Genomic basis for natural product biosynthetic diversity in the actinomycetes

Abstract

The phylum Actinobacteria hosts diverse high G + C, Gram-positive bacteria that have evolved a complex chemical language of natural product chemistry to help navigate their fascinatingly varied lifestyles. To date, 71 Actinobacteria genomes have been completed and annotated, with the vast majority representing the Actinomycetales, which are the source of numerous antibiotics and other drugs from genera such as Streptomyces, Saccharopolyspora and Salinispora. These genomic analyses have illuminated the secondary metabolic proficiency of these microbes – underappreciated for years based on conventional isolation programs – and have helped set the foundation for a new natural product discovery paradigm based on genome mining. Trends in the secondary metabolomes of natural product-rich actinomycetes are highlighted in this review article, which contains 199 references.

Fig. 1

Phylogenetic relatedness of Actinobacteria based on 16S rRNA sequence and the relative number of putative gene clusters for secondary metabolites. Strains with completed genomes are colored blue, those not yet published are noted with an asterisk, and those completed but with incomplete annotation are marked with double asterisks. Phylogenetic analysis of aligned sequences was done by a bootstrap method using bootstrap number 1000 and seed number 100.

Fig. 2

Circular representation of the actinomycete chromosomes S. coelicolor A3(2), S. erythraea NRRL2338 and S. tropica CNB-440 oriented to the dnaA gene (top). All genomes are scaled to their relative size. The inner rings show a normalized plot of GC skew, while the center rings show a normalized plot of GC content. The outer circles show the distribution of secondary metabolite gene clusters. Biosynthetic gene clusters associated with thiotemplate-based assembly (PKS, NRPS) are depicted in red, terpene clusters in blue, and loci encoding all other secondary metabolic pathways are marked in black. Clusters whose products have been isolated are labeled accordingly.

Fig. 3

Schematic representation of the S. avermitilis MA-4680 chromosome. Drawing details are the same as for Fig. 2.

Fig. 4

Schematic representation of the S. griseus IFO 13350 genome. Drawing details are the same as for Fig. 2.

Fig. 5

The comparative analysis of nucleotide sequences of S. griseus IFO 13350 (top), S. avermitilis MA-4680 (middle) and S. coelicolor A3(2) (bottom) using the MURASAKI program version 1.40 (weight; 45, length; 90). Predicted core regions (blue lines) account for 6.28 Mb of S. coelicolor A3(2), 6.50 Mb of S. avermitilis and 6.39 Mb of S. griseus and are centered about the replication of origin oriC (black arrow). The subtelomeric regions (bold lines) are less conserved with regard to sequence and ortholog distribution and contain more than half of the gene clusters for secondary metabolism (colored triangles).

Fig. 6

Conserved genomic regions amongst S. griseus IFO 13350, S. avermitilis MA-4680 and S. coelicolor A3(2), harboring (A) hopanoid and (B) desferrioxamine biosynthetic gene clusters.

Fig. 7

Examples of “island” secondary metabolic gene clusters in Streptomyces involving (A) oligomycin biosynthesis in S. avermitilis and (B) streptomycin in S. griseus.

Fig. 8

Schematic representation of the S. arenicola CNS-205 genome. Drawing details are the same as for Fig. 2.

Fig. 9

Gene organization and proposed biosynthesis of a phosphonoformate-like compound in Frankia alni ACN14a. (A) Phosphonate biosynthetic gene cluster in F. alni ACN14a. Genes that are responsible for the production of hydroxyethylphosphonate are depicted in grey (minimal cassette consisting of phosphoenolpyruvate mutase ppm, phosphonopyruvate decarboxylase ppd and phosphonoacetaldehyde dehydrogenase adh). (B) Proposed pathway to a hitherto unknown phosphonate antibiotic.