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Microneedle delivery of non-ribosomal antimicrobial peptides to treat multidrug-resistant Gram-negative infections

School of Pharmacy | PHD
Funding
Unfunded
Reference Number
CATCH/2251/01
Application Deadline
None specified
Start Date
None specified

Overview

The School of Pharmacy and the School of Chemistry and Chemical Engineering, working under the umbrella of the Centre for Advanced Technologies for Healthcare (CATCH), are offering an exciting opportunity for interested international students to apply for a number of self-funded interdisciplinary Pharmacy-Chemistry PhD projects, jointly supervised by academics from both Schools. The increasing prevalence of infections caused by multidrug-resistant (MDR) bacteria is a major global concern, with global deaths due to antimicrobrial resistance expected to hit ten million per year by 2050. Gram-negative bacteria are particularly problematic as their outer-membrane renders them immune to many antibiotics, and the World Health Organization has designated the Gram-negative pathogens carbapenem-resistant Enterobacteriaceae, Pseudomonas aeruginosa and Acinetobacter baumannii as critical targets. We need novel antibiotics and treatments.

Non-ribosomal antibacterial peptides (NRAPs) are a class of compounds that have found special use in the treatment of MDR bacteria. For example, colistin is a last resort antibiotic for the treatment of MDR P. aeruginosa, Klebsiella pneumoniae and Acinetobacter infections, and daptomycin is a key antibiotic for treating MDR enterococci. They typically kill bacteria through interactions with non-protein membrane targets, and are therefore less susceptible to many common resistance mechanisms. However, NRAPs like colistin can cause neurotoxicity and nephrotoxicity when administered intravenously. An alternative, slow release method may circumvent this problem, providing a novel treatment against critical priority pathogens. Microneedle arrays allow delivery of injectable medicines through the skin without causing pain or bleeding. They are self-applied by the patient and can be designed to sustain release over several days

This interdisciplinary project will involve peptide synthesis, polymer synthesis, antimicrobial efficacy assays and pharmacokinetic/pharmacodynamic studies. A series of novel NRAPs will be chemically synthesized and tested in advanced in vitro biological models to ascertain their efficacy against MDR Gram-negative bacteria and safety with respect to normal human cells. In vivo animal pharmacokinetic and infection studies will demonstrate the clinical potential of these novel NRAP-microneedle combinations.

Training will be provided on the synthesis of peptides by manual and automated peptide synthesis, purification of synthetic compounds by HPLC, analysis of synthetic compounds by NMR and mass spec, antibacterial susceptibility assays, pharmaceutical formulation, analysis and engineering.

Demonstration of promising antimicrobial activity may lead to interest from the pharmaceutical industry, where development of new antibiotic classes and appropriate administration methods for difficult-to-deliver antibiotics are both in need of new innovative approaches. The supervisors have extensive experience of industrial engagement and promising data emanating from this project will be made available to potential industrial partners once intellectual property is protected, thus providing further potential opportunities for the student.

Project Summary
Supervisor

Professor Ryan Donnelly.

Research Profile

Co-Supervisor: Dr Stephen Cochrane.

Mode of Study

Full-time: 3 years

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