Wilfred A. van der Donk
Richard E. Heckert Endowed Chair in Chemistry
Howard Hughes Medical Investigator
Professor van der Donk received his B.S. from Leiden University, the Netherlands, in 1989 and his Ph.D. from Rice University in 1994. He went on to do postdoctoral work at the Massachusetts Institute of Technology, and joined the faculty at Illinois in 1997. In 2008, he was appointed as an investigator of the Howard Hughes Medical Institute. His research interests are in organic chemistry and chemical biology.
Our research program focuses on the discovery and design of new antibiotics and natural products. These projects combine synthetic organic and protein chemistry to address problems at the interface of chemistry and biology.
Antibiotics Numerous reports of multi-drug resistant bacterial strains have appeared in recent years, with several strains posing the threat of becoming immune against all commercially available antibiotics. It is evident that in order to prevent potential epidemic outbreaks of infectious diseases, a renewed focus on antibiotic research is highly desired, including the search for new drugs with alternative cellular targets, the investigation of the mechanisms of cytotoxicity and resistance, and the understanding of biosynthetic pathways. Unfortunately, at this time of critical need for new antimicrobial agents, the large pharmaceutical companies have almost entirely withdrawn from this area due to small projected profits. The van der Donk group focuses on the mode of action and mechanism of biosynthesis of two classes of antibiotics that have been underexplored but have great potential for human therapeutic use, lantibiotics and phosphonate antibiotics.
Cyclic peptides are attracting increased attention for their potential applications. They are metabolically more stable than linear peptides and are promising candidates for disruption of protein-protein interactions. Natural product cyclic peptides are generated by both non-ribosomal and ribosomal pathways. The molecules produced by the latter route have rapidly expanded in recent years as a consequence of the explosion in genomic sequence information. These pathways, in which a linear precursor peptide is generated ribosomally and subsequently post-translationally modified, provide many attractive opportunities for bioengineering. First, the amino acid sequence is genetically encoded, allowing site-directed mutagenesis approaches to access analogues. Second, the pathways towards these compounds usually involve a relatively small number of biosynthetic enzymes. In turn, such relatively short pathways are more amenable to bioengineering approaches. Third, the biosynthetic enzymes are often highly promiscuous. We have demonstrated that genome mining can uncover new cyclic peptides with novel structures and activities and we have shown that these pathways lend themselves well for engineering.
Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. With the Metcalf group in Microbioloyg, the Nair group in Biochemistry, and the Zhao group in Chemical and Biomolecular Engineering, our group has developed discovery methods for novel phosphonate natural products and has investigated the unprecedented chemistry that takes place during their biosyntheses.
In summary, we use genome mining strategies to discover new natural products, use microbiology and genomic tools to determine their mode of action, use chemical biology techniques to study their biosynthesis, and use synthetic chemistry to improve their activities and therapeutic properties.
Knerr, P.J.; van der Donk, W. A. * “Chemical Synthesis and Biological Activity of Analogues of the Lantibiotic Epilancin 15X” J. Am. Chem. Soc. 2012, 134, 7648-7651.
Garg, N.; Tang, W.; Goto, Y.; van der Donk, W.A.* “Lantibiotics from Geobacillus thermodenitrificans” Proc. Natl. Acad. Sci. U.S.A. 2012, Early View.
Oman, T.J.; Knerr, P.J.; Bindman, N.A.; Velásquez, J.E.; van der Donk, W.A.* “An Engineered Lantibiotic Synthetase That Does Not Require a Leader Peptide on Its Substrate” J. Am. Chem. Soc. 2012, 134, 6952-6955.
Oman, T.O.; Lupoli, T.J.; Wang, T-S. A.; Kahne, D.; Walker, S.*; van der Donk, W.A.* “Haloduracin a Binds the Peptidoglycan Precursor Lipid II with 2:1 Stoichiometry” J. Am. Chem. Soc. 2011, 133, 17544-17547.
