Small-molecule elicitation of microbial secondary metabolites

Abstract

Microbial natural products continue to be an unparalleled resource for pharmaceutical lead discovery, but the rediscovery rate is high. Bacterial and fungal sequencing studies indicate that the biosynthetic potential of many strains is much greater than that observed by fermentation. Prodding the expression of such silent (cryptic) pathways will allow us to maximize the chemical diversity available from microorganisms. Cryptic metabolic pathways can be accessed in the laboratory using molecular or cultivation-based approaches. A targeted approach related to cultivation-based methods is the application of small-molecule elicitors to specifically affect transcription of secondary metabolite gene clusters. With the isolation of the novel secondary metabolites lunalides A and B, oxylipins, cladochromes F and G, nygerone A, chaetoglobosin-542, -540 and -510, sphaerolone, dihydrosphaerolone, mutolide and pestalone, and the enhanced production of known secondary metabolites like penicillin and bacitracin, chemical elicitation is proving to be an effective way to augment natural product libraries.

Figure 1

Selected fully sequenced prokaryotic and eukaryotic secondary metabolite producers (Gross, 2009). Dark bars show the numbers of gene clusters known to be present in the genome, based on the number of isolated secondary metabolites at the time of sequencing. Light bars show the total number of gene clusters deduced from whole genome sequence analysis (Used with permission from Harald Gross.).

Figure 2

Novel microbial secondary metabolites elicited with small molecules.