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Department Directory - Institute for Tuberculosis Research
INST AFFL, Institute for Tuberculosis Research
Professor, Pharmacy Practice
Dr. Danziger's research interests include surgical infectious disease, the unusual properties of antimicrobial agents and pharmacological aspects of the patients with infectious diseases.
Director, Institute for Tuberculosis Research
The Albert Schatz Professor of Medicinal Chemistry and Pharmacognosy, Medicinal Chemistry and Pharmacognosy
INST AFFL, Program for Collaborative Research in the Pharmaceutical Sciences
My motivation for finding new drugs for tuberculosis stems from a general desire to help alleviate suffering from diseases that disproportionately affect the poor and that have been neglected by the very countries that have the resources to make a difference. The success that we had in going from the lab to the clinic in leprosy in the 90s, gave me confidence that we can do the same for TB as these diseases are caused by related bacteria. The ITR is pursuing several strategies for discovery of new anti-TB agents. This includes large scale screening of both natural and synthetic compounds for those that demonstrate specificity of activity (i.e. inhibit the TB bacillus but not mammalian cells). Lead compounds are then optimized by semi-synthesis. In addition we are attempting to optimize the anti-TB activity of classes of antibiotics used for other infections but that have not been clinically active in tuberculosis. Activity of all lead compounds are assessed in macrophage and mouse models of TB. Ultimately clinical trials will be conducted with collaborators in TB-endemic regions.
, Institute for Tuberculosis Research
The genome projects yielded the sequences of tens of thousands of proteins. Elucidating the roles these proteins play in health and disease, and also how they can be used and/or modified for the development of novel therapeutics, biomaterials, biosensors, methods for energy production and methods for environmental remediation, will be aided by a better understanding of how a protein's amino acid sequence determines its structure and how a structure determine function. In the Jeffery lab we are using biophysical and biochemical methods along with computer-based structure analysis in several projects to study the connections between protein sequences, structures, and functions. (1) Analysis of protein sequences and structures to elucidate the connections between sequence, structure and function. This information might help in the future in developing better methods to predict a protein's function(s) from its sequence or structure. Two current projects in this area include an analysis of ligand binding sites in protein crystal structures and a study of the sequences and structures of "moonlighting proteins". Many protein functions can be inferred from the known functions of homologous proteins, but determining protein functions is complicated by an increasing number of "moonlighting proteins", proteins that have more than one function where the multiple functions are not a result of splice variants, gene fusions, or multiple isoforms (Jeffery, C. J. Moonlighting Proteins. (1999) Trends in Biochemical Sciences. 24: 8-11). We are preparing a database of the known moonlighting proteins and performing an analysis of their sequences and structures. Knowing more about moonlighting proteins could help in predicting which additional proteins might also have a second function, which would be useful in determining the function(s) of the thousands of proteins identified through the genome projects and the functions of the "unknown" proteins whose structures were solved as part of the Protein Structure Initiative. In addition, since the ability of proteins to moonlight can complicate interpretation of the results of proteomics projects, identifying the roles of proteins in disease, and the selection of biomarkers, understanding which proteins moonlight can be important for both basic research and medicine. (2) The development of novel approaches to increase the expression of transmembrane proteins for biochemical analysis and structure determination. Membrane proteins play key roles in health and disease and are the targets of the majority of pharmaceuticals in use today, but much less is known about their structures and mechanisms of function than for soluble proteins because of the challenges in their expression, purification, and structure determination. The goal of our new approaches is to alleviate the bottleneck in protein expression. (3) In a previous project, we elucidated the reaction mechanism of a glycolytic enzyme that moonlights as a tumor cell motility factor in breast cancer cells: phosphoglucose isomerase/autocrine motility factor (PGI/AMF). By solving six structures of PGI/AMF with different ligands bound, we developed a model of the multistep catalytic mechanism for this multifunctional enzyme/growth factor.
Associate Professor, Medicinal Chemistry and Pharmacognosy
Center Affiliate, Center for Biomolecular Sciences
INST AFFL, Institute for Tuberculosis Research
Faculty and Staff Committee, Diversity & Inclusion
Chemistry, drug-lead discovery, spectroscopy, aquatic microbiology