Supervisors: Carol Munro, Ian Fotheringham, Wael Houssen
Project Description:
Opportunistic fungal pathogens such as Candida albicans have become a significant risk to human health causing infections that range in severity based upon the underlying immune status of the patient. Despite treatment with current antifungal compounds the mortality of invasive fungal infection patients is unacceptably high, between 30-95% in certain clinical settings. There are a number of problems in treating patients with life- threatening fungal infections. There is only a very limited number of clinically approved drugs from 3 main classes that have limitations in spectrum of activity, associated toxic side-effects, and worryingly drug resistance has evolved due to extensive prophylaxis and new species with multi-drug resistance have emerged. There is a clear clinical need for more efficacious therapeutics to combat invasive fungal infections.
An early human defence mechanism to combat invading pathogens is the induction of antimicrobial peptides, produced naturally by a range of mammalian cells. Antimicrobial peptides have cidal activity against micro- organisms due to their membranolytic properties and also have the ability to modulate the immune system. Antimicrobial peptides have enormous potential as next generation therapeutics against a wide range of micro-organisms.
This translational project brings together 3 supervisors with the necessary know-how and complimentary expertise to develop novel peptide-based antifungal therapies. Industrial partners Ingenza Ltd have developed a novel, high throughput screening platform to identify linear peptides with antifungal activity. The peptide library design will be guided by in silico analysis and expertise from IBM Research (Science and Technologies Facilities Council, Hartree Centre), their input to peptide design would be sought from Ingenza’s current multi- year collaborative programme with IBM. Screens will be performed of peptide libraries against the major yeast pathogen C. albicans and the recently emerged drug resistant species Candida auris. Hit peptides will be macrocyclised using the expertise of Dr Houssen in chemical and synthetic biology and the various macrocyclases developed in his lab1,2. The cyclic peptide derivatives will be assessed for antifungal activity and lead peptides will be tested in pre-clinical studies including detailed mechanism of action studies using fluorescence and electron microscopy.
The efficacy and stability of the peptides will be tested in mini-host infection models and under in vivo/host mimetic conditions. The student will gain experience of working in both academic and industrial laboratories. They will acquire training in basic microbiology, culturing fungi, growth assays, drug susceptibility testing, biochemistry, enzyme heterologous expression and purification, fluorescence and electron microscopy, biofilm assays, Galleria mellonella invertebrate infection model.
References:
1- C. Alexandru-Crivac, C. Umeobika, N. Leikoski, J. Jokela, K. Rickaby, A. Grilo, P. Sjö, A. Plowright, M. Idress, E. Siebs, A. Nneoyi-Egbe, M. Wahlsten, K. Sivonen, M. Jaspars, L. Trembleau, D. P. Fewer, W. E. Houssen# (2017) “Cyclic Peptide Production Using a Macrocyclase with Enhanced Substrate Promiscuity and Relaxed Recognition Determinants” ChemComm 53, 10656-10659.
2- J. Koehnke,* A. Bent,* W. Houssen,* D. Zollman, F. Morawitz, S. Shirran, J. Vendome, A. Nneoyiegbe, L. Trembleau, C. Botting, M. Smith, M. Jaspars, J. Naismith (2012) “The mechanism of patellamide macrocyclization revealed by the structural and biochemical characterization of the PatG macrocyclase domain” Nat. Struct. Mol. Biol. 19, 767-772.
#= corresponding author
*= equal contribution
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