Genomic mining – a concept for the discovery of new bioactive natural products

Natural products continue to represent an important source for lead structures for drug discovery, but with discovery rates of novel structural classes in decline, the need to explore alternate sources of chemical diversity is evident. Genomic mining represents hereby a complementary strategy to address these issues and to access a tremendous source of new, biologically active metabolites. The base for this claim is provided by the outcomes of the recent genome sequencing projects which revealed the presence of numerous biosynthetic gene clusters for which the corresponding metabolites are currently unknown [1]. Importantly, it has been observed that the numbers of such orphan biosynthetic loci far outnumbers the quantity of the gene clusters directing the synthesis of known compounds of most of the considered organisms [2]. Apparently, only a fraction of natural products has been analyzed and the majority await discovery. Considering this discrepancy and that several hundreds of sequencing programs are ongoing, the huge potential of the genomic mining approach for natural product discovery becomes apparent. The potential of this untapped resource can be expanded even further by the exploitation of not only genomic, but also metagenomic DNA. After outlining the rationale and methods [1,3] of genomic mining, the success [2], but also the limits of this fascinating and interdisciplinary strategy will be illustrated by selected examples from plant and microbial genomes.

References: 1. Gross (2007) Appl. Microbiol. Biotechnol. 75:267–277.

2. Gross (2009) Curr. Opin. Drug Discov. Devel. 12:207–219.

3. Gross et al. (2007) Chem. Biol. 14:53–63.