Chemical Biology & Spectroscopy
| Enzymology and Inhibition of Antibacterial Drug Targets | |
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Research in the Tonge Group is focused on understanding how proteins control and modulate the properties of small molecule ligands. We are interested in understanding the fundamental aspects of enzyme catalysis and in determining how enzymes cause and stabilize charge rearrangement. Some of the enzymes we study are drug targets in pathogens such as Mycobacterium tuberculosis, Francisella tularensis, Burkholderia pseudomallei and methicillin-resistant Staphylococcus aureus (MRSA). We use mechanistic information to design and synthesize high affinity enzyme inhibitors that have long residence times on their targets based on the knowledge that drug-target residence time is a critcal factor for in vivo antibacterial activity (Lu and Tonge (2010) Curr. Opin. Chem. Biol. 14, 467-474). The long residence time inhibitors are also being used to image bacterial populations in humans using positron emission tomography (Liu et al. (2010) J. Med. Chem. 53, 2882-91). |
Mycobacterium Tuberculosis : Fatty acid Biosynthesis, Menaquinone Biosynthesis, Cell Division |
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| Imaging | |
Our hypothesis is that compounds and drugs that bind with long residence times to pathogen-specific proteins will be concentrated in infected tissues and enable the visualization of pathogens in vivo, thereby identifying and improving treatment of patients with diseases such as tuberculosis. These experiments involve the introduction of short-lived isoptopes into the drugs and visualizing the distribution of these molecules in vivo using positron emission tomography |
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| Fluorescent Proteins and Light-Activated Proteins | |
Green fluorescent proteins (GFPs) are intrinsically fluorescent and have a wide range of applications in molecular and cell biology. Importantly, it has been shown that light absorption causes structural changes in the GFP chromophore that result in alterations in the chromophore’s fluorescence. We are using a variety of spectroscopic methods, including ultrafast vibrational spectroscopy, coupled with site directed mutagenesis to determine how the protein environment controls the spectroscopic properties of the chromophore. We are also introducing isotopic labels and unnatural amino acids into the chromophore in order to study the mechanism of chromophore formation. These studies have been expanded to the light-activated antirepressor AppA. |
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GFP |
AppA: Light Driven H-Bond Rearrangement |
