Chemistry at Illinois University of Illinois at Urbana-Champaign

Douglas A. Mitchell

Assistant Professor of Chemistry
Faculty, Institute for Genomic Biology:
Mining Microbial Genomes for Novel Antibiotics
Affiliate, Department of Microbiology

Professor Mitchell received his undergraduate degree in chemistry from Carnegie Mellon University in 2002. After a short internship in medicinal chemistry at Merck Research Laboratories, he obtained his Ph.D. from the University of California, Berkeley in 2006. For postdoctoral studies, he worked with Jack Dixon at the University of California, San Diego. Professor Mitchell joined the University of Illinois faculty in 2009 and has research interests that span the interface of chemistry and biology.

Research

Our primary objective is to use a blend of chemical and biological approaches to address the alarming rise in antibiotic resistance. In this endeavour, we seek to identify and characterize novel antibiotic compounds. Our approach involves genome-mining, isolation and characterization of novel natural products, and mechanistic studies of key natural product biosynthetic enzymes. Taken together, our approach aims to expedite the discovery of future medicines from biological sources. Of special interest are compounds that only kill pathogenic bacteria or directly target mechanisms of virulence. Unlike currently deployed antibiotics, which exclusively target essential life processes, our strategy holds great potential in delaying resistance. The Mitchell laboratory is a multidisciplinary team that draws methodology from the fields of chemical biology, organic chemistry, microbiology, pharmacology, structural biology, and bioinformatics.

The focus of our current studies is centered on a recently recognized, burgeoning class of natural product: the thiazole/oxazole-modified microcins (TOMMs). Genome mining has identified that over 20% of all sequenced bacteria and archaea have the genetic capacity to biosynthesize a TOMM natural product. While only a small fraction of the known TOMMs have been characterized, these ribosomally produced products harbor a structural and functional diversity that rivals that of any non-ribosomal (NRPS, PKS, terpene) biosynthetic system. Examples include microcin B17 (DNA gyrase inhibitor), patellamide A (anti-cancer), thiostrepton (50S ribosome inhibitor; antibiotic), streptolysin S (disease-promoting cytolysin), and plantazolicin (ultra-narrow spectrum antibiotic). Given their functional relevance to human health, and the fact that the majority of all medicines are natural products or simple derivatives thereof, we view the TOMM family as a treasure trove of bioactive molecules awaiting further exploration.

Current research in the Mitchell Laboratory can be broadly divided into two categories. I.) We aim to characterize the structure and function of unique TOMM natural products and the enzymes that produce them. To achieve this, we employ chemical and biological approaches including high-resolution mass spectrometry, nuclear magnetic resonance spectroscopy, X-ray crystallography, in vitro reconstitution, and genetic manipulation techniques. II.) We aim to utilize what we have learned about TOMM natural product structure and function to exploit biosynthetic weakness or promiscuity. In the cases where a human pathogen produces a TOMM natural product that promotes virulence (i.e. streptolysin S), the development of small molecule biosynthetic inhibitors not only aids the study of toxin maturation but could also be clinically useful. In the event the TOMM natural product itself holds promise as a therapeutic, identification of enzymatic promiscuity can be harnessed to generate combinatorial libraries of natural product variants. The proper tailoring of small molecule probes and interception of engineered biosynthetic pathways are both expected to produce novel compounds that hold pharmacological value.

For a more comprehensive synopsis of Professor Mitchell's research see:
http://www.scs.illinois.edu/mitchell/research.html

Publications

For a complete publication list, see:
http://www.scs.illinois.edu/mitchell/pubs.html

Cox, C.L.; Tietz, J.I.; Sokolowski, K.; Melby, J.O.; Doroghazi, J.R.; Mitchell, D.A. "Nucleophilic 1,4-additions for natural product discovery" ACS Chem. Biol., Article ASAP (2014). doi:10.1021/cb500324n

Sinko, W.; Wang, Y.; Zhu, W.; Zhang, Y.; Feixas, F.; Cox, C.; Mitchell, D.A.; Oldfield, E.; McCammon, J.A. "Undecaprenyl diphosphate synthase inhibitors: antibacterial drug leads" J. Med. Chem., Article ASAP (2014). doi:10.1021/jm5004649

Li, K.; Schurig-Briccio, L.A.; Feng, X.; Upadhyay, A.; Pujari, V.; Lechartier, B.; Fontes, F.L.; Yang, H.; Rao, G.; Zhu, W.; Gulati, A.; No, J.H.; Cintra, G.; Bogue, S.; Liu, Y.-L.; Molohon, K.; Orlean, P.; Mitchell, D.A.; Freitas-Junior, L.; Ren, F.; Sun, H.; Jiang, T.; Li, Y.; Guo, R.-T.; Cole, S.T.; Gennis, R.B.; Crick, D.C.; Oldfield, E. "Multitarget drug discovery for tuberculosis and other infectious diseases." J. Med. Chem., 57:3126-3139 (2014). doi:10.1021/jm500131s

