Craig A. Townsend is the Alsoph H. Corwin Professor of Chemistry and holds joint appointments in the Departments of Biology and Biophysics and affiliations and collaborations in the Johns Hopkins School of Medicine.

His research interests are in the chemistry of natural products and the interface of organic chemistry, biology and medicine: stereochemical and mechanistic studies of principal biosynthetic enzymes and their engineering/directed evolution for synthetic ends; chemoenzymatic synthesis; enzymology and molecular biology of polyketides and beta-lactam antibiotics; drug design and clinical applications against antibiotic-resistant bacteria, tuberculosis and malaria; structural studies of biosynthetic enzymes.

Professor Townsend has been a Research Fellow of the A. P. Sloan Foundation, a Camille and Henry Dreyfus Teacher-Scholar; he has received the Maryland Chemist of the Year award, an Arthur C. Cope Scholar Award and the A. I. Scott Medal from the American Chemical Society, and the Stuart Pharmaceuticals (now Astra Zeneca) Award in Chemistry. He has served on NIH Study Sections as a regular and ad hoc member, and is on the Editorial Boards for Cell Chemical Biology and Helvetica Chimica Acta.

He was co-chairman and cofounder of the Bioorganic Chemistry Gordon Conference and has served as an at-large member on the governing Council of the Gordon Research Conferences. He has advised the Office of Technology Assessment, the American Chemical Society and the National Institutes of Health, and he has served as a consultant for large and small pharma.

Research in the Townsend Lab is driven by fundamental interests in natural products: their chemistry, biosynthesis, combinatorial and engineered biosynthesis, enzyme mechanism, drug design and synthesis to combat infectious diseases, cancer and obesity. The diversity of our research is reflected in the students who comprise the lab, coming from programs in Chemistry, Chemical Biology, Pharmacology, Biology, and Molecular Biophysics. Our lab has major strengths in the techniques of organic chemistry, molecular biology, mechanistic enzymology, microbiology, and bioinformatics.

Iterative polyketide natural products

Polyketide natural products encompass a structurally and functionally diverse family of molecules. Our long-standing interest in the biosynthesis of aflatoxin, a potent environmental carcinogen, led to groundbreaking results on the function of the polyketide synthases (PKS) responsible for the ‘programmed’ synthesis and complex regioselective cyclization of linear precursors. Current efforts are focused on understanding the PKS enzymes involved in the biosynthesis of calicheamicin, cercosporin, aromatic polyketides and mycotoxins.

Papers of Significant Interest

• Crawford, J. M.; Townsend, C. A. “New insights into the formation of fungal aromatic polyketides,” Nature Rev. Microbiol.2010, 12, 879-889.
• Crawford, J. M.; Korman, T. P.; Labonte, J. W.; Vagstad, A. L.; Hill, E. A.; Kamari-Bidkorpeh, O.; Tsai, S.-C.; Townsend, C. A. “Structural Basis for Biosynthetic Programming of Fungal Aromatic Polyketide Cyclization,” Nature 2009, 461, 1139-1143.
• Udwary, D. W.; Merski, M.; Townsend, C. A. “A Method for Prediction of the Locations of Linker Regions Within Large Multifunctional Proteins, and Application to a Type I Polyketide Synthase,” J. Mol. Biol. 2002, 323, 585-598.
• Minto, R. E.; Townsend, C. A. “Enzymology and Molecular Biology of Aflatoxin Biosynthesis,” Chem. Rev. 1997, 97, 2537-2555.

Biosynthesis of β-lactam antibiotics

Penicillins and cephalosporins are therapeutic mainstays in human medicine and whose industrial production has benefited from classic research into their biosynthesis. However, other clinically effective β-lactam drugs are related to natural products whose biosynthesis is less well understood. We have elucidated the biosynthetic pathway of the simple carbapenem and determined the function of key enzymes in the production of clavulanic acid, thienamycin, and nocardicin. We continue to study these natural products using a combination of synthetic chemistry, biochemistry, microbiology, and bioinformatics.

