Challenges and triumphs to genomics-based natural product discovery

Abstract

Genome sequencing is rapidly changing the field of natural products research by providing opportunities to assess the biosynthetic potential of strains prior to chemical analysis or biological testing. Ready access to sequence data is driving the development of new bioinformatic tools and methods to identify the products of silent or cryptic pathways. While genome mining has fast become a useful approach to natural product discovery, it has also become clear that identifying pathways of interest is much easier than finding the associated products. This has led to bottlenecks in the discovery process that must be overcome for the potential of genomics-based natural product discovery to be fully realized. In this perspective, we address some of these challenges in the context of our work with the marine actinomycete genus Salinispora, which is proving to be a useful model with which to apply genome mining as an approach to natural product discovery.

Figure 1

The cyanosporaside pathway cya. This pathway was originally characterized in S. pacifica strain CNS-143 [17] using a combination of fosmid sequencing and primer walking. The three S. pacifica draft genome sequences (strains CNS-103, CNT-131, and CNQ-768) all posses the pathway, which occurs on two contigs. These contigs all end at the same nucleotide position in ORF7.

Figure 2

Distribution of the sal pathway among Salinispora genomes. MultiGeneBlast [21] was used to BLAST the sal pathway from S. tropica (which is responsible for salinosporamide A production) against a database of Salinispora genomes. The resulting cumulative BLAST bit scores were normalized to the genome from which the query pathway was derived. A drop in scores to ca. 0.5 is observed for S. pacifica genomes that possess the version of the pathway responsible for salinosporamide K production. These strains lack the genes encoding the 26 kb chloroethylmalonyl-CoA portion of the pathway [7]. Scores then drop further to <0.2 in strains that do not possess the pathway.

Figure 3

Modular organization of the slm pathway as observed in S. tropica strain CNB-440 and its associated product salinilactam. ACP: acyl-carrier protein, KS: ketosynthase, AT: acyl-transferase, mAT: methyl-malonyl-CoA specific AT domain, DH: dehydratase, KR: ketoreductase, TE: thioesterase.