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 and moiramide B () which bind to the biotin carboxylase and carboxyltransferase ACC active sites, respectively. The heterobivalent compound , which has a linker of 50 Å, was a tight binding inhibitor of ACC ( 0.2 nM) and could be displaced from ACC by a combination of both and but not just by . In agreement with the prolonged occupancy of ACC resulting from forced proximity binding, the heterobivalent inhibitors produced a PAE in of 1-4 h in contrast to and 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.