Alsoph H. Corwin Professor
Craig A. Townsend is the Alsoph H. Corwin Professor of Chemistry and holds joint appointments in the Departments of Biology and Biophysics. He received his B.A. with Honors in chemistry from Williams College and his Ph.D. in organic chemistry from Yale University, where he was an NIH Predoctoral Fellow and won the Richard L. Wolfgang Prize. He was then an International Exchange Postdoctoral Fellow of the Swiss National Science Foundation at the ETH in Zurich, and joined the faculty at Johns Hopkins in 1976. 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. 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 Chemistry & Biology and Bioorganic Chemistry. 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.
The research problems in my group range from the heart of organic chemistry to the enzymology and molecular biology of secondary metabolism, mechanisms of drug action and rational drug design. Some specific examples are briefly summarized below.
Every year a portion of the U.S. corn crop is infected with aflatoxins, a family of potent mycotoxins produced by certain strains of the fungus Aspergillus. In our investigations of this and other fungal toxins great strides have been taken toward making available the key biosynthetic enzymes for more detailed study. Prominent among these are non-reducing Type I iterative polyketide synthases (NR-PKS), a group of polyfunctional proteins of great interest for their synthetic power and biotechnological potential. In the last few years our lab has played a major role in mechanistic and structural understanding of this family of proteins. Two previously unrecognized catalytic domains were identified and dissection and reconstitution ("deconstruction") experiments have allowed the coordinated roles of all six catalytic domains to be deduced. In conjunction with continuing structural studies, we have demonstrated in domain combinatorial experiments the ability to prepare “un-natural” products and deduced the “rules” of iterative synthesis that make predictable synthesis possible.
The mechanism of ß-lactam formation is central to the question of how penicillin and related antibiotics are formed. We have cloned the gene clusters that encode the enzymes of these biosynthetic pathways, which have opened the way for detailed investigations of their catalytic properties and structures. Of particular interest are the proteins such as ß-lactam synthetase, active in clavulanic acid formation yet entirely distinct from penicillin biosynthesis. Related proteins have been found to be active in carbapenem biosynthesis. X-ray structures and detailed mechanistic enzymology of both enzymes have opened the way to protein engineering and directed evolution experiments to capture the synthetic power and chiral selection of these enzymes to accept alternate substrates and produce other medicinally-useful products. Important progress has been made recently in applications to clinically important carbapenems. Separately we have isolated a pair of non-ribosomal polypeptide synthetases (NRPS) from the nocardicin A producer. A new mechanism of b-lactam formation has been discovered and yet another previously unappreciated NRPS mode of catalysis appears to be acting in monobactam biosynthesis.
In addition, collaborative programs are underway with groups in the Schools of Medicine and Public Health in mycobacterial infections as, for example, tuberculosis, and separately malaria. The former problem is centered on the discovery relatively recently of a previously unrecognized mechanism of bacterial cell wall cross-linking analogous to the step inhibited by penicillin and other b-lactam antibiotics but carried out by a family of evolutionarily and structurally distinct enzymes. This multi-group project involves in my laboratory structure-based drug design driven by X-ray structures of these enzymes with a select few inhibitors bound. The malaria project involves the isolation, purification and structural characterization of anti-malarial natural products from the microbiome of a non-transmitting mosquito. This project has the potential to lead to new field procedures to combat mosquito-borne disease transmission and/or direct human therapy.
FALL 2014 and 2015
Introductory Organic Chemistry 030.205.02
SPRING 2014 and 2015
Bioorganic & Natural Products Chemistry 030.632
Displaying the 20 most recent publications. View the Google Scholar Profile for complete publications list.
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R de Jonge, MK Ebert, CR Huitt-Roehl, P Pal, JC Suttle, JD Neubauer, ...
Ancient duplication and horizontal transfer of a toxin gene cluster reveals novel mechanisms in the cercosporin biosynthesis pathway
bioRxiv, 100545, 2017
Convergent biosynthetic pathways to β-lactam antibiotics
Current opinion in chemical biology 35, 97-108, 2016
R Li, RA Oliver, CA Townsend
Identification and Characterization of the Sulfazecin Monobactam Biosynthetic Gene Cluster
Cell Chemical Biology, 2016
P Kumar, A Kaushik, EP Lloyd, SG Li, R Mattoo, NC Ammerman, DT Bell, ...
