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 <b>1</b> and moiramide B (<b>3</b>) which bind to the biotin carboxylase and carboxyltransferase ACC active sites, respectively. The heterobivalent compound <b>17</b>, which has a linker of 50 Å, was a tight binding inhibitor of <i>Escherichia coli</i> ACC (<i>K</i><sub>i</sub><sup>app</sup> 0.2 nM) and could be displaced from ACC by a combination of both <b>1</b> and <b>3</b> but not just by <b>1</b>. In agreement with the prolonged occupancy of ACC resulting from forced proximity binding, the heterobivalent inhibitors produced a PAE in <i>E. coli</i> of 1-4 h in contrast to <b>1</b> and <b>3</b> 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.