Investigating the lifestyle of Pseudomonas aeruginosa using chemical genomics.

Doherty, Hannah ORCID: 0000-0002-1216-0621 (2024). Investigating the lifestyle of Pseudomonas aeruginosa using chemical genomics. University of Birmingham. Ph.D.

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Abstract

Chemical genomics is a powerful tool for functionally linking genotype to phenotype on a genome wide level, elucidating unknown gene function, potential drug targets and antimicrobial resistance determinants. Antimicrobial resistance is threatening the treatment of Pseudomonas aeruginosa infections. Therefore, research is required to evaluate the lifestyle of this bacterium and develop new therapies for treatment. This study utilised chemical genomics to evaluate and compare two P. aeruginosa strains, PAO1 and PA14. Due to the limited analysis software within the field, this study produced ChemGAPP, a comprehensive software for the analysis of chemical genomic screening data. Tested against real-world data, ChemGAPP showed success in revealing biologically relevant phenotypes. Following testing, ChemGAPP was employed on the PAO1 and PA14 chemical genomic screening data. Analysis revealed clear differences in the phenotypic responses of PAO1 and PA14, despite their genetic similarity. One major phenotype present in both screens was biotin mediated resistance against the diabetes drug metformin. A TraDIS library within a biotin deficient PA14 mutant was produced to reveal insights into the function of metformin. Genes highlighted within the TraDIS screen suggest that metformin disrupts energy production. This led to the hypothesis that biotin-dependent carboxylases are vital for compensation via alternative forms of energy production. Crucially, further research into the connection between metformin and biotin could lead to the development of a new therapy for P. aeruginosa infections. Specifically, a combination therapy of metformin with a biotin synthesis inhibitor.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):