Kuroki, Agnès (2019) Investigating the selectivity of sequence-controlled antimicrobial polymers synthesised by RAFT polymerisation. PhD thesis, University of Warwick.

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Abstract

Bacterial resistance has become a pressing clinical issue for which the World Health Organisation has raised awareness due to the low levels of infection control reached recently. This global issue has been considered as a failure in antibiotic drug discovery and new types of antibiotics have recently been investigated to tackle it.

For this reason, new types of antibiotics have recently been investigated. Among these, antimicrobial peptides (AMPs) have attracted an increased interest and a few of them are currently undergoing clinical trials. AMPs are peptides comprised of 10-50 amino-acids with cationic and hydrophobic residues, present in the innate immune system of multicellular organisms, hence the terminology host-defence peptides. The majority of these peptides, adopt an amphipathic helical conformation with the cationic functionalities on one side of the coil and the hydrophobic ones on the other. AMPs have demonstrated a broad-range antimicrobial activity, which is associated to their mechanism of action based on bacterial membrane disruption. Indeed, the positively charged residues of AMPs have been shown to interact with the negatively charged phospholipids of bacterial membranes. Following the binding of AMPs to bacterial membranes, the hydrophobic residues of AMPs insert into the membrane, inducing the formation of pores. Once the integrity of the bacterial membrane is compromised, there is leakage of the intracellular material, which leads to bacterial cell death. Remarkably, as AMPs seem to target bacterial membrane instead of a specific ligand, they do not seem to evoke bacterial resistance against these peptides. Indeed, only minor structural changes are required for bacteria to exhibit a reduced susceptibility towards conventional antibiotics, whereas more significant changes in the structure of the bacterial membrane would be necessary to prevent the antimicrobial action of AMPs. This membrane interaction based on electrostatic interactions allows AMPs to be selective towards bacteria over mammalian cells to a certain extent.

Item Type:	Thesis (PhD)
Subjects:	Q Science > QD Chemistry Q Science > QR Microbiology R Medicine > R Medicine (General) T Technology > T Technology (General)
Library of Congress Subject Headings (LCSH):	Antimicrobial polymers, Polymerization, Bacterial diseases, Peptide antibiotics, Immune system -- Effect of drugs
Official Date:	May 2019
Dates:	Date Event May 2019 Published
Institution:	University of Warwick
Theses Department:	Department of Chemistry
Thesis Type:	PhD
Publication Status:	Unpublished
Supervisor(s)/Advisor:	Perrier, Sebastien; Locock, Katherine
Sponsors:	Commonwealth Scientific and Industrial Research Organisation
Format of File:	pdf
Extent:	xx, 185 leaves: illustrations, charts
Language:	eng

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