Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity.
J Med Chem
; 65(24): 16510-16525, 2022 12 22.
Article
en En
| MEDLINE
| ID: mdl-36459397
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Acetil-CoA Carboxilasa
/
Escherichia coli
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos