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Identification of inhibitors of protein-protein interactions essential for virulence in pathogenic bacteria

Identification of inhibitors of protein-protein interactions essential for virulence in pathogenic bacteria
Identification of inhibitors of protein-protein interactions essential for virulence in pathogenic bacteria
There is a continous requirement for broad-spectrum post-exposure antibiotic therapeutics. Meeting this challenge relies on the production of compounds that successfully disrupt bacterial systems identified as both conserved and essential. Here, inhibitors of protein-protein interactions involved in the Phage shock protein response and toxin internalisation, within Burkholderia pseudomallei and Bacillus anthracis, respectively have been identified. This was achieved using a high-throughput screen that combines a bacterial reverse two-hybrid system and an intein-mediated method for the generation of cyclic peptide libraries.

A reverse two-hybrid system for Burkholderia pseudomallei PspA homodimerisation was constructed, alongside a heterodimeric system for the interaction between Bacillus anthracis protective antigen and the mammalian receptor, capillary morphogenesis gene-2. From both systems a series of peptide sequences were identified with potential inhibitory activity within the reverse two-hybrid system. These compounds were synthesised and their activity assessed using a selection of in vitro assays.

This study identified two cyclic peptides sequences active in the reverse two-hybrid system against PspA oligomerisation; which were not active in vitro. In contrast, three linear peptides were isolated that demonstrated the ability to disrupt the interaction between protective antigen and the mammalian receptor, with one binding specifically to the receptor. This linear inhibitor provides the foundation for the development of a more potent antimicrobial for the arsenal against Bacillus anthracis.
Male, Abigail
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Male, Abigail
cad6c2bc-04df-4078-b5d2-9f3c808e6152
Tavassoli, Ali
d561cf8f-2669-46b5-b6e1-2016c85d63b2

Male, Abigail (2014) Identification of inhibitors of protein-protein interactions essential for virulence in pathogenic bacteria. University of Southampton, Chemistry, Doctoral Thesis, 322pp.

Record type: Thesis (Doctoral)

Abstract

There is a continous requirement for broad-spectrum post-exposure antibiotic therapeutics. Meeting this challenge relies on the production of compounds that successfully disrupt bacterial systems identified as both conserved and essential. Here, inhibitors of protein-protein interactions involved in the Phage shock protein response and toxin internalisation, within Burkholderia pseudomallei and Bacillus anthracis, respectively have been identified. This was achieved using a high-throughput screen that combines a bacterial reverse two-hybrid system and an intein-mediated method for the generation of cyclic peptide libraries.

A reverse two-hybrid system for Burkholderia pseudomallei PspA homodimerisation was constructed, alongside a heterodimeric system for the interaction between Bacillus anthracis protective antigen and the mammalian receptor, capillary morphogenesis gene-2. From both systems a series of peptide sequences were identified with potential inhibitory activity within the reverse two-hybrid system. These compounds were synthesised and their activity assessed using a selection of in vitro assays.

This study identified two cyclic peptides sequences active in the reverse two-hybrid system against PspA oligomerisation; which were not active in vitro. In contrast, three linear peptides were isolated that demonstrated the ability to disrupt the interaction between protective antigen and the mammalian receptor, with one binding specifically to the receptor. This linear inhibitor provides the foundation for the development of a more potent antimicrobial for the arsenal against Bacillus anthracis.

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Published date: 1 September 2014
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 369351
URI: http://eprints.soton.ac.uk/id/eprint/369351
PURE UUID: c7dfb649-19c5-471f-aab6-96d5aff7f367
ORCID for Ali Tavassoli: ORCID iD orcid.org/0000-0002-7420-5063

Catalogue record

Date deposited: 27 Oct 2014 12:04
Last modified: 06 Jun 2018 12:40

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