harriet a. harlin Professor of Chemistry
Professor of Biophysics
Professor Eric Oldfield was educated in London, Bristol and Sheffield, then moved to the US as a European Molecular Biology Organization Fellow at Indiana University with Adam Allerhand and a Visiting Scientist at MIT with John Waugh.
In recent work, carried out in collaboration with the groups of J. Urbina, R. Docampo and S. Croft, we have branched out into yet another new area, molecular parasitology. We first found evidence for extremely large levels of inorganic di- and triphosphate in the protozoa which cause African sleeping sickness and malaria. This then led us to the idea that it might be possible to kill these and other related parasites by using stable diphosphate analog drugs to block specific metabolic pathways, and this indeed was found to be the case. The drugs used, called bisphosphonates, have been used to treat bone-resorption diseases for over 20 years, but their mode of action had been unknown. However, in recent work, we have shown that the most potent, nitrogen-containing bisphosphonates used in treating bone diseases are also potent drugs in killing parasites, and act to perturb protein prenylation and signaling by inhibiting the enzyme farnesyl pyrophosphate synthase. Using quantum chemistry and molecular modeling, we showed that the charged ammonium side-chains in the drugs act as carbocation transition state analogs, and bind into the active site of the enzyme, blocking its action. This gives a sound molecular basis for drug design, based on known protein structures and mechanisms of drug action, and is a topic of considerable current interest.
And finally, in our most recent work we have found that it is possible to apply the computational methods used in modern drug design and drug discovery to the immune system where we are employing QSAR (quantitative structure activity relationships) to probe innate immunity. In particular, we are interested in the development of drugs which activate γδ T cells, opening the way to new therapies for infectious diseases, cancer, and vaccine development.
E. Oldfield. Targeting Isoprenoid Biosynthesis for Drug Discovery: Bench to Bedside. Accts. Chem. Res. (2010)
W. Wang, J. Lia, K. Wang, C. Huang, Y. Zhang, E. Oldfield.Organometallic mechanism of action and inhibition of the 4Fe-4S isoprenoid biosynthesis protein GcpE (IspG). PNAS, 107, 11189-11193, (2010).
A.P. Singh, Y. Zhang, J.H. No, R.Docampo, V.Nussenzweig, E. Oldfield. Lipophilic Bisphosphonates Are Potent Inhibitors of Plasmodium Liver-Stage Growth Antimicrob. Agents & Chemoth., 54, 2987-2993, (2010).
K. Wang, Y. Zhang, J.H. No, R. Docampo, V. Nussenzweig, E. Oldfield. Inhibition of the Fe4S4-Cluster-Containing Protein IspH (LytB): Electron Paramagnetic Resonance, Metallacycles, and Mechanisms. JACS, 132,6719-6727 (2010).
W. Wang, K. Wang, Y.L. Liu, J.H. No, J. Li, M.J. Nilges, E. Oldfield. Bioorganometallic mechanism of action, and inhibition, of IspH. PNAS. 107, 4522-4527, (2010).
S. Mukherjee, C. Huang, F. Guerra, K. Wang, E. Oldfield. Thermodynamics of Bisphosphonates Binding to Human Bone: A Two-Site Model. JACS, 131, 8375-76, (2009)
C.H. Huang, S.B. Gabelli, E. Oldfield, L.M. Amzel. Bind of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl disphosphate synthase homodimer. Proteins, 78, 888-899, (2010).
R. Cao, Y. Zhang, F.M. Mann, C. Huang, D. Mukkamala, M.P. Hudock, M.E. Mead, S. Prisic, K. Wang, F.Y. Lin, T.K. Chang, R.J. Peters, E. Oldfield. Diterpene cyclases and the nature of the isoprene fold. Proteins, 78, 2417-2432, (2010).
Y. Zhang, R. Cao, F. Yin, F.Y. Lin, H. Wang, K. Krysiak, D. Mukkamala, K. Houlihan, J. Li, C.T. Morita, E. Oldfield.Liphilic pyridinium bisphosphonates: Potent gamma-delta T cell stimulators.Angew. Chem. Int. Ed., 49, 1136-1138, (2010).
Y. Song, C.I. Liu, F.Y. Lin, J.H. No, M. Hensler, Y.L. Liu, W.Y. Jeng, J. Low, G.Y. Liu, V. Nizet, A.H.J. Wang, E. Oldfield. Inhibition of Staphyloxanthin Virulence Factor Biosynthesis in Staphylococcus aureus: In Vitro, in Vivo, and Crystallographic Results.J. Med. Chem., 52, 3869-3880, (2009).
