Among the many remarkable discoveries emerging from the genomics era is the revelation that most microorganisms, and in particular, filamentous fungi, possess far greater numbers of gene clusters encoding for the production of secondary metabolites than the number of natural products that are reported to have been isolated from these same organisms (1).  It is not uncommon for fungi to have dozens of unique gene clusters encoding for previously uncharacterized natural products (e.g., polyketides, non-ribosomal peptides, and hybrid polyketide-non-ribosomal peptides).  Consequently, a method for accessing the structural diversity of small molecules encoded by fungal secondary-metabolite gene clusters holds considerable promise for discovering new natural products.

We (2, 3) and others (4) have proposed that epigenome-level changes are extensively involved in controlling the transcriptional accessibility of gene clusters that encode for biosynthetic enzymes.  The Natural Products Discovery Group employs a chemical epigenetic methodology that utilizes small-molecule modulators of specific molecular targets (e.g., histone deacetylase and DNA methyl transferase activities) to selectively alter the transcriptional accessibility of gene clusters encoding for biosynthetic enzymes in fungi (5, 6).  We have shown that these methods are capable of significantly altering the secondary metabolite profiles of many fungi resulting in the production of many new natural products.  We are currently applying these methods for the discovery of new antimicrobial substances and leads for Huntington’s disease.

References

1. Cichewicz, R.H., Henrikson, J.C., Wang, X. and Branscum, K.M. (2010) Baltz, R.H., Davies, J.E., Demain, A.L., Bull, A.T., Junker, B., Katz, L., Lynd, L.R., Masurekar, P., Reeves, C.D. and Zhao, H. (eds.), In Manual of Industrial Microbiology and Biotechnology. ASM Press, Washington, D.C., pp. 78-95.
2. Williams, R.B., Henrikson, J.C., Hoover, A.R., Lee, A.E. and Cichewicz, R.H. (2008) Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem., 6, 1895-1897.
3. Fisch, K.M., Gillaspy, A.F., Gipson, M., Henrikson, J.C., Hoover, A.R., Jackson, L., Najar, F.Z., Wägele, H. and Cichewicz, R.H. (2009) Chemical induction of silent pathway transcription in Aspergillus niger. J. Ind. Microbiol. Biotechnol., 36, 1199-1213.
4. Shwab, E.K., Bok, J.W., Tribus, M., Galehr, J., Graessle, S. and Keller, N.P. (2007) Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryotic Cell, 6, 1656-1664.
5. Cichewicz, R. H., (2010) Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat. Prod. Rep., 27,  11-22.
6. Williams, R.B., Henrikson, J.C., Hoover, A.R., Lee, A.E. and Cichewicz, R.H. (2008) Epigenetic remodeling of the fungal secondary metabolome. Org. Biomol. Chem., 6, 1895-1897.