Discovery and development of novel antimicrobials from gastrointestinal tract microbiomes

Abstract

The need to develop novel antimicrobials against bacterial pathogens of extreme clinical importance is an extremely pressing issue. Developing long-term strategies for the treatment of bacterial pathogens such as Acinetobacter baumannii to minimise antimicrobial resistance development is necessary for future infection control and ensuring longer lifespans for antimicrobials within healthcare settings. However there is still a need to develop innovative pipelines for the discovery of novel antimicrobials to provide treatment options in the future. Exploring non-small molecule therapies such as antimicrobial peptides (AMPs) can provide an additional dimension to the compounds currently being developed for the clinic.

This thesis focussed on utilising AMPs from gastrointestinal microbiomes, specifically the rumen of the domesticated cow and greater kudu, and the caecal environment from the domesticated chicken. These three groups of AMPs were in various stages of development, from the published Lynronne AMPs through to novel AMP sequences identified as part of this research project specifically to target A. baumannii. All three groups underwent a variety of characterisation assays to determine their efficacy and potential as treatments for infections caused by A. baumannii. These assays included activity and structural determinations, performance against survival mechanisms exhibited by A. baumannii, mechanistic studies, transcriptomic analysis and toxicity determinations, amongst others.

All three groups (containing Lynronne-1, -2 -3, K1, K14, K16, CHK_9, CHK_56, CHK_77 and CHK_103) produced candidates with high therapeutic potential and comprehensive datasets for each AMP were generated. All 10 AMPs exhibited strong performance against A. baumannii, with the majority showing notable anti-biofilm properties and low toxicity. The performance demonstrated by both previously identified AMPs and novel AMPs also strengthens the case for utilising AMPs within clinical settings, and the methods of in silico identification will allow for future rapid identification and development of targeted antimicrobials to treat antimicrobial resistant clinical infections.

Thesis is embargoed until 31 December 2025.

Date of Award	Dec 2023
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	Northern Ireland Department for the Economy
Supervisor	Sharon Huws (Supervisor), Brendan Gilmore (Supervisor) & Stephen Cochrane (Supervisor)