Agarwal, V.; Borisova, S.A.; Metcalf, W.W.; van der Donk, W.A.*; Nair, S.K.* “Structural and Mechanistic Insights into C-P Bond Hydrolysis by Phosphonoacetate Hydrolase” Chem. Biol. 2011, 18, 1230-1240.
Wang, H.; van der Donk, W.A.* “Substrate selectivity of the S-glycosyltransferase from sublancin biosynthesis” J. Am. Chem. Soc. 2011, 133, 16394–16397.
Velásquez, J.E.; Zhang, X.; van der Donk, W.A.* “Biosynthesis of the Antimicrobial Peptide Epilancin 15X and its Unusual N-terminal Lactate Moiety” Chem. Biol. 2011, 18, 857-867.
Ökesli, A.; Cooper, L.E.; Fogle, E.J.; van der Donk, W.A.* “Nine Posttranslational Modifications During the Biosynthesis of Cinnamycin” J. Am. Chem. Soc. 2011, 133, 13753–13760.
Knerr, P.J.; Tzekou, A.; Ricklin, D.; Qu, H.; van der Donk, W.A.*; Lambris, J.D.* “Synthesis and Activity of Thioether-containing Analogues of the Complement Inhibitor Compstatin” ACS Chem. Biol. 2011, 6, 753-760.
Gut, I.M.; Blanke, S.R. *; van der Donk, W.A.* “Mechanism of Nisin Inhibition of Bacillus anthracis Spore Outgrowth” ACS Chem. Biol. 2011, 6, 744-752.
Whitteck, J.T.; Malova, P.; Peck, S.C.; Cicchillo, R.M.; Hammerschmidt, F.*; van der Donk, W.A.* “On the Stereochemistry of 2-Hydroxyethylphosphonate Dioxygenase” J. Am. Chem. Soc. 2011, 133, 4236-4239.
Goto, Y.; Ökesli, A.; van der Donk, W.A.* “Mechanistic studies of Ser/Thr dehydration catalyzed by a member of the LanLlanthioninesynthetase family” Biochemistry 2011, 50, 891-898.
Oman, T.J.; Boetcher, J.D.; Wang, H.; Okalibe, X.N.; van der Donk, W.A.* “Sublancin is not a Lantibiotic but an S-linked Glycopeptide” Nat. Chem. Biol. 2011, 2, 78-80.
Shi, Y.; Yang, X.; Garg, N.; van der Donk, W.A.* “Production of Lantipeptides in Escherichia coli” J. Am. Chem. Soc., 2011, 133, 2338-2341.
Bindman, N.; Merkx R.; Koehler, R.; Herrman, N.; van der Donk, W.A.* “Photochemical Cleavage of Leader Peptides” Chem. Comm.2010, 46, 8935-8937.
Kuemin, M.; van der Donk, W.A.* “Structure-activity relationships of the phosphonate antibiotic dehydrophos” Chem. Comm. 2010, 46, 7694-7696.
Lee, J.H; Bae, B.; Kuemin, M.; Circello, B.T. Metcalf, W.W.; Nair, S.K.; van der Donk W.A.* “Characterization and Structure of DhpI, a Phosphonate O-Methyltransferase Involved in Dehydrophos Biosynthesis” Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 17557-17562.
Clark, K.M.; Yu, Y.; Marshall, N.; Sieracki, N.; Nilges, M.; Blackburn, N.; van der Donk, W.A.*; Lu, Y.* “Transforming a Blue Copper into a Red Copper Protein: Engineering Cysteine and Homocysteine into the Axial Position of Azurin using Site-Directed Mutagenesis and Expressed Protein Ligation” J. Am. Chem. Soc. 2010 132, 10093-10101.
Li, B.; Sher, D.; Kelly, L.; Shi, Y.; Huang, K.; Knerr, P.J.; Joewono, I.; Rusch, D.; Chisholm, S.W.*; van der Donk. W.A.*, “Catalytic Promiscuity in the Biosynthesis of Cyclic Peptide Secondary Metabolites in Planktonic Marine Cyanobacteria” Proc. Natl. Acad. Sci. U.S.A. 2010, 107, 10430-10435.
