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Enzyme-responsive nanocapsules for the delivery of antimicrobials


Project Description

Aim: To develop new enzyme-responsive nanocapsules for the targeted delivery of last resort antibiotics against resistant bacteria.

Background: Antimicrobial peptides and polymers (AMPs) are toxic to the host, limiting their application despite their huge potential, including their use as last resort antimicrobials. Therefore, new formulations that minimize this toxicity without compromising the activity of AMPs are needed. Moreover, uncontrolled release of these antimicrobials should be avoided, and targeted strategies that deliver them at the site of infection are desirable.

Toxicity in AMPs is associated with their polycationic and amphiphilic nature. To minimize toxicity and maintain their activity, cationic residues should be reduced without affecting the structure of the antimicrobial. Towards this end, we will synthesize enzyme-responsive nancapsules that will:
a) Shield cationic residues through electrostatic interactions with negative charges in enzymedegradable peptides/polymers.
b) Trigger AMPs’ release in the presence of the pathogen, taking advantage of the pathogen’s virulence factors. Here, we will target Pseudomonas aeruginosa, an opportunistic pathogen susceptible to AMPs.

Here, we will target Pseudomonas aeruginosa, an opportunistic pathogen susceptible to AMPs. Among the virulence factors expressed by P. aeruginosa, Pseudolysin, a metalloprotease that degrades elastin in the host tissue, constitutes a unique target for these responsive formulations. Pseudolysin degrades peptides rich in small hydrophobic amino acids (e.g. Gly, Ala), unlike host
elastases that degrade peptides with larger amino acids (e.g. Val).

Workplan
1.- Pseudolysin-Degradable Peptides (PDPs): Peptides will carry sequences degradable by
Pseudolysin (e.g. GLA), anionic residues to complex AMPs, and reactive moieties that undergo crosslinking (e.g. thiols). We will identify peptide sequences selectively degraded by Pseudolysin and not host proteases.
2.- Pseudolysin-Degradable nanocapsules: Layers of AMPs and PDPs will be sequentially
assembled onto relevant templates (eg. SiO2, PS nanoparticles) and capsules formed through removal of the template. We will evaluate the effect of cross-linking (e.g. disulfide, metal-phenolic) over stability and release of AMPs (see below).
3.- Pseudolysin-Triggered Release of AMPs: Nanocapsules will be incubated with Pseudolysin and AMPs release will be monitored to characterize release kinetics. We will target formulations where concentrations of AMPs released are above the minimum inhibitory concentration (MIC).
4.- Antimicrobial Activity: Nanocapsules will be incubated with P. aeruginosa, and the viability of the pathogen will be evaluated. MICs will be compared to those for the free AMPs.

Collaboration: This project brings together the expertise of FFT’s in antimicrobial research and the development of enzyme-responsive nanomaterials with FC’s leading expertise in the development of polyionic nanomaterials for drug-deliver and biomedicine.

Funding Notes

A fully-funded studentship, which includes tax-free Doctoral Stipend of £15,009* per annum, is available for Home/EU and Overseas students on this Joint PhD programme between the University of Birmingham and the University of Melbourne for October 2019 start. For students who are to be hosted by the University of Melbourne, the scholarship rate will be $AUD30,000 p.a. and will include provision for a return trip to Birmingham.
*subject to inflationary variation

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