Fluorescent Quinolones for β-sheet Interception
Mentor 1
Alan Schwabacher
Location
Union Wisconsin Room
Start Date
24-4-2015 2:30 PM
End Date
24-4-2015 3:45 PM
Description
Methicillin-resistant Staphylococcus aureus (MRSA) infections are responsible for 19,000 deaths per year in the US. The purpose of this research is to design a molecule that selectively binds and inhibits the bacterial protein which is responsible for mechanism of drug resistance. The target molecule of this synthesis [shown below hydrogen-bonded to a protein in the β-barrel assembly machine (BAM)] is proposed to inhibit BAM, the protein complex that folds β-barrels of membrane proteins called efflux pumps. These pumps excrete many antibiotics that are otherwise deadly to bacteria, but are removed before they can be effective. We propose a quinolone-based structure as a possible inhibitor molecule for the BAM. Quinolones are planar molecules that can be derivatized to create a rigid scaffold with a pattern of hydrogen bond donors and acceptors complementary to the hydrogen bonding in a β-sheet. This inhibitory quinolone is being pursued from the starting material dimethyl succinyl succinate. Methods of synthesis include enamine formation and cyclization to form the quinolone. Techniques such as chromatography and crystallization have been employed to purify compounds, and analysis is performed using NMR, IR, and mass spectrometry to characterize new compounds. Once the product is synthesized, binding studies of the product with the BAM will commence in collaboration with a research group that has better methods of binding studies than we currently have. This research is significant because bacteria are becoming more resistant to known antibiotics; our goal is to inhibit BAM thus preventing the folding of β-barrel efflux proteins and stop the active transport of drug molecules out of the bacterial cell before the organism is killed. So far, three synthetic intermediates have been prepared following our synthetic route to the target. Future work includes continuing the synthesis and further increasing yields for the steps thus far.
Fluorescent Quinolones for β-sheet Interception
Union Wisconsin Room
Methicillin-resistant Staphylococcus aureus (MRSA) infections are responsible for 19,000 deaths per year in the US. The purpose of this research is to design a molecule that selectively binds and inhibits the bacterial protein which is responsible for mechanism of drug resistance. The target molecule of this synthesis [shown below hydrogen-bonded to a protein in the β-barrel assembly machine (BAM)] is proposed to inhibit BAM, the protein complex that folds β-barrels of membrane proteins called efflux pumps. These pumps excrete many antibiotics that are otherwise deadly to bacteria, but are removed before they can be effective. We propose a quinolone-based structure as a possible inhibitor molecule for the BAM. Quinolones are planar molecules that can be derivatized to create a rigid scaffold with a pattern of hydrogen bond donors and acceptors complementary to the hydrogen bonding in a β-sheet. This inhibitory quinolone is being pursued from the starting material dimethyl succinyl succinate. Methods of synthesis include enamine formation and cyclization to form the quinolone. Techniques such as chromatography and crystallization have been employed to purify compounds, and analysis is performed using NMR, IR, and mass spectrometry to characterize new compounds. Once the product is synthesized, binding studies of the product with the BAM will commence in collaboration with a research group that has better methods of binding studies than we currently have. This research is significant because bacteria are becoming more resistant to known antibiotics; our goal is to inhibit BAM thus preventing the folding of β-barrel efflux proteins and stop the active transport of drug molecules out of the bacterial cell before the organism is killed. So far, three synthetic intermediates have been prepared following our synthetic route to the target. Future work includes continuing the synthesis and further increasing yields for the steps thus far.