Y.Zhang, R. Cao, F. Yin, M.P. Hudock, R.T. Guo, K. Krysiak, S. Mukherjee, Y.G. Gao, H. Robinson, Y. Song, J.H. No, K. Bergan, A. Leon, L. Cass, A. Goddard, T.K. Chang, F.Y. Lin, E.V. Beek, S. Papapoulos, A.H. Wang, T. Kubo, M. Ochi, D. Mukkamala, E. Oldfield. Lipophillic Bisphosphonates as Dual Farnesyl/Geranylgeranyl Diphosphate Synthase Inhibitors: An X-ray and NMR Investigation. JACS, 131, 5153-5162, (2009).
B. J. Wylie, C. D. Schwieters, E. Oldfield, C. M. Rienstra. Protein Structure Refinement Using 13C# Chemical Shift Tensors. JACS, online
I. Rekittke, J. Wiesner, R. Rohrich, U. Demmer, E. Warkentin, W. Xu, K. Troschke, M. Hintz, J. H. No, E. C. Duin, E. Oldfield, H. Jomaa, U. Ermler. Structure of (E)-4-Hydroxy-3-methyl-but-2-enyl Diphosphate Reductase, the Terminal Enzyme of the Non-Mevalonate Pathway.
D. Mukkamala, J. H. No, L. M. Cass, T. K. Chang, E. Oldfield. Bisphosphonate Inhibition of a Plasmodium Farnesyl Diphosphate Synthase and a General Method for Predicting Cell-Based Activity from Enzyme Data. J. Med. Chem., 51, 7827-7833, (2008).
G. Sarikonda, H. Wang, K. J. Puan, X. h. Liu, H. K. Lee, Y. Song, M. D. Distefano, E. Oldfield, G. D. Prestwich, C. T. Morita. Photoaffinity Antigens for Human gammadelta T Cells. J. Immunol., 171, 7738-7750, (2008).
C. K-M Chen, M.P. Hudock, Y. Zhang, R.T. Guo, R. Cao, J.H. No, P.H. Liang, T.P. Ko, T.H. Chang, S.C. Chang, Y. Song, J. Axelson, A. Kumar, A.H. Wang, E. Oldfield. Inhibition of geranylgeranyl diphosphate synthase by bisphosphonates: a crystallographic and computational investigation. J Med Chem., 51, 5594-607, (2008).
Y. Song,J.M. Chan, Z. Tovian, A. Secrest, E. Nagy, K. Krysiak, K. Bergan, M.A. Parniak, E. Oldfield. Bisphosphonate inhibitors of ATP-mediated HIV-1 reverse transcriptase catalyzed excision of chain-terminating 3'-azido, 3'-deoxythymidine: A QSAR investigation. Bioorg Med Chem., 16, 8959-8967, (2008).
P.K. Babu, J.-H. Chung, E. Oldfield, A. Wieckowski CO surface diffusion on platinum fuel cell catalysts by electrochemical NMR Elecrochimica Acta, 53, 6672-6679, (2008).
Y. Zhang, E. Oldfield. NMR Hyperfine Shifts in Blue Copper Proteins: A Quantum Chemical Investigation. J. Am. Chem. Soc., 130, 3814-3823, (2008).
Cao R, Chen CK, Guo RT, Wang AH, Oldfield E. Structures of a potent phenylalkyl bisphosphonate inhibitor bound to farnesyl and geranylgeranyl diphosphate synthases. Proteins, 73, 431-9, (2008).
C. Liu, G. Y. Liu, Y. Song, F. Yin, M. E. Hensler, W.-Y. Jeng, V. Nizet, A. H.-J. Wang, E. Oldfield. A Cholesterol Biosynthesis Inhibitor Blocks Staphylococcus aureus Virulence Science, 319, 1391-1394, (2008).
S. Mukherjee, Y. Song, and E. Oldfield. NMR Investigations of the Static and Dynamic Structures of Bisphosphonates on Human Bone: a Molecular Model J. Am. Chem. Soc., 130, 1264-1273, (2008).
P. K. Babu, A. Lewera, J.-H. Chung, R. Hunger, W. Jaegermann, N. Alonso-Vante, A. Wieckowski, E. Oldfield. Selenium Becomes Metallic on Ru/Se Fuel Cell Catalysts: An EC-NMR and XPS Investigation J. Am. Chem. Soc., 129, 15140-15141, (2007).
Y. Zhang, M.P. Hudock, K. Krysiak, R. Cao, K. Bergan, F. Yin, A. Leon and E. Oldfield. Activity of Sulfonium Bisphosphonates on Tumor Cell Lines J. Med. Chem., 50, 6067-6079, (2007).
