Synthesis of Avibactam Derivatives and Activity on β-Lactamases and Peptidoglycan Biosynthesis Enzymes of Mycobacteria

Chemistry. 2018 Jun 7;24(32):8081-8086. doi: 10.1002/chem.201800923. Epub 2018 May 14.


There is a renewed interest for β-lactams for treating infections due to Mycobacterium tuberculosis and M. abscessus because their β-lactamases are inhibited by classical (clavulanate) or new generation (avibactam) inhibitors, respectively. Here, access to an azido derivative of the diazabicyclooctane (DBO) scaffold of avibactam for functionalization by the Huisgen-Sharpless cycloaddition reaction is reported. The amoxicillin-DBO combinations were active, indicating that the triazole ring is compatible with drug penetration (minimal inhibitory concentration of 16 μg mL-1 for both species). Mechanistically, β-lactamase inhibition was not sufficient to account for the potentiation of amoxicillin by DBOs. Thus, the latter compounds were investigated as inhibitors of l,d-transpeptidases (Ldts), which are the main peptidoglycan polymerases in mycobacteria. The DBOs acted as slow-binding inhibitors of Ldts by S-carbamoylation indicating that optimization of DBOs for Ldt inhibition is an attractive strategy to obtain drugs selectively active on mycobacteria.

Keywords: Avibactam; Mycobacterium abscessus; Mycobacterium tuberculosis; l,d-transpeptidases; β-lactamase.

MeSH terms

  • Azabicyclo Compounds / chemical synthesis*
  • Azabicyclo Compounds / chemistry
  • Mycobacterium tuberculosis / chemistry
  • Mycobacterium tuberculosis / enzymology*
  • Peptidoglycan / biosynthesis*
  • Peptidoglycan / chemistry
  • beta-Lactamase Inhibitors / chemistry*
  • beta-Lactamases / chemistry*
  • beta-Lactamases / metabolism


  • Azabicyclo Compounds
  • Peptidoglycan
  • beta-Lactamase Inhibitors
  • avibactam
  • beta-Lactamases