Goto, Y.; Li, B.; Claesen, J.; Shi, Y.; Bibb, M.J.; van der Donk, W.A.* “Discovery of Unique Lantibiotic Synthetases Reveals Mechanistic and Evoluntionary Insights” PLoS Biol. 2010, 8, e1000339.
Borisova, S.A.; Circello B.T.; van der Donk, W.A.*; Metcalf, W.W.* “Biosynthesis of Rhizocticins, Antifungal PhosphonateOligopeptides Produced by Bacillus subtilis ATCC6633” Chem. Biol. 2010,1, 28-37.
Oman, T.; van der Donk, W.A.* “Follow the Leader: the Use of Leader Peptides to Guide Natural Product Biosynthesis” Nat. Chem. Biol.2010, 1, 9-18.
Whitteck, J.T.; Cicchillo, R.M.; van der Donk, W.A.* “Hydroperoxylation by Hydroxyethyl-phosphonateDioxygenase” J. Am. Chem. Soc. 2009, 131, 16225-16232.
Oman, T.; van der Donk, W.A.* “Insights into the Mode of Action of the Two-Component Lantibiotic Haloduracin” ACS Chem. Biol. 2009, 10, 865-874.
Levengood, M.R.; Knerr, P.J.; Oman, T.J.; van der Donk, W.A.* “In Vitro Mutasynthesis of Lantibiotic Analogs Containing Nonproteinogenic Amino Acids” J. Am. Chem. Soc. 2009, 131, 12024-12025.
Lee, M.V.; Ihnken, L.A.F.; You, Y.O.; McClerren, A.L.; van der Donk, W.A.*; Kelleher, N.L.* “Distributive and Directional Behavior of LantibioticSynthetases Revealed by High-Resolution Tandem Mass Spectrometry” J. Am. Chem. Soc. 2009, 131, 12258-12264.
Cicchillo, R.M.; Zhang, H.; Blodgett, J.A.V.; Whitteck, J.T.; Li, G.; Nair, S.K.*; van der Donk, W.A.*; Metcalf, W.W.* “An Unusual Carbon-Carbon Bond Cleavage Reaction During Phosphinothricin Biosynthesis” Nature 2009, 459, 871-874.
You, Y.O.; Levengood, M. R.; Furgerson Ihnken, L.A.; Knowlton, A.K., van der Donk, W.A.* “Lacticin 481 Synthetase as a General Ser/Thr Kinase” ACS Chem. Biol.2009, 4, 379-385.
Jacquot, C.; McGinley, C.M.; Plata, E.; van der Donk, W.A.* “Synthesis of 11-Thialinoleic Acid and 14-Thialinoleic Acid, Inhibitors of Soybean and Human Lipoxygenases” Org. Biomol. Chem. 2008, 6, 4242-4252.
Cooper, L.E.; McClerren, A.L; Chary, A.; van der Donk, W.A.* “Structure-Activity Relationship Studies of the Two-Component Lantibiotic Haloduracin” Chem. Biol. 2008, 15, 1025-1045.
Whitteck, J.T.; Ni, W.; Griffin, B.M.; Eliot, A.C.; Thomas, P.M.; Kelleher, N.M.; Metcalf, B.W.; van der Donk, W.A.* “Reassignment of the Structure of the Antibiotic A53868 Reveals an Unusual Amino Dehydrophosphonic Acid” Angew. Chem. Intl. Ed. Engl. 2007, 46, 9089-9092.
Levengood, M.R.; Patton, G.C.; van der Donk, W.A.* “The Leader Peptide is not Required for Post-translational Modification by Lacticin 481 Synthetase”J. Am. Chem. Soc. 2007, 129, 10314-10315.
Zhang, X.; Ni, W.; van der Donk, W.A.* “On the Regioselectivity of Thioether Formation by Lacticin 481 Synthetase” Org. Lett. 2007, 9, 3343-3346.
