Structure–Activity Relationships of 6- and 8-Gingerol Analogs as Anti-Biofilm Agents

Abstract

Pseudomonas aeruginosa is a causative agent of chronic infections in immunocompromised patients. Disruption of quorum sensing circuits is an attractive strategy for treating diseases associated with P. aeruginosa infection. In this study, we designed and synthesized a series of gingerol analogs targeting LasR, a master regulator of quorum sensing networks in P. aeruginosa. Structure-activity relationship studies showed that a hydrogen-bonding interaction in the head section, stereochemistry and rotational rigidity in the middle section, and optimal alkyl chain length in the tail section are important factors for the enhancement of LasR-binding affinity and for the inhibition of biofilm formation. The most potent compound 41, an analog of (R)-8-gingerol with restricted rotation, showed stronger LasR-binding affinity and inhibition of biofilm formation than the known LasR antagonist (S)-6-gingerol. This new LasR antagonist can be used as an early lead compound for the development of anti-biofilm agents to treat P. aeruginosa infections.

Antimicrobial Activity of Naturally Occurring Phenols and Derivatives Against Biofilm and Planktonic Bacteria

“…Various structure activity relationships of antimicrobial compounds, including natural products and plant metabolites, and their potency toward planktonic cells and biofilms have been evaluated (Huigens et al, 2007; Richards et al, 2008, 2009; Catto et al, 2015; Garrison et al, 2015; Peeters et al, 2016; Yang et al, 2016; Choi et al, 2017; Gill et al, 2017). Richards et al (2008) synthesized and assayed a 50-compound library of oroidin-based natural products for their anti-biofilm activity against two strains of P. aeruginosa , classifying several compounds as inhibitors of biofilm formation.…”

“…Structural factors such as stereochemistry, alkyl chain length, and substitution patterns have also been examined in the context of biofilms (Huigens et al, 2007; Choi et al, 2017; Gill et al, 2017). No uniform correlation of biofilm potency with planktonic potency is evident.…”

Antibiofilm and Antivirulence Activities of 6-Gingerol and 6-Shogaol Against Candida albicans Due to Hyphal Inhibition

“…The antibacterial activities of gingerols and shogaols have been also studied (Park et al, 2008). More recently, the antibiofilm activities of 6-gingerol (Kim et al, 2015) and 6- and 8-gingerol analogs (Choi et al, 2017) against P. aeruginosa have been reported. Interestingly, 6-gingerol inhibited biofilm formation of both P. aeruginosa (Kim et al, 2015) (Choi et al, 2017) and C. albicans without affecting the planktonic cell growth and showed no chemical toxicity.…”

“…More recently, the antibiofilm activities of 6-gingerol (Kim et al, 2015) and 6- and 8-gingerol analogs (Choi et al, 2017) against P. aeruginosa have been reported. Interestingly, 6-gingerol inhibited biofilm formation of both P. aeruginosa (Kim et al, 2015) (Choi et al, 2017) and C. albicans without affecting the planktonic cell growth and showed no chemical toxicity. 6-Gingerol including its analogs interfere the quorum sensing system in P. aeruginosa , while 6-gingerol and 6-shogaol suppressed hyphal growth in this study.…”

“…Recently, several studies have demonstrated ginger components have antibiofilm activities against pathogenic bacteria, such as, ginger water extract against Pseudomonas aeruginosa (Kim and Park, 2013) and against Salmonella Typhimurium and Escherichia coli (Khiralla, 2015), and zingerone (Kumar et al, 2013), raffinose (Kim et al, 2016a), 6-gingerol (Kim et al, 2015), and 6- and 8-gingerol analogs (Choi et al, 2017) against P. aeruginosa . However, the antibiofilm activities of ginger components have not been studied in any yeast species.…”