Development of an antibiotic treatment for Pseudomonas aeruginosa utilizing metal complexes
Disciplines
Medicinal-Pharmaceutical Chemistry | Other Chemistry
Abstract (300 words maximum)
The purpose of my research is to develop antibiotics targeting Pseudomonas aeruginosa, which is responsible for deaths in patients with cystic fibrosis. One of the main difficulties with treatment is that P. aeruginosa produces a biofilm under anaerobic conditions. I am working with a protein called Molybdate Binding Protein (ModA) that binds to molybdate extracellularly and brings it into the cell for use in the nitrogen reduction process, a crucial step in anaerobic metabolism. If ModA is disabled the entire anaerobic metabolism fails, forcing the bacterium to operate aerobically where the biofilm growth is unfavorable.
I am synthesizing a small molecule “warhead” that is similar enough to molybdate to still bind to the ModA active site but will have organic group(s) attached that can be linked to “fragments.” Fragments are small organic molecules that bind near the active site and when fused to a warhead will encourage it to irreversibly inactivate the protein. This inactivation is expected to force the cell back to aerobic metabolism and eliminate biofilm production. Two model warheads have been synthesized and their optimization is ongoing. The molecule warheads themselves also exhibit interesting chemistry, such as forming what appears to be a polymer under aqueous synthesis conditions, which I would like to investigate further to determine if it contains any useful properties.
Subsequent to optimizing the warhead synthesis reaction and purification of ModA, I will test the molecules for binding affinity to ModA via multidimensional NMR and luminescence assays. The warhead will be synthetically combined with fragment hits obtained also by NMR, and NMR and crystallography will be used to verify the binding of the chimeric drug candidate to ModA. If successful, this chimeric fragment-warhead molecule will reduce biofilm formation and synergize with existing antibiotic therapies in the treatment of cystic fibrosis lung infections.
Academic department under which the project should be listed
CSM - Chemistry and Biochemistry
Primary Investigator (PI) Name
Thomas Leeper
PowerPoint Presentation
Development of an antibiotic treatment for Pseudomonas aeruginosa utilizing metal complexes
The purpose of my research is to develop antibiotics targeting Pseudomonas aeruginosa, which is responsible for deaths in patients with cystic fibrosis. One of the main difficulties with treatment is that P. aeruginosa produces a biofilm under anaerobic conditions. I am working with a protein called Molybdate Binding Protein (ModA) that binds to molybdate extracellularly and brings it into the cell for use in the nitrogen reduction process, a crucial step in anaerobic metabolism. If ModA is disabled the entire anaerobic metabolism fails, forcing the bacterium to operate aerobically where the biofilm growth is unfavorable.
I am synthesizing a small molecule “warhead” that is similar enough to molybdate to still bind to the ModA active site but will have organic group(s) attached that can be linked to “fragments.” Fragments are small organic molecules that bind near the active site and when fused to a warhead will encourage it to irreversibly inactivate the protein. This inactivation is expected to force the cell back to aerobic metabolism and eliminate biofilm production. Two model warheads have been synthesized and their optimization is ongoing. The molecule warheads themselves also exhibit interesting chemistry, such as forming what appears to be a polymer under aqueous synthesis conditions, which I would like to investigate further to determine if it contains any useful properties.
Subsequent to optimizing the warhead synthesis reaction and purification of ModA, I will test the molecules for binding affinity to ModA via multidimensional NMR and luminescence assays. The warhead will be synthetically combined with fragment hits obtained also by NMR, and NMR and crystallography will be used to verify the binding of the chimeric drug candidate to ModA. If successful, this chimeric fragment-warhead molecule will reduce biofilm formation and synergize with existing antibiotic therapies in the treatment of cystic fibrosis lung infections.