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PhD project title: Novel Molecular Tools to Tackle the Antimicrobial Resistance (AMR) Emergency


Outline description, including interdisciplinary, intersectoral and international dimensions

BACKGROUND. Antimicrobial resistance (AMR) is one of the most urgent scientific, medical, and societal challenges. AMR is predicted to result, globally, in >10 million deaths per year and >100 trillion USD in lost economic output by 2050, if no immediate action is taken [1]. AMR arises when microorganisms that cause infection (e.g. bacteria) survive exposure to a medicine (e.g., an antibiotic) that would normally kill them or stop their growth. To tackle the AMR emergency, the development of new therapeutic approaches is an urgent priority [2-4].

AIM. We will develop novel molecular tools to study the role of bacterial glycans for AMR and establish new antibiotic strategies.

PROGRAMME. Glycans are a class of biomacromolecules that are central to many aspects of bacterial pathogenicity. To elucidate the precise role of specific glycans for AMR, we will develop small molecular inhibitors of bacterial glycan biosynthesis that can be used, uniquely, in wild-type, clinical pathogens, and universally with different bacteria. We will use these inhibitors as novel tools to study mechanisms of intrinsic and adaptive resistance in three critical clinical pathogens, Klebsiella, Pseudomonas, and Burkholderia.

INTERDISCIPLINARY, INTERSECTORAL AND INTERNATIONAL DIMENSION. The project is highly interdisciplinary, integrating elements of chemistry, chemical biology, and pathogen microbiology. It will deliver novel tools for the life sciences, to tackle a fundamental healthcare challenge. Cross-disciplinary training of scientists with both good chemical and microbiology expertise is a recognised advantage for the UK economy. The project aligns closely with the EU [2] and UK [3] Action Plans on AMR, and the “One Health” Action Plan on AMR for Northern Ireland [4]. Both supervisors have an
international network of microbiology collaborators (e.g., Szymanski/USA, Scott/Australia, Cattoir/France) which will be harnessed to fully exploit the universal applicability of the novel tools with different pathogens.

[1] https://amr-review.org

[2] https://ec.europa.eu/health/amr/sites/health/files/antimicrobial_resistance/docs/amr_2017_action-plan.pdf

[3] https://www.gov.uk/government/publications/uk-5-year-action-plan-for-antimicrobial-resistance-2019-to-2024

[4] https://www.health-ni.gov.uk/sites/default/files/publications/health/one-health-antimicrobial.pdf

 

Key words/descriptors: antimicrobial resistance, antibiotics, glycosylation, inhibitor, molecular tools


Fit to CITI-GENS theme(s) LIFE SCIENCES

Supervisor Information
First Supervisor: Prof Gerd Wagner School: School of Pharmacy
Second Supervisor: Prof Miguel Valvano School: School of Medicine
Third Supervisor: Dr Mark Sutton Company: Public Health England

Name of non-HEI partner: Public Health England (PHE)

Contribution of non-HEI partner(s) to the project:

Public Health England (PHE) will host the PhD student for at least one placement per year within the Technology Development Group (TDG), part of the National Infections Service at PHE Porton. These placements will provide unique, cross-disciplinary training opportunities. PHE will absorb all running costs and bench fees for the student placements, equivalent to an in-kind contribution of at least £4k per year.
At PHE, the student will be supervised by Dr Sutton, who is Scientific Leader for the Technology Development Group (TDG),within the National Infections Service. His main research interests are in applied infection control, bacterial pathogenesis and virulence, the development of novel antimicrobial agents, and the use of rapid detection systems. He has expertise and experience, relevant to the project, in the translation of diagnostic technologies, and the development and commercialisation of rapid diagnostic tests. This has led to filing of more than 20 separate patent families and >60 peer reviewed publications. He has successfully co-supervised 13 PhD students and is currently co-supervising PhD students at
a number of UK Universities. For this project, PHE will utilise its expertise in high-containment microbiology and provide access to well-characterised
libraries of multidrug resistant (MDR) pathogens, representing real-life challenges currently being faced in the clinic.
Access to these strains is rare resource and a critical element of the project, ensuring that the research reflects emerging trends in the clinic, and that any discoveries can be rapidly translated into clinically meaningful impacts. During the placements, the PhD student will use the molecular tools developed in the academic labs to investigate the role of bacterial glycans for innate and adaptive resistance in the bacterial pathogens Klebsiella pneumoniae and Pseudomonas aeruginosa. He/she will receive in-depth training in a broad range of experimental techniques that are essential for interdisciplinary working at the chemistry/biology interface.
The student will be trained in basic microbiology techniques, including bacterial cell culture and containment microbiology, as well as advanced antibiotic susceptibility testing, observation of growth over time after challenge with antibiotics, synergy tests with antibiotic combinations, and analysis of multi-drug resistant clinical pathogens.  All relevant facilities and resources are in place at PHE, including a large collection of Klebsiella and Pseudomonas isolates from several clinically relevant clonal lineages. Both Klebsiella and Pseudomonas are WHO Priority Pathogens
(https://www.who.int/medicines/publications/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf). Like Burkholderia they are likely to have been involved as a very significant component in secondary infections in CoVID-19 patients, making the development of new therapeutic approaches even more urgent.
The project builds on, and significantly expands, the recently established multidisciplinary collaboration between Wagner (QUB) and Sutton (PHE). It gives each partner access to unique skills and materials that are not readily available at their own institution and is perfectly aligned with PHE’s strategic “chemical microbiology” agenda. The investigation of AMR mechanisms and a holistic understanding of their impact on the environment is one of the priority areas for PHE over the next 5 years (www.gov.uk). By bringing together expertise from the public sector and academia, this project will deliver novel molecular tools to enable such investigations.

Subject area: Pharmacy, Chemical biology, Chemistry, Microbiology