Home Products Cited in Publications Worldwide Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity
Cifone, Matthew T.; He, YongLe; Basu, Rajeswari; Wang, Nan; Davoodi, Shabnam; Spagnuolo, Lauren A.; Si, Yuanyuan; Daryaee, Taraneh; Stivala, Craig E.; Walker, Stephen G.; Tonge, Peter J.
DOI:10.1021/acs.jmedchem.2c01380 PMID:36459397
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, resp. 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.