Activation of a Cryptic Gene Cluster in <i>Lysobacter enzymogenes</i> Reveals a Module/Domain Portable Mechanism of Nonribosomal Peptide Synthetases in the Biosynthesis of Pyrrolopyrazines

<i>Lysobacter</i> are considered “peptide specialists”. However, many of the nonribosomal peptide synthetase genes are silent. Three new compounds were identified from <i>L. enzymogenes</i> upon activating the six-module-containing <i>led</i> cluster by the strong promoter <i>P</i>_HSAF. Although <i>ledD</i> was the first gene under <i>P</i>_HSAF control, the second gene <i>ledE</i> was expressed the highest. Targeted gene inactivation showed that the two-module LedE and the one-module LedF were selectively used in pyrrolopyrazine biosynthesis, revealing a module/domain portable mechanism

Hygrocins C–G, Cytotoxic Naphthoquinone Ansamycins from <i>gdmAI</i>-Disrupted <i>Streptomyces</i> sp. LZ35

Six hygrocins, polyketides of ansamycin class, were isolated from the <i>gdmAI</i>-disrupted Streptomyces sp. LZ35. The planar structure of hygrocins C–E (<b>1</b>–<b>3</b>) was determined by one-dimensional and two-dimensional NMR spectroscopy and high-resolution mass spectrometry. They are derivatives of hygrocin A but differ in the configuration at C-2 and the orientation of the C-3,4 double bond. Hygrocin F­(<b>4</b>) and G­(<b>5</b>) were shown to be isomers of hygrocin C (<b>1</b>) and B (<b>6</b>), respectively, due to the different alkyl oxygen participating in the macrolide ester linkage. Hygrocins C, D, and F were found to be toxic to human breast cancer MDA-MB-431 cells (IC₅₀ = 0.5, 3.0, and 3.3 μM, respectively) and prostate cancer PC3 cells (IC₅₀ = 1.9, 5.0, and 4.5 μM, respectively), while hygrocins B, E, and G were inactive

Activating a Cryptic Ansamycin Biosynthetic Gene Cluster To Produce Three New Naphthalenic Octaketide Ansamycins with <i>n</i>‑Pentyl and <i>n</i>‑Butyl Side Chains

Genome mining is a rational approach to discovering new natural products. The genome sequence analysis of <i>Streptomyces</i> sp. LZ35 revealed the presence of a putative ansamycin gene cluster (<i>nam</i>). Constitutive overexpression of the pathway-specific transcriptional regulatory gene <i>nam1</i> successfully activated the <i>nam</i> gene cluster, and three novel naphthalenic octaketide ansamycins were discovered with unprecedented <i>n</i>-pentylmalonyl-CoA or <i>n</i>-butylmalonyl-CoA extender units. This study represents the first example of discovering novel ansamycin scaffolds via activation of a cryptic gene cluster