Chemistry at Illinois University of Illinois at Urbana-Champaign

Douglas A. Mitchell

Associate 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.

To view the Mitchell Lab twitter page, see:
https://twitter.com/theDAMlab

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.

For a more detailed research description see:
http://www.scs.illinois.edu/mitchell/research.html

Publications

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

Deane, C.D.; Burkhart, B.J.; Blair, P.M.; Tietz, J.I.; Lin, A.; Mitchell, D.A. "In vitro biosynthesis and substrate tolerance of the plantazolicin family of natural products." ACS Chem. Biol., 2016, 11: 2232−2243 (2016). doi:10.1021/acschembio.6b00369

Molloy, E.M.; Tietz, J.I.; Blair, P.M.; Mitchell, D.A. "Biological characterization of the hygrobafilomycin antibiotic JBIR-100 and bioinformatic insights into the hygrolide family of natural products." Bioorg. Med. Chem., In Press, Accepted Manuscript (2016). doi:10.1016/j.bmc.2016.05.021

Molohon, K.; Blair, P.; Park, S.; Doroghazi, J.R.; Maxson, T.; Hershfield, J.; Flatt, K.; Schroeder, N.; Ha, T.; Mitchell, D.A. "Plantazolicin is an ultra-narrow spectrum antibiotic that targets the Bacillus anthracis membrane." ACS Infect. Dis., 2:207-220 (2016). doi:10.1021/acsinfecdis.5b00115

Hudson, G.A.; Zhang, Z.; Tietz, J.I.; Mitchell, D.A.; van der Donk, W.A. "In vitro biosynthesis of the core scaffold of the thiopeptide thiomuracin." J. Am. Chem. Soc., 137:16012-16015 (2015). doi:10.1021/jacs.5b10194

Burkhart, B.J.; Hudson, G.A.; Dunbar, K.L.; Mitchell, D.A. "A prevalent peptide-binding domain guides ribosomal natural product biosynthesis" Nat. Chem. Biol., 11:564-570 (2015). doi:10.1038/nchembio.1856

Dunbar, K.L.; Tietz, J.I.; Cox, C.L.; Burkhart, B.J.; Mitchell, D.A. "Identification of an auxiliary leader peptide-binding protein required for azoline formation in ribosomal natural products" J. Am. Chem. Soc., 137:7672-7677 (2015). doi:10.1021/jacs.5b04682

Maxson, T.; Deane, C.D.; Molloy, E.M.; Cox, C.L.; Markley, A.L.; Lee, S.W.; Mitchell, D.A. "HIV protease inhibitors block streptolysin S production" ACS Chem. Biol., 10:1217–1226 (2015). doi:10.1021/cb500843r

Metelev, M.; Tietz, J.I.; Melby, J.O.; Blair, P.M.; Zhu, L.; Livnat, I.; Severinov, K.; Mitchell, D.A. "Structure, bioactivity, and resistance mechanism of streptomonomicin, an unusual lasso peptide from an understudied halophilic actinomycete" Chem. Biol., 22:241-250 (2015). doi:10.1016/j.chembiol.2014.11.017

Dunbar, K.L.; Chekan, J.R.; Cox, C.L.; Burkhart, B.J.; Nair, S.K.; Mitchell, D.A. "Discovery of a new ATP-binding motif involved in peptidic azoline biosynthesis" Nat. Chem. Biol., 10:823-829 (2014). doi:10.1038/nchembio.1608

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., 9:2014-2022 (2014). doi:10.1021/cb500324n

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

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

Dunbar, K.L.; Melby, J.O.; Mitchell, D.A. "YcaO domains use ATP to activate amide backbones during peptide cyclodehydrations." Nat. Chem. Biol., 8:569-575 (2012). doi:10.1038/nchembio.944

Awards

  • 2015 National Fresenius Award, Phi Lambda Upsilon (National Chemistry Honor Society)
  • 2015 Camille Dreyfus Teacher-Scholar Award
  • 2015-2016 Helen Corley Petit Scholar (UIUC College of Liberal Arts and Sciences)
  • 2015 Pfizer Award in Enzyme Chemistry (ACS Division of Biological Chemistry)
  • 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

ACS Press Pac - February 25, 2015: Could an HIV drug beat strep throat, flesh-eating bacteria?

Carl R. Woese Institute for Genomic Biology, July - 2014: Innovative Technique May Transform the Hunt for New Antibiotics and Cancer Therapies.

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

ACS Chemical Biology podcast on the discovery of a novel narrow-spectrum antibiotic, December, 2011.

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

Carl R. Woese Institute for Genomic Biology, September, 2009: Removing Bacteria from Between Rock and Hard Place: A Different Approach to Fighting Harmful Bacteria.

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