R.-T. Guo, R. Cao, T.-H. Chang, T.-P. Ko, W.-Y. Jeng, C. K.-M. Chen, M. P. Hudock, Y. Zhang, Y. Song, P.-H. Liang, E. Oldfield and A. H.-J. Wang. Bisphosphonates target multiple sites in both cis- and trans- prenyltransferases: a crystallographic investigation Proc. Natl. Acad. Sci. USA, 104, 10022-10027 (2007).
D. Mukkamala, Y. Zhang and E. Oldfield. A Solid State 13C NMR, Crystallographic and Quantum Chemical Investigation of Phenylalanine and Tyrosine Residues in Dipeptides and Proteins J. Am. Chem. Soc., 129, 7385-7392 (2007).
H. Yano, J. Inukai, H. Uchida, M. Watanabe, P.K. Babu, T. Kobayashi, J.H. Chung, E. Oldfield, A. Wieckowski. Particle-size effect in a platinum nanoscale catalyst on the oxygen reduction reaction: An electrochemical and 195Pt EC-NMR study. Phys. Chem. Chem. Phys., 8, 4932-4939 (2006).
Takeshi Kobayashi, Panakkattu K Babu, Jong Ho Chung, Eric Oldfield and Andrzej Wieckowski. Coverage dependence of CO surface diffusion on Pt nanoparticles: an EC-NMR investigation. J. Phys. Chem. C, 111, 7078-7083, (2007)
C.E. Sanz-Rodriguez, J.L. Conception, S. Pekerar, E. Oldfield and J.A. Urbina. Bisphosphonates as allosteric inhibitors of Trypanosoma cruzi hexokinase: Kinetic and metabolic studies J. Biol. Chem., 282, 12377-87 (2007).
- Thomas Malkin Prize (1968)
- William Edward Garner Prize (1969)
- European Molecular Biology Organization Fellowship (1972-1974)
- The Meldola Medal and Prize of The Royal Institute of Chemistry (1977)
- Alfred P. Sloan Research Fellowship (1978-1980) U.S. Public Health Service Research Career Development Award (1979-1984)
- American Heart Association Louis N. Katz Basic Science Research Prize (1980)
- Fellow of the Royal Society of Chemistry (1981)
- Fellow, American Institute of Chemists (1982)
- The Colworth Medal of the Biochemical Society (1983)
- American Chemical Society Award in Pure Chemistry (1984)
- Fellow, American Physical Society (1993)
- Richard G. and Carole J. Cline University Senior Scholar (1995)
- Royal Society of Chemistry Award in Spectroscopy (1995)
- Associate, Center for Advanced Study (2000-2001)
- Alumni Research Scholar Professor of Chemistry (2002-2007)
- Campus Award for Excellence in Guiding Undergraduate Research (2006)
- Fellow of the American Association for the Advancement of Science (2008)
- Soft Matter and Biophysical Award from the Royal Society of Chemistry (2009)
- Biophysical Society Avanti Award in Lipids (2011)
"New antibiotics on the horizon?" Read the article from Nature Reviews Drug Discovery.
"New Drug Effective Against MRSA in Mice" Read the article from NIH Research Matters here.
“Chemists document workings of key staph enzyme– and how to block it” Read the article from the UI News Bureau.
“Enzyme’s Dual Nature Revealed” Read the article and Chemical and Engineering News.
“Diterpene cyclases and the nature of the isoprene fold” Read the article here.
“Heads and tails” Read the article at Nature Chemical Biology.
“Mechanism of action and inhibition of dehydrosqualene synthase” Read the article here.
"Enzyme's Metal Cluster is Nailed" Read the article at Chemical and Engineering News
"Targeting Isoprenoid Biosynthesis for Drug Discovery: Bench to Bedside" Read the article at Accounts of Chemical Research
"Inhibition of the Fe(4)S(4)-Cluster-Containing Protein IspH (LytB): Electron Paramagnetic Resonance, Metallacycles, and Mechanisms" Read the article from Faculty of 1000
Oldfield Group Member Jordan Axelson receives ACS Scholarship Award Read the article from Chemical and Engineering News
"Isoprenoid Reducatase Could Become Target for Novel Antimicrobials" Read the article at Microbe Magazine
"Team develops new weapon to fight disease-causing bacteria, malaria" Read the Illinois News Bureau article.
"Better Bisphosphonates" Read the article from Chemistry and Engineering News
Naked Scientists Podcast About Staph Inhibitor See the podcast on the Oldfield Group Site.
"Antimicrobials: Cholesterol-biosynthesis inhibitor stops infection" by Sarah Crunkhorn. Read the Nature Reviews Drug Discovery article
"Lowering Cholesterol Good for Us, Bad for Bacteria": Read the Naked Scientists article about Dr. Oldfield's research.
"Novel Approach Strips Staph of Virulence": Read the National Institute of General Medical Sciences article about Dr. Oldfield's research.