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

Barbara Parrino, Daniela Carbone, Stella Cascioferro, Camilla Pecoraro, Elisa Giovannetti, Dongmei Deng, Veronica di Sarno, Simona Musella, Giulia Auriemma, Maria Grazia Cusimano, Domenico Schillaci, Girolamo Cirrincione, Patrizia Diana*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Article number112892
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Jan 2021

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