Targeted synthesis and biological evaluation of heterocycles as bacterial inhibitors

Carmody, Muireann

Controlled Access. Restriction lift date: 2031-12-31

Targeted synthesis and biological evaluation of heterocycles as bacterial inhibitors

dc.check.chapterOfThesis	I would like to put a 5 year embargo on my thesis. Specifically on the research chapters 2, 3 and 4.	en
dc.check.date	2031-12-31
dc.check.info	Controlled Access
dc.contributor.advisor	McGlacken, Gerard
dc.contributor.advisor	Reen, F.Jerry
dc.contributor.author	Carmody, Muireann	en
dc.contributor.funder	Research Ireland	en
dc.date.accessioned	2026-10-01T11:17:40Z
dc.date.available	2026-10-01T11:17:40Z
dc.date.issued	2026-03-26
dc.date.submitted	2026-03-26
dc.description	Controlled Access
dc.description.abstract	Antimicrobial resistance (AMR) is a major challenge whereby microorganisms such as bacteria, viruses, fungi, and parasites acquire or develop mechanisms that diminish or nullify the efficacy of antimicrobial agents. This results in a reduction of therapeutic options, prolongs infections, and increases rates of morbidity, mortality, and transmission. This thesis aimed to address AMR in bacterial pathogens through two complementary strategies: disrupting bacterial cell-to-cell communication that drives virulence and expanding access to new antibiotics through late-stage functionalisation of established scaffolds. Cell-to-cell communication in microbial systems is known for its vital role in cellular signalling and gene expression. Microbial functions associated with bacterial virulence, pathogenicity, host-microbe interaction, and biofilm development are mediated by cell-to-cell communication. Disrupting these communication networks using anti-virulence therapies is desirable, as a non-biocidal approach reduces the evolutionary pressure on microbes to develop resistance to these agents. Chapter 2 provides evidence that coumarin compounds interfere with the Pseudomonas quinolone signal (PQS) system by inhibiting PqsR, a LysR-type transcriptional regulator (LTTR), within the nosocomial pathogen Pseudomonas aeruginosa. Mechanistic studies indicate, for the first time, that these compounds act by competitive inhibition, resulting in reduced activity of a PqsR translational fusion and suppression of biofilm formation. This offers an attractive approach to controlling P. aeruginosa virulence. The genetic flexibility of PqsR was also explored to examine its suitability as a potential drug target. During this investigation an interesting phenomenon was revealed whereby a large 608 kb region of the P. aeruginosa genome was found to be free of LTTR encoding genes. Pyrones (structurally related to coumarins) have recently emerged as signalling molecules targeting LuxR-type receptors. Chapter 3 investigates how a suite of pyrones (and pyridinone analogues) elicit behavioural changes in P. aeruginosa and other multidrug resistant/opportunistic pathogens, thereby identifying another class of compounds with anti-virulence properties. Biological pathways impacted by the lead compound were elucidated through proteomic profiling, targeted gene expression analysis by qRT‑PCR, and promoter fusion reporter assays. While molecules targeting bacterial communication systems present a promising strategy of combatting AMR, traditional antibiotics remain the most effective treatment to date for bacterial infections. Therefore, innovative strategies allowing access to new antibiotics are critically important. Chapter 4 details the selective iridium-catalysed C−H borylation of 6-fluoroquinolones, a well-established traditional biocidal antibiotic framework. The synthesised boronate esters were isolated in moderate to excellent yields and have the potential to exhibit antibacterial activity. Furthermore, these compounds serve as versatile intermediates for subsequent derivatisation, enabling late-stage functionalisation of the desired antibiotic scaffold, specifically at the C-7 position.	en
dc.description.status	Not peer reviewed	en
dc.description.version	Accepted Version	en
dc.format.mimetype	application/pdf	en
dc.identifier.citation	Camody, M. 2026. Targeted synthesis and biological evaluation of heterocycles as bacterial inhibitors. PhD Thesis, University College Cork.
dc.identifier.endpage	378
dc.identifier.uri	https://hdl.handle.net/10468/19394
dc.language.iso	en	en
dc.publisher	University College Cork	en
dc.relation.project	Research Ireland (Postgraduate Scholarship GOIPG/2021/692)
dc.rights	© 2026, Muireann Carmody.
dc.rights.uri	https://creativecommons.org/licenses/by-nc-nd/4.0/
dc.subject	Coumarin	en
dc.subject	Pseudomonas aeruginosa	en
dc.subject	Pathogens	en
dc.subject	Antimicrobial resistance	en
dc.subject	Quorum Sensing	en
dc.subject	Anti-virulence therapies	en
dc.subject	Pyrone	en
dc.subject	Proteomics	en
dc.subject	Borylation	en
dc.subject	Fluoroquinolone	en
dc.subject	C-H functionalisation	en
dc.subject	Iridium catalysis	en
dc.subject	Antibiotics	en
dc.title	Targeted synthesis and biological evaluation of heterocycles as bacterial inhibitors
dc.type	Doctoral thesis	en
dc.type.qualificationlevel	Doctoral	en
dc.type.qualificationname	PhD - Doctor of Philosophy	en