An urgent demand for the development of new antibiotics has been caused by the increase in drug-resistant pathogenic bacteria. Targeting the enzymes involved in fatty acid synthesis offers a solution for developing new inhibitors for drug discovery.  A novel approach is to focus on the multifunctional enzyme acetyl-CoA carboxylase, which catalyzes the first committed step in fatty acid synthesis and is an essential enzyme in both prokaryotes and eukaryotes. The bacterial form of the enzyme consists of three proteins: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. There is an aminooxazole inhibitor for biotin carboxylase that was determined to be bactericidal, while the natural product moiramide B was discovered to be an inhibitor for carboxyltransferase and was found to be a broad-spectrum agent. The ability to inhibit two different enzymes with the same compound expounds on the theory of increasing overall potency while also impeding the ability for the development of resistance. We have synthesized each inhibitor individually and have covalently attached them via hydrocarbon linkers. This generated a dual-ligand inhibitor to halt fatty acid synthesis in pathogenic bacteria while also being selective for the bacterial form of the enzyme. Our studies have revealed that a sixteen carbon saturated hydrocarbon linker reduced the effectiveness of each inhibitor to impede bacterial growth, while shortening the length of the linkers increased their potency. Degrees of saturation and hydrophilicity will also be tested to determine whether or not it affects the ability of the molecule to diffuse through the bacterial membrane. These linker studies allow for greater insight into what structural characteristics may be necessary for antibacterial compounds to enter bacterial cells. The optimum linker will be determined using bacterial growth assays and be incorporated into our dual-ligand molecule and compared to our initial compounds for increased potency and broad-spectrum activity.

Design and synthesis of a dual-ligand inhibitor for acetyl-CoA carboxylase

247th National Meeting (2014)

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