Abstract
Like many fields of the biosciences, actinomycete natural products research has been revolutionised by next-generation DNA sequencing (NGS). Hundreds of new genome sequences from actinobacteria are made public every year, many of them as a result of projects aimed at identifying new natural products and their biosynthetic pathways through genome mining. Advances in these technologies in the last five years have meant not only a reduction in the cost of whole genome sequencing, but also a substantial increase in the quality of the data, having moved from obtaining a draft genome sequence comprised of several hundred short contigs, sometimes of doubtful reliability, to the possibility of obtaining an almost complete and accurate chromosome sequence in a single contig, allowing a detailed study of gene clusters and the design of strategies for refactoring and full gene cluster synthesis. The impact that these technologies are having in the discovery and study of natural products from actinobacteria, including those from the marine environment, is only starting to be realised. In this review we provide a historical perspective of the field, analyse the strengths and limitations of the most relevant technologies, and share the insights acquired during our genome mining projects.
Highlights
Actinobacteria produce more than 70% of all natural product scaffolds used for the manufacture of clinically-relevant anti-infectives [1]
During the sequencing of the Streptomyces coelicolor genome in the late 1990s [5] it became evident that actinomycetes carry the genetic potential to produce many more natural products than those detected under laboratory conditions, and during the following years many previously-unknown metabolites produced by S. coelicolor were identified and characterised [6]
The backbone of these compounds is synthesised by large enzymes, polyketide synthases (PKS), and non-ribosomal peptide synthetases (NRPS), which consist of a highly-conserved modular enzymatic architecture that is reflected at the nucleotide sequence level by highly similar intragenic and intergenic tandem repeats, frequently spanning over 700 bp; e.g., S. coelicolor coelimycin PKS gene sco6274 positions 3879–4533 and sco6275 11986–12639 share 99%
Summary
Actinobacteria produce more than 70% of all natural product scaffolds used for the manufacture of clinically-relevant anti-infectives [1]. Since the late 2000s we have seen the continuous release of new DNA sequencing technologies that have pushed forward both sequencing capacity and accuracy, and lowered the cost per sequenced nucleotide. These technologies are referred to as next-generation sequencing (NGS) and are defined as “non-Sanger-based, high-throughput, and eliminating the need for fragment-cloning and amplification in Escherichia coli prior to sequencing” (adapted from [11]). NGS technologies make affordable the high-throughput sequencing of bacterial genomes which, when coupled with a continuous advance in computing algorithms and databases for the automated scanning and annotation of specialised metabolite gene clusters like AntiSMASH [12] and MIBiG [13], are enabling the continuous discovery and study of natural products biosynthetic pathways by genome mining. Coupled with the difficulty of growing some of these organisms at a large scale, the sequence-based approach to natural product discovery described here should be pertinent and useful
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