Exploiting the genome sequence of Streptomyces nodosus for enhanced antibiotic production

Abstract

The genome of the amphotericin producer Streptomyces nodosus was sequenced. A single scaffold of 7,714,110 bp was obtained. Biosynthetic genes were identified for several natural products including polyketides, peptides, siderophores and terpenes. The majority of these clusters specified known compounds. Most were silent or expressed at low levels and unlikely to compete with amphotericin production. Biosynthesis of a skyllamycin analogue was activated by introducing expression plasmids containing either a gene for a LuxR transcriptional regulator or genes for synthesis of the acyl moiety of the lipopeptide. In an effort to boost amphotericin production, genes for acyl CoA carboxylases, a phosphopantetheinyltransferase and the AmphRIV transcriptional activator were overexpressed, and the effects on yields were investigated. This study provides the groundwork for metabolic engineering of S. nodosus strains to produce high yields of amphotericin analogues.

Polyene macrolide biosynthesis in streptomycetes and related bacteria: recent advances from genome sequencing and experimental studies

“…Overproduction of the pathway-specific activator AmphRIV increased yields on Streptomyces medium (Sweeney et al, 2016). No improvements were observed following overproduction of acetyl and propionyl CoA carboxylases, a methylmalonyl CoA epimerase or a phosphopantetheine transferase specific for ACP domains of modular synthases.…”

“…This information will give insights into tetraene biosynthesis. The genome of S. nodosus has been sequenced (Sweeney et al, 2016). Until recently, this organism was the only one known to synthesise amphotericin B.…”

“…As well as the amphotericin cluster, the S. nodosus genome contains 24 biosynthetic gene clusters, although 18 of these specify previously known compounds (Sweeney et al, 2016). It has been suggested that genomes of rare non-streptomycete actinomycetes may be a richer source of biosynthetic genes for new antibiotics and bioactive compounds (Jose and Jeukumar, 2013).…”

“…It has not yet been possible to identify a gene for a 3, 4 ketoisomerase enzyme within the S. nodosus genome. There are no obvious homologs of the 3, 4 isomerases that act on TDP-4-keto-6-deoxy--D-glucose in the biosynthesis of D-mycaminose and other deoxysugars (Hutchinson et al, 2010;Sweeney et al, 2016). …”

“…Genome sequencing revealed that S. nodosus contains no other modular PKS that might compete with amphotericin production (Sweeney et al, 2016). The tetramycin producer Streptomyces ahygroscopicus also contains biosynthetic genes for nystatin (Cui et al, 2015).…”