title: Production of the Bengamide Class of Marine Natural Products in Myxobacteria: Biosynthesis and Structure-Activity Relationships.
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.
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universität des Saarlandes, 66123 Saarbrücken (Germany).
authors.forename: Silke C
authors.initials: SC
authors.lastname: Wenzel
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Holger
authors.initials: H
authors.lastname: Hoffmann
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Jidong
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Laurent
authors.initials: L
authors.lastname: Debussche
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Sabine
authors.initials: S
authors.lastname: Haag-Richter
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Frederico
authors.initials: F
authors.lastname: Nardi
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universität des Saarlandes, 66123 Saarbrücken (Germany).
authors.forename: Peer
authors.initials: P
authors.lastname: Lukat
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universität des Saarlandes, 66123 Saarbrücken (Germany).
authors.forename: Irene
authors.initials: I
authors.lastname: Kochems
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Heiko
authors.initials: H
authors.lastname: Tietgen
authors.affiliation: TH Mittelhessen, Wiesenstrasse 14, 35390 Gießen (Germany).
authors.forename: Dietmar
authors.initials: D
authors.lastname: Schummer
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Nicolas
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Loreley
authors.initials: L
authors.lastname: Calvet
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Valerie
authors.initials: V
authors.lastname: Czepczor
authors.affiliation: Sanofi R&D, Industriepark Hoechst, 65926 Frankfurt (Germany).|13 Quai Jules Guesde, Vitry sur Seine 94403 (France).
authors.forename: Patricia
authors.initials: P
authors.lastname: Vrignaud
authors.affiliation: Technische Universität Berlin, Str.d.17. Juni 124, 10623 Berlin (Germany).
authors.forename: Agnes
authors.initials: A
authors.lastname: Mühlenweg
authors.affiliation: Evonik Nutrition & Care, Kantstrasse 2, 33790 Halle (Germany).
authors.forename: Stefan
authors.initials: S
authors.lastname: Pelzer
authors.affiliation: Helmholtz Institut für Pharmazeutische Forschung Saarland, Helmholtz Zentrum für Infektionsforschung and Universität des Saarlandes, 66123 Saarbrücken (Germany). Rolf.Mueller@helmholtz-hzi.de.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
authors.affiliation: Helmholtz Zentrum für Infektionsforschung, Inhoffenstrasse 7, 38124 Braunschweig (Germany). Mark.Broenstrup@helmholtz-hzi.de.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001381:Azepines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001688:Biological Products / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006207:Half-Life; D008386:Marine Biology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009231:Myxococcales / Q000378:metabolism*; D011161:Porifera / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D001381:Azepines; D001688:Biological Products
keywords: bengamides; biosynthesis; drug discovery; natural products; resistance