Garcia Maset, Ramon (2022) Synthetic nanoengineered antimicrobial polymer peptides (SNAPPs) : investigation of antimicrobial and antibiofilm properties. PhD thesis, University of Warwick.

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Abstract

This thesis investigates the antimicrobial activity of a library of synthetic nanoengineered antimicrobial polymer peptides (SNAPPs) synthetized via RAFT polymerization. We investigated the effect of media composition on the antimicrobial activity of the polymeric materials. Undeniably, the media played an important role in the antimicrobial effect of SNAPPs, improving the antimicrobial activity of the material in synthetic wound fluid (SWF) against S. aureus strains, and in synthetic cystic fibrosis medium (SCFM) against P. aeruginosa strains. We investigated the cytotoxicity of the copolymers against red blood cells, mammalian cells and against an insect model in vivo. A good correlation of the cytotoxicity profiles between the in vitro and in vivo assays was reported. The guanidinium copolymers exhibited higher cytotoxic profiles in comparison with the ammonium counterparts, and the low molecular weight copolymers were not toxic even at the highest concentration tested. Subsequently, we investigated the mechanism of action of SNAPPs against P. aeruginosa. The segregation of the hydrophobic block shown to be crucial in the antimicrobial activity, being diblock copolymers inactive against P. aeruginosa in comparison with the highly active triblock copolymer counterparts. The data indicated that both diblock and triblock copolymers interacted strongly with the lipopolysaccharide (LPS) of the outer membrane, while membrane disruption effects were only observed for the triblock copolymers. Neutron reflectometry measurements in lipid bilayer model indicated that the triblock copolymer structure drove the insertion of the copolymer into the lipid bilayer whilst the diblock copolymers acted more as surfactant-like compounds. Membrane depolarization assays showed that all the copolymers could cause membrane potential dissipation against the inner membrane of the bacterial cells. Therefore, we hypothesised that diblock copolymers were inactive for their inability to insert into the outer membrane, while the triblock copolymers could insert into the outer membrane causing membrane disruption effects. Lastly, we investigated the pairwise combination of SNAPPs with conventional antibiotics against planktonic S. aureus and P. aeruginosa. The synergistic pairs were tested against S. aureus biofilms and P. aeruginosa biofilms in advanced models. Selected SNAPPs/antibiotic combinations were able to prevent biofilm formation and eradicate mature biofilms in ex vivo biofilm models, indicating a potent synergistic effect between the copolymer and the conventional antibiotic

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry R Medicine > RB Pathology R Medicine > RM Therapeutics. Pharmacology R Medicine > RS Pharmacy and materia medica T Technology > TP Chemical technology
Library of Congress Subject Headings (LCSH):	Peptide antibiotics, Biofilms, Anti-infective agents, Antimicrobial polymers, Addition polymerization, Polymerase chain reaction
Official Date:	July 2022
Dates:	Date Event July 2022 UNSPECIFIED
Institution:	University of Warwick
Theses Department:	Warwick Medical School
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Perrier, Sébastien ; Harrison, Freya
Format of File:	pdf
Extent:	A-G, xxxvi, 289 leaves : colour illustrations
Language:	eng

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