Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity

The relationship between drug–target residence
time and
the post-antibiotic effect (PAE) provides insights into target vulnerability.
To probe the vulnerability of bacterial acetyl-CoA carboxylase (ACC),
a series of heterobivalent inhibitors were synthesized based on pyridopyrimidine 1 and moiramide B (3) which bind to the biotin
carboxylase and carboxyltransferase ACC active sites, respectively.
The heterobivalent compound 17, which has a linker of
50 Å, was a tight binding inhibitor of Escherichia
coli ACC (Kiapp 0.2 nM) and could be displaced from ACC by a combination of both 1 and 3 but not just by 1. In agreement
with the prolonged occupancy of ACC resulting from forced proximity
binding, the heterobivalent inhibitors produced a PAE in E. coli of 1–4 h in contrast to 1 and 3 in combination or alone, indicating that ACC
is a vulnerable target and highlighting the utility of kinetic, time-dependent
effects in the drug mechanism of action.