Papers of Significant Interest

• Bodner, M. J.; Phelan, R. M.; Townsend, C. A. “A Catalytic Asymmetric Route to Carbapenems,” Org. Lett. 2009, 11, 3606-3609.
• Townsend, C. A. “New Reactions in Clavulanic Acid Biosynthesis,” Curr. Opin. Chem. Biol. 2002, 6, 583-589.
• Li, R.; Stapon, A.; Blanchfield, J. T.; Townsend, C. A. “Three Unusual Reactions Mediate Carbapenem and Carbapenam Biosynthesis,” J. Am. Chem. Soc. 2000, 122, 9296-9297.
• Bachmann, B. O.; Li, R.; Townsend, C. A. “β-Lactam Synthetase: A New Biosynthetic Enzyme,” Proc. Natl. Acad. Sci. 1998, 95, 9082-9086.

Metabolic and enzyme engineering

The natural products we study are often related to chemicals that are of pharmaceutical or industrial interest. We have probed how biosynthetic enzymes involved in both polyketide and β-lactam biosynthesis may be altered to produce new compounds and how metabolic engineering may be used to make strains with desirable chemical properties.

Papers of Significant Interest

• Sokha, T.; Heins, R. A.; Phelan, R. M.; Greisler, J. M.; Townsend, C. A.; Ostermeier, M. “An Externally Tunable Bacterial Band-Pass Filter,” Proc. Natl. Acad. Sci. 2009, 106, 10135-10140
• Li, R.; Townsend, C. A. “Rational Strain Improvement for Enhanced Clavulanic Acid Production by Genetic Engineering of the Glycolytic Pathway in Streptomyces clavuligerus,” Metabol. Eng. 2006, 8, 240-252.Muller, U.; van Assema, F.; Gunsior, M.; Orf, S.; Kremer, S.; Schipper, D.; Wagemans, A.; Townsend, C; Sonke, T.; Bovenberg, R.; Wubbolts, M. “Metabolic Engineering of the E. coli l-Phenylalanine pathway for the production of d-Phenylglycine (d-Phg),” Metabol. Eng. 2006, 8, 196-208.

Mechanistic Enzymology

Biosynthetic enzymes often perform chemically difficult and mechanistically interesting reactions. Our discovery and study of β-lactam synthetases has led to a thorough understanding of their chemical mechanism and has shown how protein dynamics affect catalysis. We continue to investigate complex molecular phenomena catalyzed by biosynthetic enzymes such as regiospecific polyketide cyclization , protein autoproteolysis, and remarkably diverse chemical reactions coupled to thioesterase activity.

Papers of Significant Interest

• Buller, A.R.; Townsend, C. A. “Intrinsic Evolutionary Constraints on Protease Structure, Enzyme Acylation, and the Identity of the Catalytic Triad,” Proc. Natl. Acad. Sci. 2013, 110(8), E653-661.
• Crawford, J. M.; Korman, T. P.; Labonte, J. W.; Vagstad, A. L.; Hill, E. A.; Kamari-Bidkorpeh, O.; Tsai, S.-C.; Townsend, C. A. “Structural Basis for Biosynthetic Programming of Fungal Aromatic Polyketide Cyclization,” Nature 2009, 461, 1139-1143.
• Raber, M. L.; Arnett, S. O.; Townsend, C. A. “A Conserved Tyrosyl-Glutamyl Catalytic Dyad in Evolutionarily Linked Enzymes: Carbapenam Synthetase and β-Lactam Synthetase,” Biochemistry 2009, 48, 4959-4971.
• Miller, M. T.; Bachmann, B. O.; Townsend, C. A.; Rosenzweig, A. C. “The Catalytic Cycle of β-Lactam Synthetase Observed by x-Ray Crystallographic Snapshots,” Proc. Natl. Acad. Sci. 2002, 99, 14752-14757.
• Challis, G. L.; Ravel, J.; Townsend, C. A. “Predictive, Structure-Based Model of Amino Acid Recognition by Nonribosomal Peptide Synthetase Adenylation Domains,” Chemistry & Biology 2000, 7, 211-224.

