1,2,4-Oxadiazole topsentin analogs as staphylococcal biofilm inhibitors targeting the bacterial transpeptidase sortase A

Eur J Med Chem. 2021 Jan 1;209:112892. doi: 10.1016/j.ejmech.2020.112892. Epub 2020 Sep 29.


The inhibition or prevention of biofilm formation represents an emerging strategy in the war against antibiotic resistance, interfering with key players in bacterial virulence. This approach includes the inhibition of the catalytic activity of transpeptidase sortase A (Srt A), a membrane enzyme responsible for covalently attaching a wide variety of adhesive matrix molecules to the peptidoglycan cell wall in Gram-positive strains. A new series of seventeen 1,2,4-oxadiazole derivatives was efficiently synthesized and screened as potential new anti-virulence agents. The ability of inhibiting biofilm formation was evaluated against both Gram-positive and Gram-negative pathogens. Remarkably, all these compounds inhibited S. aureus and/or P. aeruginosa biofilm formation in a dose dependent manner, with 50% biofilm inhibitory concentrations (BIC50s) below 10 μM for the most active compounds. Inhibition of SrtA was validated as one of the possible mechanisms of action of these new 1,2,4-oxadiazole derivatives, in the tested Gram-positive pathogen, using a specific enzymatic assay for a recombinant S. aureus SrtA. The three most active compounds, eliciting BIC50 values for S. aureus ATCC 25923 between 0.7 and 9.7 μM, showed a good activity toward the enzyme eliciting IC50 values ranging from 2.2 to 10.4 μM.

Keywords: 1,2,4-Oxadiazoles; Anti-virulence agents; Antibiofilm activity; Marine alkaloids; Sortase A inhibitors; Topsentin analogs.

MeSH terms

  • Aminoacyltransferases / antagonists & inhibitors*
  • Aminoacyltransferases / metabolism
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / antagonists & inhibitors*
  • Bacterial Proteins / metabolism
  • Biofilms / drug effects*
  • Cell Line
  • Cysteine Endopeptidases / metabolism
  • Humans
  • Imidazoles / chemistry
  • Imidazoles / pharmacology*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Pseudomonas Infections / drug therapy
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / drug effects*
  • Pseudomonas aeruginosa / physiology
  • Staphylococcal Infections / drug therapy
  • Staphylococcal Infections / microbiology
  • Staphylococcus aureus / drug effects*
  • Staphylococcus aureus / physiology


  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Imidazoles
  • Indoles
  • Oxadiazoles
  • topsentin
  • Aminoacyltransferases
  • sortase A
  • Cysteine Endopeptidases