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Protease-resistant antimicrobial peptides to target bacterial and fungal pathogens


Project Description

Antimicrobial resistance is quickly becoming a serious global health problem. The emergence of multidrug-resistant microbial strains combined with the drying up of the antibiotic pipeline in the pharmaceutical industry has significantly worsened the situation in recent years. This has resulted in a renewed interest in the development of new classes of therapeutics inspired on natural antimicrobial peptides (AMPs), integral to the animal innate immune systems for broad-spectrum protection against invading pathogenic microorganisms.
Cationic AMPs interact with negatively charged microbial cell membranes through electrostatic interactions. Their primary structures contain a relatively high proportion of cationic and hydrophobic amino acids, which can make them intrinsically vulnerable to protease degradation. Therefore, proteolytic instability of AMPs is a serious barrier for their effective translation into the clinic. This project aims to investigate different mechanisms for increasing the resistance of cationic AMPs to protease digestion.
Cationic AMPs engineered to withstand protease degradation will be produced, purified and characterized biochemically. The antimicrobial properties of these AMPs will be investigated against a collection of bacterial and fungal pathogens, including Mycobacterium tuberculosis and Aspergillus fumigatus. These protease-resistant AMPs will offer a novel platform for the development of a new class of antimicrobial agents with improved efficacy and resistance to degradation.

Training/techniques to be provided:
Peptide design; protein engineering; recombinant protein expression and purification; biochemical characterisation; circular dichroism spectroscopy; bacterial cultures, cell culture, antimicrobial assays to determine minimum inhibitory and minimal bactericidal concentrations.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a first class or upper second class honours degree (or equivalent) in biochemistry, biology, or microbiology. Candidates with experience in Microbiology or with an interest in Infectious Diseases and Antimicrobial Resistance are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Fernandez-Soto P, Bruce AJE, Fielding AJ, Cavet JS, Tabernero L. Mechanism of catalysis and inhibition of Mycobacterium tuberculosis SapM, implications for the development of novel antivirulence drugs (2019). Sci Rep, Jul 16; 9(1): 10315.
doi: 10.1038/s41598-019-46731-6
Vickers CF, Silva A, Chakraborty A, Fernandez P, Kurepina N, Saville C, Naranjo Y, Pons M, Schnettger LS, Gutierrez MG, Park S, Kreiswith BN, Perlin DS, Thomas EJ, Cavet JS, Tabernero L. Structure-based design of MptpB inhibitors that reduce multi-drug-resistant Mycobacterium tuberculosis survival and infection burden in vivo (2018). J Med Chem, 61(18): 8337-8352. doi: 10.1021/acs.jmedchem.8b00832

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