Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure–Activity Relationships |
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| Authors: | Dr Silke C Wenzel Dr Holger Hoffmann Dr Jidong Zhang Dr Laurent Debussche Dr Sabine Haag‐Richter Dr Michael Kurz Dr Frederico Nardi Dr Peer Lukat Irene Kochems Dr Heiko Tietgen Prof?Dr Dietmar Schummer Jean‐Paul Nicolas Dr Loreley Calvet Dr Valerie Czepczor Dr Patricia Vrignaud Dr Agnes Mühlenweg Priv‐Doz?Dr Stefan Pelzer Prof?Dr Rolf Müller Prof?Dr Mark Brönstrup |
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| Affiliation: | 1. Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universit?t des Saarlandes, 66123 Saarbrücken (Germany);2. Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany);3. 13 Quai Jules Guesde, Vitry sur Seine 94403 (France);4. TH Mittelhessen, Wiesenstrasse 14, 35390 Gie?en (Germany);5. Technische Universit?t Berlin, Str.d.17. Juni 124, 10623 Berlin (Germany);6. Evonik Nutrition & Care, Kantstrasse 2, 33790 Halle (Germany);7. Helmholtz Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig (Germany) |
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| 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. |
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| Keywords: | bengamides biosynthesis drug discovery natural products resistance |
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