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.
Bibliographical noteFunding Information:
This research was funded by European Union 2014–2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education, University and Research , entitled “PROGEMA—Processi Green per l’Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non” ( ARS01_00432 ) in favour of P.D.
This research was funded by European Union 2014?2020 PON Ricerca e Innovazione grant from the Italian Ministry of Education, University and Research, entitled ?PROGEMA?Processi Green per l'Estrazione di Principi Attivi e la Depurazione di Matrici di Scarto e Non? (ARS01_00432) in favour of P.D.
© 2020 Elsevier Masson SAS
- Anti-virulence agents
- Antibiofilm activity
- Marine alkaloids
- Sortase A inhibitors
- Topsentin analogs