Produktion mariner Naturstoffe aus der Klasse der Bengamide in Myxobakterien: Biosynthese und Struktur-Aktivitäts-Beziehungen

Bengamide, aus marinen Schwammen stammende und als Inhibitoren der Methionin-Aminopeptidase (MetAP) charakterisierte Naturstoffe, wurden intensiv als Wirkstoffe gegen Krebs erforscht. In einem multidisziplinaren Forschungsprojekt haben wir die Bereitstellung von Bengamiden uber Fermentation des terrestrischen Myxobakteriums M. virescens, die Aufklarung ihrer Biosynthese und die Optimierung ihrer Eigenschaften als Arzneistoff-Leitstrukturen untersucht. Die Charakterisierung des Biosyntheseweges zeigte auf, dass bakterielle Resistenz gegenuber Bengamiden durch Leu154 des myxobakteriellen MetAP-Proteins vermittelt wird, und ermoglichte den Transfer des gesamten Biosynthesegenclusters in den geeigneteren Produktionsstamm M. xanthus DK1622. Eine Kombination aus Semisynthese mikrobiell gewonnener Bengamide und Totalsynthese fuhrte zum optimierten Derivat 8 a. Die nanomolare zellulare Wirksamkeit und die hohe metabolische Stabilitat waren mit einer verbesserten Halbwertszeit in Mausen sowie mit Antitumor-Effizienz in einem Melanom-Mausmodell verbunden.

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