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.