Blodgett, J.A.V.; Thomas, P.M.; Li, G.; Velasquez, J.E.; van der Donk, W.A.; Kelleher, N.L.; Metcalf, W.W.* “Unusual transformations in the biosynthesis of the antibiotic phosphinothricin tripeptide” Nat. Chem. Biol. 2007, 3, 480-485.
Li, B.; van der Donk, W.A.* “Identification of Essential catalytic Residues of the NisinCyclaseNisC” J. Biol. Chem. 2007, 282, 21169-21175.
Zhang, X.; van der Donk, W.A.* “On the Substrate Specificity of Dehydration by Lacticin 481 Synthetase” J. Am. Chem. Soc. 2007, 129, 2212-2213.
Levengood, M.; van der Donk, W.A.* “Dehydroalanine-containing peptides: preparation from Phenylselenocysteine and utility in convergent ligation strategies” Nat. Protocols 2007, 1, 3001-3010.
McClerren,A.L.; Cooper, L.E.; Quan, C.; Thomas, P.M.; Kelleher, N.L.; van der Donk, W.A.* “Discovery and in vitro Biosynthesis of Haloduracin, a New Two-component Lantibiotic” Proc. Natl. Acad. Sci. USA 2006, 103, 17243-17248.
Li, B.; Yu, J.-P. J.; Brunzelle, J. S.; Moll, G. N.; van der Donk, W. A.*; Nair, S. K.* “Structure and Mechanism of the LantibioticCyclase Involved in Nisin Biosynthesis” Science, 2006, 311, 1464-1467.
Xie, L.; Miller, L.; Chatterjee, C.; Averin, O.; Kelleher, N.L.;* van der Donk, W.A.* “Lacticin 481: in vitro reconstitution of lantibioticsynthetase activity” Science 2004, 303, 679-681.
- 2011 Fellow of the American Academy of Microbiology
- 2011 Fellow of the American Association for the Advancement of Science (AAAS)
- 2010 Jeremy Knowles Award, Royal Society of Chemistry
- 2010 Fellow of the Royal Society of Chemistry
- 2009 RSC Organic & Biomolecular Chemistry Lecture Award
- 2009 OBC Lecture Award
- 2008 Investigator of the Howard Hughes Medical Institute
- Tetrahedron Young Investigator Award in Bioorganic & Medicinal Chemistry Cope Scholar Award
- University Scholar, UIUC
- Pfizer Award
- Helen Corley Petit Award
- Burroughs-Wellcome New Investigator Award
- Beckman Young Investigator Award
- Research Corporation Innovation Award
- Alfred P. Sloan Fellowship
- Cottrell Scholar
- Camille Dreyfus Teacher-Scholar
“3 Open Minutes with Wilfred van der Donk” Progressive Dairyman May 14, 2012.
“New Antibiotic Could Make Food Safer and Cows Healthier” Illinois News Desk March 19, 2012.
“Two Illinois Professors Elected to American Academy of Microbiology” Illinois News Desk April 4, 2011.
“Rare Sugar Linkage Revealed” C&EN 2011, 89, 10.
“A Most Versatile Enzyme” C&EN Archive 2010, 88, 56.
“Biosynthesis: Lantipeptides from lyases” Nat Chem Biol highlight 2010, 6, 310.
“Enzyme Makes a Tough Cut” C&EN 2009, 87, 8.
“Amended Route to Odd Natural Product” C&EN 2007, 85, 928.
“Hot Article” Biochemistry (ACS Publications) 2007.
“Methyl mystery unraveled” Chemical Biology December 21, 2006 (UK).
“Antimicrobials: A ringing success” Nature Reviews Microbiol. 2006, 4, 322-323.
“Resisting the Resistence” ACS Chem. Biol. 2006, 1, 119.
“Getting Back to Nature” NIGMS Newsletter "Biomedical Beat" April 18, 2006.
“Scientists Discover Two-component Lantibiotic with Therapeutic Potential” ScienceDaily October 30, 2006.
“Cloning techniques produce FDA-approved antibiotic” Innovations Report November 28, 2006.
“Toward Novel Lantibiotics” C&EN 2004 82, 10.