Rational development of novel small molecule leads against the transcriptional activator protein ExsA of Pseudomonas aeruginosa
type: CreativeWork
description: Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen. It is present in aquatic, marine, and soil environments and can also be found in a variety of anthropological environments, including water distribution systems and hospitals. This prevalence is concerning due to P. aeruginosa’s status as an opportunistic pathogen, and the latter particularly so because it is a common cause of nosocomial infections. Burn victims and cystic fibrosis patients are particularly vulnerable to P. aeruginosa infections. The pathogen is highly virulent, and consequently it is a leading cause of death in intensive care units, especially among cases of ventilator associated pneumonia. Treating P. aeruginosa infections is complicated by its resistance to multiple drugs. Besides acquiring resistance mutations to antibiotic targets, the pathogen also possesses a suite of efflux pumps capable of exporting a wide range of antibiotics. P. aeruginosa has two distinct virulent lifestyles which correspond to acute and chronic infections. P. aeruginosa’s type three secretion system (T3SS) dominate in acute infection, and the expression of this system is regulated by the transcription factor ExsA. The latter therefore represents an attractive target for developing anti-virulence drugs against this pathogen. I have further characterised ExsA and its regulon with a proteomics experiment utilising deletion mutants which have an “ExsA always on” phenotype as well as an exsA deletion mutant. An extended ExsA regulon was revealed, including well known virulence factors such as HCN, and potential novel factors such as an uncharacterised non-ribosomal peptide synthase. Effectors of, and components for, the type six secretion system (associated with chronic infections and generally inversely regulated compared to the type three secretion system) were also identified as overexpressed in the “ExsA always on” mutants. Potential connections to other signalling systems are also examined. This work stre…
abstract: Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen. It is present in aquatic, marine, and soil environments and can also be found in a variety of anthropological environments, including water distribution systems and hospitals. This prevalence is concerning due to P. aeruginosa’s status as an opportunistic pathogen, and the latter particularly so because it is a common cause of nosocomial infections. Burn victims and cystic fibrosis patients are particularly vulnerable to P. aeruginosa infections. The pathogen is highly virulent, and consequently it is a leading cause of death in intensive care units, especially among cases of ventilator associated pneumonia. Treating P. aeruginosa infections is complicated by its resistance to multiple drugs. Besides acquiring resistance mutations to antibiotic targets, the pathogen also possesses a suite of efflux pumps capable of exporting a wide range of antibiotics. P. aeruginosa has two distinct virulent lifestyles which correspond to acute and chronic infections. P. aeruginosa’s type three secretion system (T3SS) dominate in acute infection, and the expression of this system is regulated by the transcription factor ExsA. The latter therefore represents an attractive target for developing anti-virulence drugs against this pathogen. I have further characterised ExsA and its regulon with a proteomics experiment utilising deletion mutants which have an “ExsA always on” phenotype as well as an exsA deletion mutant. An extended ExsA regulon was revealed, including well known virulence factors such as HCN, and potential novel factors such as an uncharacterised non-ribosomal peptide synthase. Effectors of, and components for, the type six secretion system (associated with chronic infections and generally inversely regulated compared to the type three secretion system) were also identified as overexpressed in the “ExsA always on” mutants. Potential connections to other signalling systems are also examined. This work stre…
author: Greenhalgh, Jack
language: eng
keywords: pseudomonas aeruginosa, T3SS, type three secretion system, virtual screening
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2022-06-30
date modified: 2026-07-22T22:23:59Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.93261