Itaconimides as Novel Quorum Sensing Inhibitors of Pseudomonas aeruginosa

Abstract

Pseudomonas aeruginosa is known as an opportunistic pathogen that often causes persistent infections associated with high level of antibiotic-resistance and biofilms formation. Chemical interference with bacterial cell-to-cell communication, termed quorum sensing (QS), has been recognized as an attractive approach to control infections and address the drug resistance problems currently observed worldwide. Instead of imposing direct selective pressure on bacterial growth, the right bioactive compounds can preferentially block QS-based communication and attenuate cascades of bacterial gene expression and production of virulence factors, thus leading to reduced pathogenicity. Herein, we report on the potential of itaconimides as quorum sensing inhibitors (QSI) of P. aeruginosa. An initial hit was discovered in a screening program of an in-house compound collection, and subsequent structure-activity relationship (SAR) studies provided analogs that could reduce expression of central QS-regulated virulence factors (elastase, rhamnolipid, and pyocyanin), and also successfully lead to the eradication of P. aeruginosa biofilms in combination with tobramycin. Further studies on the cytotoxicity of compounds using murine macrophages indicated no toxicity at common working concentrations, thereby pointing to the potential of these small molecules as promising entities for antimicrobial drug development.

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

“…For example, it was reported that treatment with a QS inhibitor and TOB resulted in an increased clearance of P. aeruginosa in a foreign body infection model, demonstrating that this approach can work in vivo [23]. Another study demonstrated eradication of P. aeruginosa biofilms when a QS inhibitor and TOB were combined [51]. Sub-MIC CAD and 2×MIC of TOB had demonstrated a significant inhibition of P. aeruginosa biofilms [22].…”

2,4-Di-Tert-Butylphenol Isolated From an Endophytic Fungus, Daldinia eschscholtzii, Reduces Virulence and Quorum Sensing in Pseudomonas aeruginosa

“…In addition, several natural substances with known biological properties act as QS inhibitors as they intervene in QS-associated pathways, attenuate QS gene expression, and impair the infection. Recently, several reports claim to quench QS or ameliorate the QS signals through various synthetic molecules, natural products, and enzymes (Fong et al, 2018). For instance, acyl homoserine lactone analogs such as N-acyl cyclopentyl amines (Cn-CPAs), lactonase SsoPox, N-acylhomoserine lactonase, and AiiM (Guendouze et al, 2017;López-Jácome et al, 2019) were effective as QSIs against P. aeruginosa.…”

Potassium 2-methoxy-4-vinylphenolate: a novel hit exhibiting quorum-sensing inhibition inPseudomonas aeruginosa viaLasIR/RhlIR circuitry

“…[21][22][23][24] Literature is full of reports particularly on quorum sensing inhibition in Pseudomonas aeruginosa. [25][26][27][28][29][30][31][32][33][34][35][36] Carvacrol (essential oil) was reported to inhibit biolm formation in S. aureus and P. aeruginosa and pyocyanin production in P. aeruginosa signicantly. 37 Baicalein (avonoid from the roots of Scutellaria baicalensis) was demonstrated to inhibit several virulence factors and biolm formation.…”