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A Theoretical and Experimental Screening of Molecules for the Inhibition of Fatty Acid Synthesis
Screening molecules to inhibit fatty acid synthesis
Achievement/Results
The increased use of antibiotics has led to a dramatic rise in the number of antibiotic-resistant bacteria, which has necessitated a search for new antibiotic targets. An attractive new direction is the inhibition of bacterial fatty acid synthesis since it is required for lipid membrane growth, and critical for bacterial survival. The goal is to search for potential new antibiotics via this fatty acid pathway by developing and applying a hierarchical set of tools from computer modeling to experiment. A preliminary virtual screen of biotin carboxylase enzymes has suggested potential lead candidates, in which three common molecular moieties (a hydrophobic fused ring connected to a hydrophilic linker chain and a smaller five member nitrogen ring) have been identified. These common moieties and similar compounds based upon these three fragments were tested for their inhibition. Only one compound inhibited the enzyme in the micro-molar range. Although not a lead candidate, it offers a basic molecular scaffold for further development. For example, studies are underway to examine possible structural modifications to this basic scaffold, compare the structures from the virtual docking study to the structure of the co-crystallized enzyme-inhibitor complex, determine the structure-activity relationships of these moieties, and develop a more sophisticated docking algorithm. The synergy between theoretical chemistry and biochemistry is a promising route in the search for novel antibiotic agents. Advancing science requires a multidisciplinary approach to solve current problems and to project future research directions through collaborative effort of both experimentalists and theoreticians.
Address Goals
The student, Matt McKenzie, performed the computer search and was able to do lab experiments as well. Additionally, this student availed himself to international travel opportunities, spending an extended period of time at an industrial pharmaceutical laboratory in England. Neither the lab experiments nor the international travel would have been possible without the IGERT program.
