Heterobivalent Inhibitors of Acetyl-CoA Carboxylase: Drug Target Residence Time and Time-Dependent Antibacterial Activity

  • J Med Chem. 2022 Dec 22;65(24):16510-16525. doi: 10.1021/acs.jmedchem.2c01380.
Matthew T Cifone  1  2 ,  YongLe He  1  2 ,  Rajeswari Basu  1  2 ,  Nan Wang  1 ,  Shabnam Davoodi  1  2 ,  Lauren A Spagnuolo  2 ,  Yuanyuan Si  2 ,  Taraneh Daryaee  2 ,  Craig E Stivala  3 ,  Stephen G Walker  4 ,  Peter J Tonge  1  2  5
Affiliations
  • 1. Center for Advanced Study of Drug Action, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 2. Department of Chemistry, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 3. Discovery Chemistry, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, United States.
  • 4. Department of Oral Biology and Pathology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
  • 5. Department of Radiology, Stony Brook University, John S. Toll Drive, Stony Brook, New York 11794-3400, United States.
PMID: 36459397 DOI: 10.1021/acs.jmedchem.2c01380
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.

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