Deane, C.D.; Mitchell, D.A. "Lessons learned from the transformation of natural product discovery to a genome-driven endeavor." J. Ind. Microbiol. Biot., 41:315-331 (2014). doi:10.1007/s10295-013-1361-8

Melby, J.O.; Li, X.; Mitchell, D.A. "Orchestration of enzymatic processing by thiazole/oxazole-modified microcin dehydrogenases." Biochemistry, 53:413-422 (2014). doi:10.1021/bi401529y

Sharma, A.; Blair, P.M.; and Mitchell, D.A. "Synthesis of plantazolicin analogues enables dissection of ligand binding interactions of a highly selective methyltransferase." Org. Lett., 15:5076-5079 (2013). doi:10.1021/ol402444a

Lee, J.; Hao, Y.; Blair, P.M.; Melby, J.O.; Agarwal, V.; Burkhart, B.J.; Nair, S.K.; Mitchell, D.A. "Structural and functional insight into an unexpectedly selective N-methyltransferase involved in plantazolicin biosynthesis." Proc. Natl. Acad. Sci. USA, 110:12954-12959 (2013). doi:10.1073/pnas.1306101110

Deane, C.D.; Melby, J.O.; Molohon, K.J.; Susarrey, A.R.; Mitchell, D.A. "Engineering unnatural variants of plantazolicin through codon reprogramming." ACS Chem. Biol., 8:1998-2008 (2013). doi:10.1021/cb4003392

Dunbar, K.L.; Mitchell, D.A. "Insights into the mechanism of peptide cyclodehydrations achieved through the chemoenzymatic generation of amide derivatives." J. Am. Chem. Soc., 135:8692-9701 (2013). doi:10.1021/ja4029507

Hu, Y.; Jia, S.; Ren, F.; Huang, C.-H.; Ko, T.-P.; Mitchell, D.A.; Guo, R.-T.; Zheng, Y. "Crystallization and preliminary X-ray diffraction of YisP protein from Bacillus subtilis subsp. subtilis strain 168," Acta Cryst., F69:77-79 (2013). doi:10.1107/S1744309112049330

Dunbar, K.L.; Mitchell, D.A. "Revealing Nature's synthetic potential through the study of ribosomal natural product biosynthesis." ACS Chem. Biol., 8:473-487 (2013). doi:10.1021/cb3005325

Zhu, W.; Zhang, Y.; Sinko, W.; Hensler, M.E.; Olson, J.; Molohon, K.J.; Lindert, S.; Cao, R.; Li, K.; Wang, K.; Wang, Y.; Liu, Y.-L.; Sankovsky, A.; de Oliveira, C.A.F.; Mitchell, D.A.; Nizet, V.; McCammon, J.A.; Oldfield, E. "Antibacterial drug leads targeting isoprenoid biosynthesis." Proc. Natl. Acad. Sci. USA, 110:123-128 (2013). doi:10.1073/pnas.1219899110

Arnison, P., et al. "Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature." Nat. Prod. Rep., 30:108-160 (2013). doi:10.1039/C2NP20085F

Awards

  • Tomorrow's PI: Genome Technology magazine

  • Packard Fellowship in Science and Engineering

  • NIH Director's New Innovator Award

  • Hartwell Foundation Biomedical Research Fellowship
  • American Heart Association Predoctoral Fellowship
  • American Society of Pharmacology and Experimental Therapeutics Research Fellowship

Highlights

News and Views: Kelly, W.L., "Biosynthesis: Ringing in a new view" Nat. Chem. Biol., 8:505 (2012)

Schmidt, E.W.; "The hidden diversity of ribosomal peptide natural products" BMC Biol., 8:83 (2010)

Walsh, C.T.; Nolan, E.M., "Morphing Peptide Backbones into Heterocycles" Proc. Natl. Acad. Sci. USA, 105: 5655-5656 (2008)

Tannenbaum, S.R. and White, F.M., "Regulation and Specificity of S-Nitrosylation and Denitrosylation" ACS Chem. Biol., 1: 615-618 (2006)

Tannenbaum, S.R. and Kim, J., "Controlled S-Nitrosation" Nat. Chem. Biol., 1: 126-127 (2005)

Patents

The Board of Trustees of the University of Illinois; Mitchell, D.A.; Molohon, K.J., “Antibiotics and Methods for Manufacturing the Same.” PCT/US2011/57333.

Photo of Douglas A. Mitchell