Biofilm penetrating and disrupting polymers to effectively treat endotracheal-tube-associated biofilm infections.

Abstract

Endotracheal-tube-associated biofilm infections (ETTABIs) are directly responsible for most of ventilator-associated pneumonia (VAP), one of the most frequent ICU-acquired infections with up to 13% mortality rates. Herein, we report a new type of biofilm penetrating and disrupting polymers that can be readily used to effectively treat the ETTABIs. A series of mixed-charge brush polymers with dextran main-chains and random copolypeptide side-chains (e.g., Dex-G_nE_m) were synthesized by a combination of ring-opening polymerization and side-chain or end-group modifications. The effects of α-amino-acid residue compositions, cationic species, and brush-like topological structures on antibiofilm activities were revealed. The top-performing polymer, namely Dex-G₁₅E₁₅ with equivalent guanidinium-modified L-lysine and L-glutamic acid residues showed efficient biofilm penetrating activity significantly outperforming its cationic polymer counterpart. It also showed potent biofilm disrupting activity that over 90% biofilm can be readily eradicated within 24 h. The majority of the bacteria in the biofilms were killed by a membrane disruption mechanism. In addition, Dex-G₁₅E₁₅ could eradicate biofilms formed in endotracheal tubes, inhibit lung infections, and reduce inflammatory responses in a mouse endotracheal intubation model. This work provides a promising antibiofilm reagent candidate to efficiently treat ETTABIs and VAP. STATEMENT OF SIGNIFICANCE: Endotracheal-tube-associated biofilm infections (ETTABIs) present a major challenge in critical care settings, driving persistent infections, antimicrobial resistance, and ventilator-associated pneumonia. Conventional antimicrobial strategies often fail to penetrate biofilms or inadvertently promote bacterial adaptation. Herein, we developed a biofilm penetrating and disrupting polymer to effectively treat ETTABIs. The polymer with brush-like structure and mixed-charge side-chain showed potent biofilm eradication efficacy by efficient penetrating the biofilm, disrupting both biofilm EPS and bacterial membranes, outperforming conventional antibiotics (e.g., ceftazidime, tobramycin, and ciprofloxacin) and linear or brush-like cationic polymers. It also showed potent inhibition of lung infections and reduction of inflammatory responses in a mouse endotracheal intubation model, making it a promising candidate to combat the ETTABIs.