Natural Products Inhibit Bacterial Growth and Modulate Quorum-Sensing Systems Las and Rhl in Pseudomonas aeruginosa PA14.

Quorum sensing (QS) is a bacterial cell communication system in Pseudomonas aeruginosa, which regulates the production of several virulence factors, including pyocyanin, exoproteases, and biofilm formation. Natural products (NPs) have demonstrated their ability to control QS in different bacteria. This work evaluated the antimicrobial and anti-QS potential of a small library of NPs from Mexican biodiversity against P. aeruginosa PA14. Alternariol 4-methyl ether (12), iridoskyrin (17), and 5,8-epi-dioxyergosta-6,9(11),22-trien-3-ol (39) showed the most potent antimicrobial activity at both test concentrations. Regarding anti-QS activity, fuscin (13), neosartorin (18), 8'-hydroxy zearalenone (21), penicillic acid (26), 5,6-dehydroxypenicillic acid (27), pitholide B (36), and citrinin (38) inhibited pyocyanin production, exoproteases activity, and biofilm formation at the lowest concentration without significantly altering growth. Subsequently, in silico studies of deep-learning molecular docking and molecular dynamics indicated the putative mechanism of action of these compounds through their binding to the ligand-binding domains of LasR and RhlR, target proteins that control QS systems. These results demonstrate that NPs, such as pitholide B (36) and citrinin (38), are potential candidates against P. aeruginosa.