Fatty Acid Synthase Inhibition

An extensive web of collaborative research has been developed over several years with scientists at the Johns Hopkins School of Medicine. The unifying theme of this effort has been the selective modulation (inhibition and allosteric stimulation) of enzymes involved in fatty acid metabolism as a therapeutic approach to the treatment of a variety of human cancers, tuberculosis, and a potential breakthrough therapy for obesity. Members of the lab are engaged in mechanism- and structure-based drug design and synthesis and perform SAR studies on key enzymes with the goal to produce more potent and selective inhibitors.

Papers of Significant Interest

• Aja, S.; Landree, L. E.; Kleman, A. M.; Medghalchi, S. M.; Vadlamudi, A.; McFadden, J. M.; Aplasca, A.; Hyun, J.; Plummer, E.; Daniels, K.; Kemm, M.; Townsend, C. A.; Thupari, J. N.; Kuhajda, F. P.; Moran, T. H.; Ronnett, G. V. “Pharmacological Stimulation of Brain Carnitine Palmitoyl-Transferase-1 Decreases Food Intake and Body Weight,” Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008, 294, R352-R361.
• McFadden, J. M.; Medghalchi, S. M.; Thupari, J. N.; Pinn, M, L.; Vadlamudi, A.; Miller, K. I.; Kuhajda, F. P.; Townsend, C. A. “Application of a Flexible Synthesis of (5R)-Thiolactomycin to Develop New Inhibitors of Type I Fatty Acid Synthase,” J. Med. Chem. 2005, 48, 946-961.
• Loftus, T. M.; Jaworsky D. E.; Frehywot, G. L.; Townsend, C. A.; Ronnett, G. V.; Lane, M. D.; Kuhajda, F. P. “Reduced Food Intake and Body Weight in Mice Treated with Fatty Acid Synthase Inhibitors,” Science 2000, 288, 2379-2381.
• Kuhajda, F. P.; Pizer, E. S.; Li J. N.; Mani, N. S.; Frehywot, G. L.; Townsend, C. A. “Synthesis and Anti-tumor Activity of an Inhibitor of Fatty Acid Synthase,” Proc. Natl. Acad. Sci. 2000, 97, 3450-3454.

A full list of publications is available on Google Scholar.

Selected recent publications

Doctoral Students

• A. Scott Neese, Ph.D. ’80
• Alan B. Theis, Ph.D. ’81
• Alethia M. Brown, Ph.D. ’81
• Meng-fei Ho, Ph.D. ’83
• Ellen B. Barrabee, Ph.D. ’83
• Siegfried B. Christensen, Ph.D. ’84
• Loan T. Nguyen, M.D. Ph.D. ’84
• Steven G. Davis, Ph.D. ’85
• Gino M. Salituro, Ph.D. ’86
• Shi-Shan Mao, Ph.D. ’87
• Susan W. Brobst, Ph.D. ’88
• Brenda A. Wilson, Ph.D. ’88
• Todd L. Graybill, Ph.D. ’90
• Walter J. Krol, Ph.D. ’91
• Dirk Reuyl, Ph.D. ’92
• Sean M. McGuire, Ph.D. ’92
• Anne McE. Reeve, Ph.D. ’92
• Margaret D.-T. Chang, Ph.D. ’93
• Laura A. Egan Pontzer, Ph.D. ’96
• Eduard G. Casillas, Ph.D. ’96
• Robert W. Busby, Ph.D. ’96
• Jeffrey C. Silva, Ph.D. ’96
• Tung-Kung Wu, Ph.D. ’96
• Coran M. H. Watanabe, Ph.D. ’98
• Linda K. Neely Casillas, Ph.D. ’99
• Steven D. Breazeale, Ph.D. ’99
• Nusrat Khaleeli, Ph.D. ’00
• Gojeb L. Frehywot, Ph.D. ’00
• Minwan Wu, Ph.D. ’00
• Brian O. Bachmann, Ph.D. ’00
• Mary F. (Tofani) Kawa, M.A. ’02
• Katherine I. (Miller) Needleman, M.A. ’02
• Kevin M. Henry, Ph.D. ’02
• Daniel W. Udwary, Ph.D. ’03
• Michele Gunsior, Ph.D. ’03
• Wendy L. Kelly, R.Ph. Ph.D. ’03
• Anthony Stapon, Ph.D. ’03
• Minerva A. Hughes, Ph. D. ’06
• Kristin A. LeChevet, M.A. ’06
• Matthew T. Merski, Ph.D. ’07
• Jason M. Crawford, Ph.D. ’07
• Samantha O. Arnett, Ph.D. ’08
• Michael F. Freeman, Ph.D. ’08
• Mary L. Raber, Ph.D. ’09
• Micah J. Bodner, Ph.D. ’10
• Edward A. Wydysh, Ph.D. ’10
• Kristos A. Moshos, Ph.D. ’11
• Ryan M. Phelan, Ph.D. ’11
• Jason W. Labonte, Ph.D. ’11
• Anna L. Vagstad, Ph.D. ’12
• Katherine Belecki, Ph.D. ’13
• Andrew Buller, Ph.D. ’13
• Nicole Gaudelli, Ph.D. ’13
• Victor K. Outlaw, Ph.D. ’15
• Daniel R. Marous, Ph.D. ’15
• Adam G. Newman, Ph.D. ’15
• Evan P. Lloyd, Ph.D. ’17

