Soukarieh, F. orcid.org/0000-0002-6730-2543, Gurnani, P. orcid.org/0000-0002-6559-5514, Romero, M. orcid.org/0000-0001-6902-6776 et al. (4 more authors) (2023) Design of quorum sensing inhibitor–polymer conjugates to penetrate Pseudomonas aeruginosa biofilms. ACS Macro Letters, 12 (3). pp. 314-319. ISSN 2161-1653
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2023 The Authors. This publication is licensed under CC-BY 4.0 - https://creativecommons.org/licenses/by/4.0/. |
Keywords: | Quorum Sensing; Pseudomonas aeruginosa; Biofilms; Anti-Bacterial Agents; Ciprofloxacin |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Health Sciences School (Sheffield) |
Funding Information: | Funder Grant number BIOTECHNOLOGY AND BIOLOGICAL SCIENCES RESEARCH COUNCIL BB/R012415/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 31 Jan 2025 14:17 |
Last Modified: | 31 Jan 2025 14:17 |
Status: | Published |
Publisher: | American Chemical Society (ACS) |
Refereed: | Yes |
Identification Number: | 10.1021/acsmacrolett.2c00699 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:222697 |