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The antimicrobial mode of action of tropolone: selective metal chelation and targeted inhibition of metalloenzymes

   Department of Biosciences

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  Dr GJ Sharples, Dr J Munoz  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

The emergence of antimicrobial resistance is a global concern requiring innovative approaches to tackle the threat to animal and human health. Chelating agents have affinity for metal ions and function as antimicrobials and potentiators of antibiotic efficacy. Chelants are widely employed in industry and consumer goods to control metal availability, with bacterial growth restriction as a secondary benefit for preservation. Our research group is studying the antibacterial mode of action of chelants and their impact on bacterial growth and metal homeostasis. Specific metals, notably iron, manganese and zinc, are selectively targeted by several of these chelants in Escherichia coli (see figure), akin to the nutritional immunity displayed by the human innate immune system. This PhD project aims to determine the antimicrobial mechanism of action of the chelant tropolone against bacteria and fungi.

Tropolone and its derivatives possess non-benzenoid, 7-carbon ring structures and have long been recognised as potent antibacterial and antifungal agents. Recent studies have revealed that they can function as specific inhibitors of a variety of metalloenzymes, including tyrosinases, elastases, epimerases and enolases, where they associate with the metal cation at the enzyme active site to disrupt functionality. However, in several cases the enzymes recognised by tropolone are not essential suggesting that multiple metalloenzymes may be targeted in a similar fashion. Details on which molecular pathways are disrupted by these compounds remain unclear. Tropolone also has the ability to function as a metal chelator and the contribution of this factor to antimicrobial activity has yet to be explored. However, further work is needed to define precisely their metalloenzyme targets, the metabolic pathways affected and the contribution of metal deprivation to antimicrobial activity. Tropolone is highly effective against species that are notoriously difficult to eliminate, the bacterium Serratia marcescens and the fungus Candida albicans. Both organisms are notable opportunistic human pathogens, so in addition to benefits for industrial applications, a better understanding of the multifunctionality of tropolone will also inform its potential as a new antimicrobial agent to combat infections.

The project presents an outstanding cross-disciplinary training opportunity at the microbiology-biochemistry-structural biology interface at both academic institutions and P&G. The student will receive diverse multidisciplinary training in the culture, safe handling and disposal of microorganisms, methods of antibacterial testing, determination of cellular metal content, protein purification, biochemical assays and structural biology. Research training is further supported by interaction with members of our research groups and more specialised training provided by senior research officers and technical staff who support some of the key technologies employed (e.g. mass spectroscopy, ICP-MS, proteomics and X-ray crystallography). The lead-PI (Gary Sharples) has extensive expertise in microbiology and chelants, while the Co-I (Jose Munoz) has extensive experience of enzymology and structural biology (experimentally through X-ray crystallography and bioinformatically using Alpha fold), especially with metalloenzymes, such as tyrosinase, and their small-molecule inhibitors in industrial biotechnology settings and applications.

Durham and Northumbria provide an outstanding training environment for learning new skills and specialist techniques. A 3-month placement in purpose-built R&D facilities at P&G offers an industrial perspective, with additional training in microbiological testing linked to optimisation of product formulations. Hence the project will produce a well-rounded PhD graduate who will be well placed for a research career in industry or academia.

How to apply:

  • Candidates wishing to apply for a studentship must apply directly to this E-mail address [Email Address Removed] by 31st January 2022 by sending 4 documents:
  1. Current CV: [maximum 2 pages] – this needs to include qualifications & two references.
  2. A personal statement (maximum 500 words).
  3. A completed BISCOP CTP Equal Opportunities Monitoring form
  4. A cover note indicating which project within the CTP you are applying for as their first choice and whether interested in any of the other projects.
  • Name all the documents with your ‘Name and Type of Form’ e.g., Joe Bloggs CV, Joe Bloggs Personal Statement.
  • For more information, please see the Policies & Procedures for applicants.
  • In the meantime, if you have any issues or questions please contact [Email Address Removed]

More information about the BiSCop CTP

This studentship is part of the first cohort of the BiSCoP CTP (Bioscience for Sustainable Consumer Products Collaborative Training Partnership), a BBSRC-funded inclusive, collaborative environment for high quality doctoral training that will prepare over 30 students with the knowledge and skills needed for successful careers at the forefront of global bioscience. This will help ensure the UK maintains a leadership position in bioscience with improved translation of frontier research into economic and societal impact.

The BiSCoP CTP will be an outstanding environment for PhD research between Durham, Northumbria, Newcastle and other UK universities, biotech company Prozomix and consumer products company Procter & Gamble. The first cohort of 12 PhD students starting in October 2022 will embark upon a 4-year research training programme with modules in hands-on lean innovation, an Accredited Certificate in Strategic Management and Leadership Practice (a Durham University mini-MBA), Intellectual Property, at least a 3-month placement (P&G UK or USA innovation centre or Prozomix UK) and other events.

Funding Notes

UKRI-aligned stipend, approved host University fees and a research budget.
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