Postdoctoral Researchers

• Alan B. Theis, Ph.D. ’81
• Alethia M. Brown, Ph.D. ’81
• Charles P. Lewis III, ’78-’80
• Michael J. DiNovi, ’82-’85
• Paul R. O. Whittamore, ’84-’86
• Kathleen A. Plavcan, ’85-’86
• Yasuo Isomura, ’85-’86
• Shanta Bantia, ’85-’86
• Kollol Pal, ’87-’89
• Scott P. Salowe, ’87-’90
• E. Neil G. Marsh, ’88-’90
• Amit Basak, ’87-’91
• James J. DeVoss, ’88-’91
• Clifton E. Barry III, ’89-’91
• Katherine D. Cramer, ’90-’92
• Koren A. Holland, ’90-’92
• Douglas B. McIlwaine, ’90-’93
• Moneesh Chatterjee, ’91-’95
• Chun-Gyu Kim, ’94-’95
• Paul J. Smith, ’93-’95
• James W. Janc, ’91-’95
• Robert J. Duff, ’93-’96
• Todd A. Houston, ’93-’96
• Janos Pitlik, ’93-’97
• Robert E. Minto, ’94-’97
• Neelakhanda S. Mani, ’93-’97
• Joanne T. Blanchfield, ’96-’98
• Doris Stoermer, ’96-’98
• Gregory L. Challis, ’98-’00
• Paul B. Jones, ’98-’00
• Timothy S. Hitchman, ’98-’00
• Eric W. Schmidt, ’99-’01
• Jacques Ravel, ’99-’02
• Fumitaka Kudo, ’00-’02
• Jason D. Galpin, ’00-’03
• Jill M. McFadden, ’00-’03
• Barbara Gerratana, ’01-’04
• David M. Bartley, ’04-’06
• Tsion Bililign, ’04-’06
• Jonathan R. Scheerer
• Martina Adams
• Jesse Li, ’11-’13
• Courtney Hastings, ’11-’14

To undertake the interdisciplinary research we seek to accomplish requires skilled and committed scientists operating individually and in small teams. Applications for postdoctoral study are encouraged from disciplines ranging from natural product synthesis and biosynthesis to molecular biology, protein structure and bioinformatics.

Please email Professor Townsend  and include in your cover letter your rationale for study in the Townsend laboratory as well as 1) an up-to-date C. V. and list of publications, 2) summary of research accomplishments and future professional plans, and 3) names and contact information for 2-3 knowledgeable references.