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GW4 BioMed2 MRC DTP PhD project: How are antifungal usage and environment change on our farms driving cross-resistance in clinical pathogens?


   Department of Life Sciences

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  Dr Neil Brown  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is one of a number that are in competition for funding from the GW4 BioMed2 MRC Doctoral Training Partnership which is offering up to 20 studentships for entry in October 2023.

The DTP brings together the Universities of Bath, Bristol, Cardiff and Exeter to develop the next generation of biomedical researchers. Students will have access to the combined research strengths, training expertise and resources of the four research-intensive universities. More information may be found on the DTP’s website.

Supervisory Team:

  • Dr Neil Brown (lead), University of Bath, Department of Life Sciences, Milner Centre for Evolution
  • Dr Hans-Wilhelm Nuetzmann, University of Bath, Department of Life Sciences, Milner Centre for Evolution
  • Prof Ivana Gujelj, University of Exeter, Living Systems Institute
  • Dr Helen Fones (Eyles), University of Exeter, Department of Biosciences

The Project:

THE FUNGAL THREAT: Fungal pathogens cause deadly human infections, destroy our crops, and poison our food with harmful toxins. Despite our best efforts, we still lose ~10% of our crops to fungal diseases, ~25% of all food is contaminated with fungal toxins, and human infections have extremely high mortality rates. Worryingly, our population is becoming more vulnerable to infection, as the numbers of susceptible patients with immune disorders, major trauma, or viral co-infections rises. 

ENVIRONMENTALLY ACQUIRED RESISTANCE: We rely on a few antifungal drugs to secure our safe food supply and to cure human infection. This has created a perfect storm for the evolution of antifungal resistance (AFR), as many of the major fungal pathogens of people are also present on our arable farms. It is believed that the exposure of pathogens to agricultural antifungals has driven the evolution of cross-resistance to similar antifungals in hospitals, termed environmentally acquired resistance. Examples include Aspergilli and Fusaria which causes toxic cereal rots and life-threatening pulmonary, skin and eye infections, where antifungal resistance has been reported to contribute to poor treatment outcomes. But what is driving the increased threat of environmentally acquired resistance, is it changes to our environment or altered agricultural practices? Also, where are these cross-over pathogens acquiring AFR on our farms?

DIRECTED EVOLUTION: We will evolve Aspergillus and Fusarium species under conditions replicate our changing agricultural environments in the presence of differing levels of agricultural antifungals. These environmental stresses will replicate the impacts of climate change and agricultural intensification, i.e. temperature, humidity, salt, and pH stress. Evolved and non-evolved strains will harbour constitutive GFP or RFP markers to facilitate comparative assays. Minimum inhibitory concentration (MIC) will be used to evaluate adaptations to different stresses along the evolutionary timeframe, and how this confers cross-resistance to clinical antifungals. Competition assays and fitness cost experiments will be used to model how these adaptations may influence the structure of the fungal population. This will enable us to determine which scenarios are driving the rise in environmentally acquired resistance on our farms. For example, does the use of irrigation in agriculture, which increases soil salinity, drive soil dwelling fungi such as Aspergilli and Fusaria to evolve stress tolerance mechanisms that promote AFR to both agricultural and clinical antifungals? Or, will future climatic environmental stress increase the rate at which AFR evolves? We will use genomics and epigenetic (bisulfite) sequencing to identify genetic changes acquired through exposure to stress and antifungals, in multiple fungal lineages with phenotypic adaptations. Finally, CRISPR-Cas9 genome editing will be used to confirm these genetic adaptations confer phenotypic adaptations that enhance environmental stress tolerance and AFR evolution.

CROSS-OVER PATHOGEN COMMUNITIES: We will sample distinct arable environments (crops, soils, residues) throughout the cycles of a farming year to create a collection of Aspergillus and Fusarium species. This will be used to monitor how pathogen abundance and AFR profiles change in response to altered practices and the environment. Comparative genomics will be used to identify the genetic basis of adaptation in natural pathogens, which will be correlated with our lab-evolved strains.

IMPORTANCE: This research will help us determine what is driving environmentally acquired resistance on our farms and where cross-over pathogens are becoming antifungal resistant. This knowledge will support then development of improved farming practices to mitigate the risk of environmentally acquired resistance, protecting the shelf-life of our limited antifungal drugs, to the benefit of our food security and human health.

Requirements:

Applicants must have obtained, or be expected to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in an area appropriate to the skills requirements of the project. Academic qualifications are considered alongside significant relevant non-academic experience.

Non-UK applicants will also be required to have met the English language entry requirements of the University of Bath.

Enquiries and Applications:

Informal enquiries are welcomed and should be directed to Dr Neil Brown on email address [Email Address Removed].

Formal applications must be submitted direct to the GW4 BioMed2 DTP using their online application form.

A list of all available projects and guidance on how to apply may be found on the DTP’s website. You may apply for up to 2 projects.

APPLICATIONS CLOSE AT 17:00 (GMT) ON 2 NOVEMBER 2022.

IMPORTANT: You do NOT need to apply to the University of Bath at this stage – only those applicants who are successful in obtaining an offer of funding from the DTP will be required to submit an application for an offer of study from Bath.


Funding Notes

Candidates may be considered for a 4-year GW4 BioMed2 MRC DTP studentship covering tuition fees, a stipend (£17,668 p/a in 2022/23) and a Research & Training Support grant of between £2,000 and £5,000 p/a dependent on project requirements. Studentships are open to both Home and International students; however, International applicants should note that funding does NOT cover the cost of a student visa, healthcare surcharge and other costs of moving to the UK. In line with guidance from UK Research and Innovation (UKRI), the number of awards available to International candidates will be limited to 30% of the total.

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