Resistance by microorganisms to conventional treatments is a growing global challenge with wide ranging impacts on both healthcare and food security. Antibiotic resistance is well known, however, resistance by yeasts and fungi to antifungals is now becoming apparent. In India, Covid treatments have allowed the normally benign mucor fungus to cause opportunistic infections by travelling through the respiratory tract to the brain and mucormycosis has now killed over 4,000 people since the start of the pandemic. More widespread is the problem of Candida auris infection. The yeast, only identified in 2009, is resistant to all classes of antifungal and has a mortality rate between 30 and 60%. Overall, human fungal infections account for a similar level of global deaths to HIV and tuberculosis. In addition, current estimates suggest 20% of crop yields are lost due to fungal infection. Fungal resistance will become a societal problem in the near future affecting both developed and developing nations.
For the past five years, chemists at the University of Brighton have been preparing compounds, known as amphiphiles, to target the lipids encasing bacterial and fungal cells. Preliminary biological tests have revealed different activities related to the type of microorganism rather than the amphiphile. This project seeks to find out what causes this selectivity and to use the results to focus on designing more potent antifungal drugs. The project bridges the gap between theoretical studies and experimental behaviour, laying a foundation for future work in this area.
Using a multidisciplinary approach, the PGR will develop skills in computational drug design and metabolomic profiling/bioinformatics to design membrane disrupting amphiphiles. This project will utilise the University’s facilities in Huxley Laboratories and make use of a recently acquired Orbitrap mass spectrometer.
The project builds on our previous research on lipidomics and phospholipid homeostasis, and amphiphiles that form supramolecular interactions with lipids found in bacterial and fungal membranes. Lipidomic analyses will be performed by mass spectrometry and the impacts on lipid biosynthesis and toxicity screen will be performed using in-house microbiology facilities. The work comprises three themes:
WP 1 Metabolomic profiling: characterising the fungal lipidome
Using an in-house library of fungal strains, high-throughput targeted lipidomics profiling will be performed using advanced mass spectrometric methods (HPLC MS/MS) and analysed using established bioinformatic software protocols. This will quantify and identify the thousands of lipids present in fungal membranes and provide key data for the parameterisation of the computational work performed in WP2.
WP 2 Design rules of antifungal efficacy; in silico screening for unique fungal-lipid interactions.
Computational chemistry will be used to screen a library of virtual amphiphiles designed around fungal-lipid specific molecular interactions. The team are particularly interested in the possibility ergosterol, found more or less exclusively in fungal lipid membranes, will preferentially interact with the amphiphiles. This process disrupts key regulated physical properties of membranes leading to membrane failure and cell death.
WP 3 Mechanisms of toxicity and metabolic stability
The experimental behaviour of candidates from our existing compound library, and others to be synthesised by UoB chemists, will be compared to their calculated antifungal effects. Structure activity relationships will be constructed and rationalised against in silico design rules generated in WP 2 using data from differential scanning calorimetry and polarising optical microscopy.
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