02/22/18 - 9:45 AM to 11:00 AM
Department Seminar: Professor Neil L. Kelleher
"Scalable Approaches to Harvest Drug Leads from Nature’s Microbes"
Natural products are a major historical source of drugs. Since 1981, ~60% of all approved small molecule drugs have been natural products, their derivatives, or their mimics. However there is a need for renewable, reliable sources for the discovery of new natural products as the biopharma industry has largely abandoned the field in recent years. The genomics era has marshaled in a wealth of information about the natural product biosynthetic arsenals of both fungi and bacteria, promising the potential for vast new collections of fine chemicals. However, lacking are tools to convert that genomic knowledge into the promised wealth of new molecules. My lab has worked on this problem in both bacteria and fungi using two distinct approaches. In the first approach, called metabologenomics, we utilize the correlation of biosynthetic gene clusters with metabolites detected from actinomycete bacteria through large-scale sequencing and metabolomics and report the discovery of the gene clusters for tambromycin and other compounds. In the second approach, we use high throughput heterologous expression of fungal biosynthetic gene clusters through fungal artificial chromosomes with metabolomic scoring (FAC-MS), resulting in discovery of 15 new natural products, including the molecule valactamide A.[2, 3]
- Doroghazi JR, Albright JC, Goering AW, Ju K, Haines RR, Tchalukov KA, Labeda DP, Kelleher NL, & Metcalf WW (2014) A Roadmap for Natural Product Discovery Based on Large-Scale Genomics and Metabolomics. Nat. Chem. Biol. 10(11):963-968.
- Bok J, Ye R, Clevenger KD, Mead D, Wagner M, Krerowicz A, Albright J, Goering A, Thomas P, Kelleher NL, Keller NP, Wu C. (2015) Fungal Artificial Chromosomes for Mining of the Fungal Secondary Metabolome. BMC Gen. 16:343.
- Clevenger KD, Bok JW, Ye R, Miley GP, Velk T, Chen C, Yang K, Gao P, Lamprecht M, Thomas P, Islam M, Wu CC, Keller NP, Kelleher NL (2017) A Scalable Platform to Identify Fungal Secondary Metabolites and their Gene Clusters. Nat. Chem. Biol. [Epub ahead of print]
Professor Kelleher’s research is composed of three main sub-groups that continue working in the areas of top down proteomics, natural products biosynthesis/discovery, and chromatin biology. The core of the Kelleher Team is built around expertise in technology development for complex mixture analysis using Fourier-Transform Mass Spectrometry for targeted applications in proteomics and metabolomics. Professor Kelleher harbors specific interests in the biosynthesis and discovery of polyketides and non-ribosomally produced peptides. Further themes of the Kelleher laboratory include using intact proteins for efficient detection of their post-translational modifications, with specific interests in chromatin and cancer biology.
Professor Kelleher earned a Bachelor of Science degree in chemistry and a Bachelor of Arts degree in German from Pacific University in 1992. After finishing his joint graduate work with professors Tadhg Begley and Fred McLafferty at Cornell University in 1997, Kelleher moved to the laboratory of Professor Christopher Walsh at Harvard Medical School. This training in high performance mass spectrometry and enzymology explains much of the research performed by his independent laboratory at the University of Illinois in Urbana-Champaign. In 2010, the Kelleher Group relocated to Northwestern University. He has about 150 publications, an H-factor of 39, and provides ProSight software via the web to more than 650 labs around the world.