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

Nam7 Hydroxylase Is Responsible for the Formation of the Naphthalenic Ring in the Biosynthesis of Neoansamycins

Ten new benzenic ansamycins, 5,10-<i>seco</i>-neoansamycins A–J (<b>1</b>–<b>10</b>), were isolated from the <i>nam7</i>-disrupted mutant strain SR201<i>nam1</i>OEΔ<i>nam7</i>. These are the benzenic counterparts of the neoansamycins, which provide direct evidence that the putative hydroxylase Nam7 is involved in the formation of naphthalenic ring in neoansamycin biosynthesis and connect benzenic and naphthalenic ansamycins for the first time

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