Design, Synthesis, and Antibacterial
Properties of
Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase
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Abstract
There is an urgent demand for the
development of new antibiotics
due to the increase in drug-resistant pathogenic bacteria. A novel
target is the multifunctional enzyme acetyl-CoA carboxylase (ACC),
which catalyzes the first committed step in fatty acid synthesis and
consists of two enzymes: biotin carboxylase and carboxyltransferase.
Covalently attaching known inhibitors against these enzymes with saturated
hydrocarbon linkers of different lengths generated dual-ligand inhibitors.
Kinetic results revealed that the dual-ligands inhibited the ACC complex
in the nanomolar range. Microbiology assays showed that the dual-ligand
with a 15-carbon linker did not exhibit any antibacterial activity,
while the dual-ligand with a 7-carbon linker displayed broad-spectrum
antibacterial activity as well as a decreased susceptibility in the
development of bacterial resistance. These results suggest that the
properties of the linker are vital for antibacterial activity and
show how inhibiting two different enzymes with the same compound increases
the overall potency while also impeding the development of resistance