title: Bacterial Synthesis of Unusual Sulfonamide and Sulfone Antibiotics by Flavoenzyme-Mediated Sulfur Dioxide Capture.
abstract: Sulfa drugs, such as sulfonilamide and dapsone, are classical antibiotics that have been in clinical use worldwide. Despite the relatively simple architectures, practically no natural products are known to feature such aromatic sulfonamide or diarylsulfone substructures. We report the unexpected discovery of three fully unprecedented, sulfonyl-bridged alkaloid dimers (sulfadixiamycins A-C) from recombinant Streptomyces species harboring the entire xiamycin biosynthesis gene cluster. Sulfadixiamycins exhibit moderate antimycobacterial activities and potent antibiotic activities even against multidrug-resistant bacteria. Gene inactivation, complementation, and biotransformation experiments revealed that a flavin-dependent enzyme (XiaH) plays a key role in sulfadixiamycin biosynthesis. XiaH mediates a radical-based, three-component reaction involving two equivalents of xiamycin and sulfur dioxide, which is reminiscent of radical styrene/SO2 copolymerization.
authors.affiliation: Department of Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany).
authors.forename: Martin
authors.initials: M
authors.lastname: Baunach
authors.affiliation: Department of Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany).
authors.forename: Ling
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany).
authors.forename: Karsten
authors.initials: K
authors.lastname: Willing
authors.affiliation: Department of Biomolecular Chemistry, and Bio Pilot Plant, Leibniz Institute for Natural Product Research and Infection Biology, HKI, Beutenbergstrasse 11a, 07745 Jena (Germany). christian.hertweck@leibniz-hki.de.|Chair for Natural Product Chemistry, Friedrich Schiller University, Jena (Germany). christian.hertweck@leibniz-hki.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Hertweck
mesh_terms: D000900:Anti-Bacterial Agents / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005420:Flavoproteins / Q000378:metabolism*; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D012717:Sesquiterpenes / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013302:Streptomyces / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000378:metabolism*; D013450:Sulfones / Q000737:chemistry / Q000378:metabolism*; D013458:Sulfur Dioxide / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D005420:Flavoproteins; D012717:Sesquiterpenes; D013449:Sulfonamides; D013450:Sulfones; C556785:xiamycin; D013458:Sulfur Dioxide
keywords: sulfadixiamycin; sulfonamide; sulfone; sulfur dioxide; xiamycin