City Research Online

Abstract

Antimicrobial resistance is widely recognised as one of the greatest threats to global healthcare. Its increasing prevalence necessitates the development of novel therapeutics with mechanisms of action that are still effective against multidrug resistant pathogens. This is particularly relevant in the context of the ESKAPE pathogens, a group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and the Enterobacter species) known to cause virulent and multidrug resistant hospital-acquired infection across the globe.

Antimicrobial peptides (AMPs) are attractive candidates for therapeutic development due to their exhibited activity against an array of pathogens with differing profiles of resistance. This project explored the viability of two sources of AMPs. Peptides were isolated from human lung airway surface liquid (ASL) samples or identified within 1 of 20 organism genomes using a metagenomic screening and prediction software. The software identified over 4000 sequences with predicted activity, 2000 of which were selected and synthesised on cellulose membranes. These were then screened against E. coli in 10% human serum solution, with candidates showing high a ntimicrobial activity being selected for synthesis on resin and subsequent purification.

Purified candidates were then tested for activity against the ESKAPE pathogens in 0, 10, and 25% serum solutions. In addition to serum tolerance, haemolytic and cytotoxic capacities of the candidates were investigated, and their mechanisms of action were characterised following generation of dose-response and time-kill curves. Lastly, selected candidates were assessed for in vivo activity using a G. mellonella infection model.

Peptides isolated from the lung peptidome were also investigated for antimicrobial activity; these peptides were then screened further for inhibition or stimulation of cell growth and calcium signalling. Candidates were then further characterised through investigations into the dose-response relationships of the observed effects.

Publication Type:	Thesis (Doctoral)
Subjects:	Q Science > QR Microbiology R Medicine R Medicine > RA Public aspects of medicine > RA0421 Public health. Hygiene. Preventive Medicine
Departments:	School of Health & Medical Sciences > Infection and Immunity Research Institute School of Health & Medical Sciences > School of Health & Medical Sciences Doctoral Theses Doctoral Theses

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