Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships. Issue 51 (30th October 2015)

• Record Type: Journal Article
• Authors: Wenzel, Silke C.; Hoffmann, Holger; Zhang, Jidong; Debussche, Laurent; Haag‐Richter, Sabine; Kurz, Michael; Nardi, Frederico; Lukat, Peer; Kochems, Irene; Tietgen, Heiko; Schummer, Dietmar; Nicolas, Jean‐Paul; Calvet, Loreley; Czepczor, Valerie; Vrignaud, Patricia; Mühlenweg, Agnes; Pelzer, Stefan; Müller, Rolf; Brönstrup, Mark
• Is Part Of: Angewandte Chemie international edition. Volume 54:Issue 51(2015)
• Page Start: 15560
• Page End: 15564
• Publication Date: 2015-10-30
• Subjects: bengamides -- biosynthesis -- drug discovery -- natural products -- resistance; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201508277
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The bengamides, sponge‐derived natural products that have been characterized as inhibitors of methionine aminopeptidases (MetAPs), have been intensively investigated as anticancer compounds. We embarked on a multidisciplinary project to supply bengamides by fermentation of the terrestrial myxobacterium M. virescens, decipher their biosynthesis, and optimize their properties as drug leads. The characterization of the biosynthetic pathway revealed that bacterial resistance to bengamides is conferred by Leu 154 of the myxobacterial MetAP protein, and enabled transfer of the entire gene cluster into the more suitable production host M. xanthus DK1622. A combination of semisynthesis of microbially derived bengamides and total synthesis resulted in an optimized derivative that combined high cellular potency in the nanomolar range with high metabolic stability, which translated to an improved half‐life in mice and antitumor efficacy in a melanoma mouse model. Abstract : A terrestrial dive to bengamides : Bengamides, sponge‐derived natural products, have been generated from a terrestrial source. Their biosynthesis and self‐resistance mechanism against methionine aminopeptidases was elucidated, a heterologous expression platform was established, and their pharmaceutical properties were improved by medicinal chemistry.