Disulfide Bond-Containing Ajoene Analogues As Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa

Abstract

Since its discovery 22 years ago, the bacterial cell-to-cell communication system, termed quorum sensing (QS), has shown potential as antipathogenic target. Previous studies reported that ajoene from garlic inhibits QS in opportunistic human pathogen Pseudomonas aeruginosa. In this study, screening of an in-house compound library revealed two sulfur-containing compounds which possess structural resemblance with ajoene and inhibit QS in bioreporter assay. Following a quantitative structure-activity relationship (SAR) study, 25 disulfide bond-containing analogues were synthesized and tested for QS inhibition activities. SAR study indicated that the allyl group could be replaced with other substituents, with the most active being benzothiazole derivative (IC = 0.56 μM). The compounds were able to reduce QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin) and successfully inhibit P. aeruginosa infection in murine model of implant-associated infection. Altogether, the QS inhibition activity of the synthesized compounds is encouraging for further exploration of novel analogues in antimicrobial drug development.

Quorum Sensing: A Prospective Therapeutic Target for Bacterial Diseases

“…Many studies have confirmed the synergistic effect of antibiotics and anti-QS agents ( Table 6). Ajoene, furanone c-30, and horseradish extract have been revealed to reduce the expression of virulence factors in Pseudomonas aeruginosa and make Pseudomonas aeruginosa easier to be cleared by tobramycin [107][108][109][110][111]. Another study has confirmed the synergistic effects of curcumin, gentamicin, and azithromycin on Pseudomonas aeruginosa; that is, the expressions of virulence genes were significantly downregulated by the combining use of curcumin together with gentamicin or azithromycin, and the therapeutic doses of gentamicin and azithromycin were minimized by curcumin supplementation [112].…”

Activity of Cinnamaldehyde on Quorum Sensing and Biofilm Susceptibility to Antibiotics in Pseudomonas aeruginosa

“…A number of publications have identified natural compounds and their synthetic analogues that interfere with QS and that have been shown to reduce virulence factor expression in vitro or virulence in vivo [10][11][12][13][14][15][16][17]. Some natural foods have compounds with QS inhibitory activity, and such foods might offer a natural prophylaxis against chronic P. aeruginosa infections [15,16].…”

Synergy of Quorum Quenching Enzyme and Quorum Sensing Inhibitor in InhibitingP.aeruginosaQuorum Sensing

“…Bacteria were grown in Luria-Bertani (LB) broth (1% tryptone, 0.5% yeast extract, and 0.5% NaCl). Media used for biological assay was ABTGC (AB minimal medium supplemented with 0.2% glucose and 0.2% casamino acids) 62 . Bacterial strains used in this study are shown in Table 1.…”