Develop Cutting-Edge Peptide Therapies to Fight Antimicrobial Resistance in Eye Infections

About the Project

The cornea, a dome-shaped, transparent tissue at the front of the eye, is crucial for vision. Corneal infections, such as bacterial keratitis (BK), are among the leading causes of unilateral blindness worldwide. BK is predominantly caused by bacteria including Staphylococcus aureus, Streptococcus pneumoniae, coagulase-negative staphylococci, and Pseudomonas aeruginosa. The prevalence of BK varies geographically, with extended contact lens wear and ocular trauma being the most common risk factors. Patients with BK often present with severe corneal ulceration and typically require aggressive antibiotic therapy. However, due to the severity of the infection, the prognosis is often poor, frequently resulting in visual impairment or blindness in the affected eye(s). Furthermore, the increasing threat of antimicrobial resistance (AMR) among causative bacteria and the lack of new antibiotic developments have exacerbated the prevalence of corneal blindness globally. Thus, there is an urgent clinical need to develop alternative antimicrobial therapies to effectively manage corneal infections and combat AMR.

Recent advancements in peptide-based therapies offer promising alternatives for managing bacterial infections. Cell-penetrating peptides (CPPs) are naturally derived, membrane-active peptides that facilitate the delivery of various molecular cargoes into cells. Studies have demonstrated that CPPs, particularly those with amphipathic and cationic amino acid residues, are non-immunogenic and possess intrinsic antimicrobial properties akin to traditional antimicrobial peptides. Our team has recently identified novel CPPs with potent antimicrobial activity against a range of bacteria, including antibiotic-resistant strains. The primary aim of this proposed project is to enhance the structure of these novel CPPs and assess their antimicrobial efficacy through various laboratory-based assay systems. In this PhD project, the student will have the opportunity to develop skills in microbiology and pharmaceutical sciences, ultimately aiming to test the newly optimised CPPs in an in vivo model of corneal infection.

We will employ a stepwise approach to develop effective CPPs for managing corneal infections. First, we will optimise the amino acid sequences of our newly discovered CPPs through structure-activity relationship studies. This will involve assessing the biochemical importance of each amino acid in the CPP sequence for its antimicrobial function via alanine scanning and modification of key amino acid residues. CPP derivatives with strong bactericidal activity will be evaluated for their safety profiles against human corneal cells. Additionally, we will investigate the mechanisms of action of the identified CPPs using well-established techniques. Finally, peptides demonstrating potent bactericidal activity with minimal toxicity to host cells will be tested in an ex vivo cadaver corneal tissue model and subsequently validated in a mouse corneal infection model.

Key Techniques:

• Microbiological assay procedures
• Cell culture of corneal cells
• Confocal and electron microscopy
• Plate-based assay procedures
• Organ culture of cadaver animal corneal tissue
• In vivo animal model of corneal infection

This project offers the student the opportunity to learn all of the above techniques and more. They will work within two schools (the School of Pharmacy and Pharmaceutical Sciences and the School of Optometry and Vision Sciences) and have access to state-of-the-art facilities and equipment.

As this project involves the use of live animals in the later stages, the prospective student must be comfortable with animal models.

Funding Notes

Students with self-funding or through their local government will be considered.

We may also consider students with funding via doctoral training programme, British Council or Commonwealth funding sources. Kindly inquire for any relevant queries before making an application.