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Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships
Author(s) -
Wenzel Silke C.,
Hoffmann Holger,
Zhang Jidong,
Debussche Laurent,
HaagRichter Sabine,
Kurz Michael,
Nardi Frederico,
Lukat Peer,
Kochems Irene,
Tietgen Heiko,
Schummer Dietmar,
Nicolas JeanPaul,
Calvet Loreley,
Czepczor Valerie,
Vrignaud Patricia,
Mühlenweg Agnes,
Pelzer Stefan,
Müller Rolf,
Brönstrup Mark
Publication year - 2015
Publication title -
angewandte chemie international edition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.831
H-Index - 550
eISSN - 1521-3773
pISSN - 1433-7851
DOI - 10.1002/anie.201508277
Subject(s) - myxobacteria , natural (archaeology) , biosynthesis , class (philosophy) , biology , computer science , bacteria , biochemistry , genetics , gene , artificial intelligence , paleontology
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.