Document Type

Thesis

Degree Name

Master of Science (MSc)

Department

Chemistry

Faculty/School

Faculty of Science

First Advisor

Anthony J Clarke

Advisor Role

Supervisor

Second Advisor

Joel Weadge

Advisor Role

Thesis committee member

Third Advisor

Geoff Horsman

Advisor Role

Thesis committee member

Abstract

Experts project that by 2050, 10 million lives will be lost annually as a result of antimicrobial resistant infections, surpassing all current leading causes of death, and costing the global economy $100 trillion USD on healthcare efforts. To promote research and development of novel antibiotics, the World Health Organization and Centers for Disease Control and Prevention released a list of priority pathogens regarded as serious or urgent threats of antimicrobial resistance. Many pathogenic bacteria, including several priority pathogens, produce O-acetylated peptidoglycan to establish infection and avoid host immune responses. Consequently, the enzymes responsible for producing O-acetylated peptidoglycan in Gram-negative pathogenic bacteria, peptidoglycan O-acetyltransferase A and B (PatA/PatB), are recognized as a virulence factor. In this thesis, the identification of aurintricarboxylic acid, purpurin, and a presumed degradation product of compound 89224 (a benzothiazolyl-pyrazolo-pyridine from the ChemBridge Collection) are presented as amongst the first known inhibitors of PatB from Neisseria gonorrhoeae (NgPatB). Additionally, several residues on NgPatB were identified to be essential for O-acetyltransferase activity using a surrogate peptidoglycan acetyl-acceptor, as well as making significant interactions with the identified inhibitors. This thesis serves as a foundation upon which novel broad-spectrum inhibitors of peptidoglycan O-acetyltransferases and ­O-acetylesterases can be derived, ultimately allowing the possibility to mitigate the threats of antimicrobial resistance.

Convocation Year

2022

Convocation Season

Spring

Available for download on Wednesday, September 21, 2022

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