Design of Quorum Sensing Inhibitor–Polymer Conjugates to Penetrate Pseudomonas aeruginosa Biofilms

Soukarieh, Fadi; Gurnani, Pratik; Romero, Manuel; Halliday, Nigel; Stocks, Michael; Alexander, Cameron; Cámara, Miguel

Abstract

Antimicrobial resistance (AMR) is a global threat to public health with a forecast of a negative financial impact of one trillion dollars per annum, hence novel therapeutics are urgently needed. The resistance of many bacteria against current drugs is further augmented by the ability of these microbes to form biofilms where cells are encased in a slimy extracellular matrix and either adhered to a surface or forming cell aggregates. Biofilms form physiochemical barriers against the penetration of treatments such as small molecule antibacterials, rendering most treatments ineffective. Pseudomonas aeruginosa, a priority pathogen of immediate concern, controls biofilm formation through multiple layers of gene regulation pathways including quorum sensing (QS), a cell-to-cell signaling system. We have recently reported a series of inhibitors of the PqsR QS regulator from this organism that can potentiate the action of antibiotics. However, these QS inhibitors (QSIs) have shown modest effects on biofilms in contrast with planktonic cultures due to poor penetration through the biofilm matrix. To enhance the delivery of the inhibitors, a small library of polymers was designed as carriers of a specific QSI, with variations in the side chains to introduce either positively charged or neutral moieties to aid penetration into and through the P. aeruginosa biofilm. The synthesized polymers were evaluated in a series of assays to establish their effects on the inhibition of the Pqs QS system in P. aeruginosa, the levels of inhibitor release from polymers, and their impact on biofilm formation. A selected cationic polymer-QSI conjugate was found to penetrate effectively through biofilm layers and to release the QSI. When used in combination with ciprofloxacin, it enhanced the biofilm antimicrobial activity of this antibiotic compared to free QSI and ciprofloxacin under the same conditions.

Citation

Soukarieh, F., Gurnani, P., Romero, M., Halliday, N., Stocks, M., Alexander, C., & Cámara, M. (2023). Design of Quorum Sensing Inhibitor–Polymer Conjugates to Penetrate Pseudomonas aeruginosa Biofilms. ACS Macro Letters, 12(3), 314-319. https://doi.org/10.1021/acsmacrolett.2c00699

• Journal Article Type: Article
• Acceptance Date: Feb 1, 2023
• Online Publication Date: Feb 15, 2023
• Publication Date: Mar 21, 2023
• Deposit Date: Apr 18, 2023
• Publicly Available Date: Apr 18, 2023
• Journal: ACS Macro Letters
• Electronic ISSN: 2161-1653
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 3
• Pages: 314-319
• DOI: https://doi.org/10.1021/acsmacrolett.2c00699
• Keywords: Materials Chemistry; Inorganic Chemistry; Polymers and Plastics; Organic Chemistry
• Public URL: https://nottingham-repository.worktribe.com/output/16801602
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsmacrolett.2c00699