholtz International Lab for Anti\u2010infectives Shandong University\u2010Helmholtz Institute of Biotechnology State Key Laboratory of Microbial Technology Shandong University  Qingdao 266237 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyi","family":"Wei","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Plant Diversity and Specialty Crops Guangdong Provincial Key Laboratory of Applied Botany South China Botanical Garden Chinese Academy of Sciences  Guangzhou 510650 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Rybniker","sequence":"additional","affiliation":[{"name":"Department I of Internal Medicine Division of Infectious Diseases Medical Faculty and University Hospital Cologne University of Cologne  Cologne 50937 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