Non-classical transpeptidases yield insight into new antibacterials
Nature Chemical Biology, 2016
J Zhou, VK Outlaw, CA Townsend, AE Bragg
Quenching of pH‐Responsive Luminescence of a Benzoindolizine Sensor by an Ultrafast Hydrogen Shift
Chemistry-A European Journal 22 (43), 15212-15215, 2016
JF Barajas, K Finzel, TR Valentic, G Shakya, N Gamarra, D Martinez, ...
Structural and Biochemical Analysis of Protein–Protein Interactions Between the Acyl‐Carrier Protein and Product Template Domain
Angewandte Chemie International Edition 55 (42), 13005-13009, 2016
CA Townsend, MJ Bodner, RM Phelan, MF Freeman, , MF Freeman
Method for late introduction of the (8R) hydroxyl group carbapenem β-lactam antibiotic synthesis
US Patent 9,458,479, 2016
L Basta, Y Pan, A Kaushik, E Lloyd, C Townsend, B Staker, C Lukacs, ...
Investigating Mycobacterium tuberculosis L, D-transpeptidases as novel drug targets
The FASEB Journal 30 (1 Supplement), 613.6-613.6, 2016
AG Newman, CA Townsend
Molecular characterization of the cercosporin biosynthetic pathway in the fungal plant pathogen cercospora nicotianae
Journal of the American Chemical Society 138 (12), 4219-4228, 2016
VK Outlaw, J Zhou, AE Bragg, CA Townsend
Unusual blue-shifted acid-responsive photoluminescence behavior in 6-amino-8-cyanobenzo [1, 2-b] indolizines
RSC Advances 6 (66), 61249-61253, 2016
LAB Basta, A Ghosh, Y Pan, J Jakoncic, EP Lloyd, CA Townsend, ...
Loss of a functionally and structurally distinct ld-transpeptidase, LdtMt5, compromises cell wall integrity in mycobacterium tuberculosis
Journal of Biological Chemistry 290 (42), 25670-25685, 2015
D Conradt, MA Schätzle, J Haas, CA Townsend, M Müller
New Insights into the Conversion of Versicolorin A in the Biosynthesis of Aflatoxin B1
Journal of the American Chemical Society 137 (34), 10867-10869, 2015
DR Marous, EP Lloyd, AR Buller, KA Moshos, TL Grove, AJ Blaszczyk, ...
Consecutive radical S-adenosylmethionine methylations form the ethyl side chain in thienamycin biosynthesis
Proceedings of the National Academy of Sciences 112 (33), 10354-10358, 2015
NM Gaudelli, DH Long, CA Townsend
[bgr]-Lactam formation by a non-ribosomal peptide synthetase during antibiotic biosynthesis
Nature 520 (7547), 383-387, 2015
VK Outlaw, FB d’Andrea, CA Townsend
One-Pot Synthesis of Highly Substituted N-Fused Heteroaromatic Bicycles from Azole Aldehydes
Organic letters 17 (8), 1822-1825, 2015
CR Huitt-Roehl, EA Hill, MM Adams, AL Vagstad, JW Li, CA Townsend
Starter unit flexibility for engineered product synthesis by the nonreducing polyketide synthase PksA
ACS chemical biology 10 (6), 1443-1449, 2015
VK Outlaw, CA Townsend
A Practical Route to Substituted 7-Aminoindoles from Pyrrole-3-carboxaldehydes
Organic letters 16 (24), 6334-6337, 2014
DECONSTRUCTION OF ITERATIVE POLYKETIDE SYNTHASES
New Chemistry and New Opportunities from the Expanding Protein Universe ..., 2014
J Bruegger, RW Haushalter, AL Vagstad, J Beld, G Shakya, N Mih, ...
Probing the Selectivity and Protein⋅ Protein Interactions of a Nonreducing Fungal Polyketide Synthase Using Mechanism-Based Crosslinkers
Chemistry & Biology 21 (7), 913, 2014
AR Buller, MF Freeman, JF Schildbach, CA Townsend
Exploring the Role of Conformational Heterogeneity in cis-Autoproteolytic Activation of ThnT
Biochemistry 53 (26), 4273-4281, 2014