Specific quorum sensing-disrupting activity (AQSI) of thiophenones and their therapeutic potential

Abstract

Disease caused by antibiotic resistant pathogens is becoming a serious problem, both in human and veterinary medicine. The inhibition of quorum sensing, bacterial cell-to-cell communication, is a promising alternative strategy to control disease. In this study, we determined the quorum sensing-disrupting activity of 20 thiophenones towards the quorum sensing model bacterium V. harveyi. In order to exclude false positives, we propose a new parameter (AQSI) to describe specific quorum sensing activity. AQSI is defined as the ratio between inhibition of quorum sensing-regulated activity in a reporter strain and inhibition of the same activity when it is independent of quorum sensing. Calculation of AQSI allowed to exclude five false positives, whereas the six most active thiophenones (TF203, TF307, TF319, TF339, TF342 and TF403) inhibited quorum sensing at 0.25 μM, with AQSI higher than 10. Further, we determined the protective effect and toxicity of the thiophenones in a highly controlled gnotobiotic model system with brine shrimp larvae. There was a strong positive correlation between the specific quorum sensing-disrupting activity of the thiophenones and the protection of brine shrimp larvae against pathogenic V. harveyi. Four of the most active quorum sensing-disrupting thiophenones (TF 203, TF319, TF339 and TF342) were considered to be promising since they have a therapeutic potential of at least 10.

Indole signalling and (micro)algal auxins decrease the virulence of Vibrio campbellii, a major pathogen of aquatic organisms

“…), indicating that the inhibition of bioluminescence in wild type V. campbellii was indeed caused by interference with the three‐channel quorum sensing system. We recently proposed the specific quorum sensing inhibitory activity A QSI as a new parameter to reliably identify quorum sensing inhibitors based on experiments with signal molecule reporter strains (Yang et al ., ; Defoirdt, ). The A QSI values obtained for indole were 32, 49 and 28 at 50, 100 and 200 µM respectively.…”

“…We investigated the interaction of indole signalling with other key regulatory mechanisms, and found that indole interferes with quorum sensing‐regulated bioluminescence in V. campbellii . This activity could be specifically attributed to inhibition of the three‐channel quorum sensing system since the specific quorum sensing‐disrupting activity A QSI of indole was higher than 10, which is comparable to the most specific quorum sensing inhibitors revealed previously (Yang et al ., ). Consistent with this, we found that indole decreased the mRNA levels of the quorum sensing master regulator LuxR.…”

Quorum sensing is required for full virulence of Vibrio campbellii towards tiger grouper (Epinephelus fuscoguttatus) larvae

“…These signal molecules are detected by membrane‐bound receptors that feed a shared signal transduction cascade (Figure ). Several virulence factors are regulated by quorum sensing in V. campbellii , including biofilm formation (Anetzberger, Pirch, & Jung, ), type III secretion (Henke & Bassler, 2004a), production of a siderophore (Lilley & Bassler, ), the Vhp metalloprotease (Mok, Wingreen, & Bassler, ), chitinase A (Defoirdt, Ruwandeepika, Karunasagar, Boon, & Bossier, ), three phospholipase genes (Natrah, Ruwandeepika, et al., ) and flagellar motility (Yang, Aamdal Scheie, Benneche, & Defoirdt, ; Yang & Defoirdt, ). The V. campbellii quorum‐sensing system is required for full virulence towards various aquatic organisms (Defoirdt, Bossier, Sorgeloos, & Verstraete, ; Pande, Natrah, Sorgeloos, Bossier, & Defoirdt, ; Tinh et al., ), and the activity of the quorum‐sensing system during infection of a host is proportional to the virulence to that host (Defoirdt & Sorgeloos, ).…”

“…Given its role in virulence , quorum sensing is considered to be an interesting target for the development of novel therapies to control disease caused by V. campbellii (Defoirdt, ). During the past 10 years, we have identified several agents (including natural and synthetic quorum‐sensing inhibitors and signal molecule‐degrading bacteria) that are capable of inhibiting the quorum‐sensing system of V. campbellii , and these agents have been proven effective in controlling disease in various hosts (Defoirdt et al., , ; Natrah, Kenmegne, et al., ; Pande, Aamdal Scheie, et al., ; Yang et al., ).…”

Scaffold of Selenium Nanovectors and Honey Phytochemicals for Inhibition of Pseudomonas aeruginosa Quorum Sensing and Biofilm Formation

“…Emergence of multi-drug resistant bacteria has driven studies for disabling virulence preferentially through quorum sensing (QS) inhibition tactics instead of bactericidal and bacteriostatic strategies (Singh et al, 2009a; Defoirdt et al, 2013; Kim et al, 2015; Lidor et al, 2015; Srivastava et al, 2015; Wang et al, 2015; Yang et al, 2015). P. aeruginosa , a Gram-negative bacterium causes cystic fibrosis in immunocompromised patients, burn units of hospitals, and in implanted medical devices including intubation tubes and stents (Singh et al, 2012; Singh B. R. et al, 2015; Kalferstova et al, 2016).…”