Inhibiting Quorum Sensing by Active Targeted pH-Sensitive Nanoparticles for Enhanced Antibiotic Therapy of Biofilm-Associated Bacterial Infections

Inhibitionof quorum sensing (QS) is considered as an effectivestrategy in combatting biofilm-associated bacterial infections. However,the application of quorum sensing inhibitors (QSI) is strongly restrictedby poor water-solubility and low bioavailability. We herein fabricatepH-sensitive curcumin (Cur) loaded clustered nanoparticles with activetargeting ability (denoted as anti-CD54@Cur-DA NPs) to inhibit QSfor enhanced antibiotic therapy. Cur-DA NPs are first prepared throughelectrostatic interaction between Cur loaded amino-ended poly-(amidoamine)dendrimer (PAMAM) and 2,3-dimethyl maleic anhydride (DA) modifiedbiotin-poly-(ethylene glycol)-polylysine (biotin-PEG-PLys). Anti-CD54@Cur-DANPs are then obtained by the modification of Cur-DA NPs with anti-CD54.Cur loaded PAMAM can be released from Cur-DA NPs in acidic pH, leadingto simultaneous charge reversal and size decrease, which is beneficialfor biofilm penetration. Cur-DA NPs are hence much better in inhibitingQS than free Cur due to enhanced biofilm penetration. Compared tofree Cur, Cur-DA NPs exhibit stronger capability in inhibiting thedevelopment of biofilm architecture and maturation, thus downregulatingefflux pump-related genes and improving bactericidal performance ofmultiple antibiotics, including Penicillin G, ciprofloxacin, and tobramycin.Moreover, since anti-CD54 can selectively bind to inflamed endothelialcells, anti-CD54@Cur-DA NPs can be targeted accumulated in bacteria-infectedtissues. The sequential treatment using anti-CD54@Cur-DA NPs and freeantibiotics can effectively reduce bacterial burden and alleviateinflammation in a chronic lung infection model in vivo. This research provides an effective way to improve the therapeuticperformance of QSI to enhance the anti-biofilm effects of antibiotics,which radiate a vitality of conventional antibiotics in treating biofilm-associatedbacterial infections.

Automated summary

This research focuses on the development of pH-sensitive curcumin-loaded nanoparticles for inhibiting quorum sensing (QS) and enhancing antibiotic therapy. The nanoparticles show enhanced biofilm penetration and increased bactericidal performance against antibiotics. Additionally, they can selectively accumulate in bacteria-infected tissues through active targeting. This research offers a promising approach to enhance the therapeutic effects of quorum sensing inhibitors and improve antibiotic treatment for biofilm-associated bacterial infections.