Induced Production, Synthesis, and Immunomodulatory Action of Clostrisulfone, a Diarylsulfone from Clostridium acetobutylicum

• Published in: Chemistry : a European journal Vol. 26; no. 68; pp. 15855 - 15858
• Main Authors: Neuwirth, Toni, Letzel, Anne‐Catrin, Tank, Cedric, Ishida, Keishi, Cyrulies, Michael, Schmölz, Lisa, Lorkowski, Stefan, Hertweck, Christian
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 04.12.2020; Wiley Subscription Services, Inc; John Wiley and Sons Inc
• Subjects: Animals; Biomimetics; Chemical synthesis; Chemistry; Chemistry, Multidisciplinary; clostridia; Clostridium acetobutylicum; Clostridium acetobutylicum - chemistry; Clostridium acetobutylicum - drug effects; Clostridium acetobutylicum - genetics; Clostridium acetobutylicum - metabolism; Communication; Communications; Cysteine - pharmacology; diphenylsulfone; Gene clusters; Genomes; Griess assay; Immunologic Factors - metabolism; Immunologic Factors - pharmacology; Immunomodulation; Lipopolysaccharides; Macrophages; Macrophages - drug effects; Metabolism; Mice; Multigene Family; Natural products; Nitric oxide; NMR; Nuclear magnetic resonance; Physical Sciences; Science & Technology; Sulfones - metabolism; Sulfones - pharmacology; Sulfur; Sulfur dioxide; tocopherol; clostridia; diphenylsulfone; macrophages; ANTIBIOTICS; SULFUR-DIOXIDE; CLOSTHIOAMIDE; Griess assay; ANAEROBIC-BACTERIA; tocopherol
• ISSN: 0947-6539; 1521-3765; 1521-3765
• DOI: 10.1002/chem.202003500

The anaerobe Clostridium acetobutylicum belongs to the most important industrially used bacteria. Whereas genome mining points to a high potential for secondary metabolism in C. acetobutylicum, the functions of most biosynthetic gene clusters are cryptic. We report that the addition of supra‐physiological concentrations of cysteine triggered the formation of a novel natural product, clostrisulfone (1). Its structure was fully elucidated by NMR, MS and the chemical synthesis of a reference compound. Clostrisulfone is the first reported natural product with a diphenylsulfone scaffold. A biomimetic synthesis suggests that pentamethylchromanol‐derived radicals capture sulfur dioxide to form 1. In a cell‐based assay using murine macrophages a biphasic and dose‐dependent regulation of the LPS‐induced release of nitric oxide was observed in the presence of 1. Induction of the industrial anaerobe Clostridium acetobutylicum with cysteine led to the discovery of an unprecedented diarylsulfone natural product named clostrisulfone that likely results from sulfur dioxide capture by chromane‐derived radicals. Its structure was elucidated by NMR and confirmed by synthesis. The tocopherol‐related molecule exerts immunomodulatory activities (see figure).