Development of Quinazolinone Derivatives as Modulators of Virulence Factors of <i>Pseudomonas aeruginosa</i> Cystic Fibrosis Strains
Gabriele Carullo,
Giovanni Di Bonaventura,
Sara Rossi,
Veronica Lupetti,
Valeria Tudino,
Simone Brogi,
Stefania Butini,
Giuseppe Campiani,
Sandra Gemma,
Arianna Pompilio
Affiliations
Gabriele Carullo
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Giovanni Di Bonaventura
Department of Medical, Oral and Biotechnological Sciences, School of Medicine and Health Sciences “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
Sara Rossi
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Veronica Lupetti
Department of Medical, Oral and Biotechnological Sciences, School of Medicine and Health Sciences “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
Valeria Tudino
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Simone Brogi
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Stefania Butini
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Giuseppe Campiani
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Sandra Gemma
Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Arianna Pompilio
Department of Medical, Oral and Biotechnological Sciences, School of Medicine and Health Sciences “G. d’Annunzio” University of Chieti-Pescara, Via dei Vestini 31, 66100 Chieti, Italy
Pseudomonas aeruginosa (PA), one of the ESKAPE pathogens, is an opportunistic Gram-negative bacterium responsible for nosocomial infections in humans but also for infections in patients affected by AIDS, cancer, or cystic fibrosis (CF). Treatment of PA infections in CF patients is a global healthcare problem due to the ability of PA to gain antibiotic tolerance through biofilm formation. Anti-virulence compounds represent a promising approach as adjuvant therapy, which could reduce or eliminate the pathogenicity of PA without impacting its growth. Pyocyanin is one of the virulence factors whose production is modulated by the Pseudomonas quinolone signal (PQS) through its receptor PqsR. Different PqsR modulators have been synthesized over the years, highlighting this new powerful therapeutic strategy. Based on the promising structure of quinazolin-4(3H)-one, we developed compounds 7a–d, 8a,b, 9, 10, and 11a–f able to reduce biofilm formation and the production of virulence factors (pyocyanin and pyoverdine) at 50 µM in two PA strains responsible for CF acute and chronic infections. The developed compounds did not reduce the cell viability of IB3-1 bronchial CF cells, and computational studies confirmed the potential ability of novel compounds to act as potential Pqs system modulators.
