2 research outputs found
Design, Synthesis, and Antibacterial Properties of Dual-Ligand Inhibitors of Acetyl-CoA Carboxylase
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
Crystal Structure of Carboxyltransferase from <i>Staphylococcus aureus</i> Bound to the Antibacterial Agent Moiramide B
The
dramatic increase in the prevalence of antibiotic-resistant
bacteria has necessitated a search for new antibacterial agents against
novel targets. Moiramide B is a natural product, broad-spectrum antibiotic
that inhibits the carboxyltransferase component of acetyl-CoA carboxylase,
which catalyzes the first committed step in fatty acid synthesis.
Herein, we report the 2.6 Ã… resolution crystal structure of moiramide
B bound to carboxyltransferase. An unanticipated but significant finding
was that moiramide B bound as the enol/enolate. Crystallographic studies
demonstrate that the (4<i>S</i>)-methyl succinimide moiety
interacts with the oxyanion holes of the enzyme, supporting the notion
that an anionic enolate is the active form of the antibacterial agent.
Structure–activity studies demonstrate that the unsaturated
fatty acid tail of moiramide B is needed only for entry into the bacterial
cell. These results will allow the design of new antibacterial agents
against the bacterial form of carboxyltransferase