A Potential Quorum-Sensing Inhibitor for Bronchiectasis Therapy: Quercetin–Chitosan Nanoparticle Complex Exhibiting Superior Inhibition of Biofilm Formation and Swimming Motility of Pseudomonas aeruginosa to the Native Quercetin

Abstract

Quercetin (QUE)—a plant-derived flavonoid, is recently established as an effective quorum sensing (QS) inhibiting agent in Pseudomonas aeruginosa—the main bacterial pathogen in bronchiectasis lungs. Successful clinical application of QUE, however, is hindered by its low solubility in physiological fluids. Herein we developed a solubility enhancement strategy of QUE in the form of a stable amorphous nanoparticle complex (nanoplex) of QUE and chitosan (CHI), which was prepared by electrostatically driven complexation between ionized QUE molecules and oppositely charged CHI. At its optimal preparation condition, the QUE–CHI nanoplex exhibited a size of roughly 150 nm with a 25% QUE payload and 60% complexation efficiency. The complexation with CHI had no adverse effect on the antibacterial and anticancer activities of QUE, signifying the preservation of QUE’s bioactivities in the nanoplex. Compared to the native QUE, the QUE–CHI nanoplex exhibited superior QS inhibition in suppressing the QS-regulated swimming motility and biofilm formation of P. aeruginosa, but not in suppressing the virulence factor production. The superior inhibitions of the biofilm formation and swimming motility afforded by the nanoplex were attributed to (1) its higher kinetic solubility (5-times higher) that led to higher QUE exposures, and (2) the synergistic QS inhibition attributed to its CHI fraction.

Hydrophobic Chitosan Nanoparticles Loaded with Carvacrol against Pseudomonas aeruginosa Biofilms

“…Tran and Hadinoto [ 24 ] proposed a similar approach to our study. They used quercetin due to its excellent antimicrobial effects and limited use as a treatment due to its low solubility.…”

“…They described that subinhibitory concentrations of quercetin in the nanocomplex produced lower rates of biofilm formation and a 40% reduction in motility of P. aeruginosa compared to control and native quercetin. Furthermore, a synergistic effect was observed among chitosan and quercetin due to a higher quercetin exposure because of its greater solubility [ 24 ]. Mohammed, Rayyif [ 46 ] created a nanostructured system using Fe 3 O 4 nanoparticles and eugenol, a natural plant compound previously shown to inhibit microbial virulence.…”

“…A previous study showed that pure carvacrol at 1.2 mg·mL −1 decreased violacein production in C. violaceum by approximately 50% [ 29 ], while, in our study, the encapsulated carvacrol reduced more pigment production at the same concentration. This effect could be attributed to the anti-quorum-sensing activity of chitosan [ 24 ] and carvacrol by interfering with lactones, synthase CviI, receptor CviR, or related gene expression. It has been reported that carvacrol reduces biofilm formation and motility through QS inhibition [ 15 ].…”

“…This biopolymer has been used to encapsulate essential oils and other plant-derived compounds [ 23 ]. For example, Tran and Hadinoto [ 24 ] managed to encapsulate quercetin into chitosan nanoparticles; this treatment improved the quercetin solubility in physiological fluids and reduced P. aeruginosa biofilm formation by reducing motility and quorum-sensing activities. Therefore, the revised evidence showed the potential use of chitosan nanoparticles with carvacrol as an antibiofilm treatment of P. aeruginosa .…”

Dual-Functional Surfaces Based on an Antifouling Polymer and a Natural Antibiofilm Molecule: Prevention of Biofilm Formation without Using Biocides

“…Compared with either repelling bacterial adhesion or killing attached bacteria in the early stage, it is more challenging to prevent the formation of biofilm for a long period of time, in particular, under the condition with sufficient nutrients because a small number of living bacteria remaining on the surface will form biofilms in a short time as long as they have the opportunity to proliferate and colonize. As a typical plant-derived antibiofilm molecule, Qe has been well demonstrated to interfere with the biofilm developmental processes of both Gram-negative and Gram-positive bacteria. ,− More importantly, inhibition of the biofilm in developmental stages related to microbiological behaviors by Qe does not cause a “live or die” selection pressure on bacteria, thus slowing down the evolution of microorganisms to “super-bacteria” . Here, to investigate the long-term antibiofilm performance, after being incubated in bacterial suspension for 4 h, the sample surfaces were rinsed gently and transferred to new wells containing nutrient medium to provide sufficient nutrients for the growth of biofilms.…”