Quinolones for β–Sheet Interception
Mentor 1
Alan Schwabacher
Location
Union Wisconsin Room
Start Date
28-4-2017 1:30 PM
End Date
28-4-2017 4:00 PM
Description
Much of antibiotic resistance results from membrane proteins that, through the process of active transport, remove antibiotics from within the membrane to outside the membrane, rendering said antibiotics useless. Many membrane proteins called efflux protein complexes responsible for this are, in part, folded by a different protein-complex called the β-barrel assembly machine (Bam). The secondary structure of proteins folded by this machine is of the form of a β-barrel, composed of β-pleated sheets. Currently, a rigid quinolone structure, a common structure of many antibiotics that act by other mechanisms, with strategic hydrogen-bonding sites is being pursued as a molecular template that will hydrogen-bond small peptides by mimicking the interactions in a β-sheet. These templates will be used to study intramolecular forces in β-sheets and β-barrels. Inhibition of the β-barrel assembly machine with modified substrate peptides has been shown to be bactericidal in vitro. However, these peptides make poor drug candidates due to their inherently poor quality of being metabolized by the patient to which these drugs may be given. Therefore, we propose possible inhibition of the β-barrel assembly machine by our synthetic target molecule, mimicking the interactions of that modified substrate peptide.
Quinolones for β–Sheet Interception
Union Wisconsin Room
Much of antibiotic resistance results from membrane proteins that, through the process of active transport, remove antibiotics from within the membrane to outside the membrane, rendering said antibiotics useless. Many membrane proteins called efflux protein complexes responsible for this are, in part, folded by a different protein-complex called the β-barrel assembly machine (Bam). The secondary structure of proteins folded by this machine is of the form of a β-barrel, composed of β-pleated sheets. Currently, a rigid quinolone structure, a common structure of many antibiotics that act by other mechanisms, with strategic hydrogen-bonding sites is being pursued as a molecular template that will hydrogen-bond small peptides by mimicking the interactions in a β-sheet. These templates will be used to study intramolecular forces in β-sheets and β-barrels. Inhibition of the β-barrel assembly machine with modified substrate peptides has been shown to be bactericidal in vitro. However, these peptides make poor drug candidates due to their inherently poor quality of being metabolized by the patient to which these drugs may be given. Therefore, we propose possible inhibition of the β-barrel assembly machine by our synthetic target molecule, mimicking the interactions of that modified substrate peptide.
