Targeted Discovery and Combinatorial Biosynthesis of Polycyclic Tetramate Macrolactam Combamides A–E

Abstract

Polycyclic tetramate macrolactams (PoTeMs) are a growing class of natural products with distinct structure and diverse biological activities. By promoter engineering and heterologous expression of the cryptic <i>cbm</i> gene cluster, four new PoTeMs, combamides A–E (<b>1</b>–<b>4</b>), were identified. Additionally, two new derivatives, combamides E (<b>5</b>) and F (<b>6</b>), were generated via combinatorial biosynthesis. Together, our findings provide a sound base for expanding the structure diversities of PoTeMs through genome mining and combinatorial biosynthesis