Antibacterial theranostics based on luminescent metal complexes.
Lead Research Organisation:
University of Sheffield
Department Name: Chemistry
Abstract
Multidrug resistance is a huge emerging global challenge. Diseases that were easily treated with antibiotics are increasingly becoming resistant to these drugs And the number of infective bacterial strains that display multiple antibiotic resistances is rapidly increasing. Worryingly, the "development pipeline" for new antibiotics is running dry.
This multidisciplinary project involves the synthesis and development of luminescent coordination compounds that not only bind to and image cellular structures through optical microscopy, but display potent bacteriostatic/bactericidal properties against the known pathogen Staphylococcus aureus.
The project will include cell biology investigations into the mechanism through which these compounds exert these effects and the chemical synthesis of new compounds designed to optimize their potency. The overall aim of these studies will be the identification and development of a new paradigm for antibiotics
This multidisciplinary project involves the synthesis and development of luminescent coordination compounds that not only bind to and image cellular structures through optical microscopy, but display potent bacteriostatic/bactericidal properties against the known pathogen Staphylococcus aureus.
The project will include cell biology investigations into the mechanism through which these compounds exert these effects and the chemical synthesis of new compounds designed to optimize their potency. The overall aim of these studies will be the identification and development of a new paradigm for antibiotics
People |
ORCID iD |
| James Thomas (Primary Supervisor) |
Publications
Varney AM
(2021)
Transcriptomic Analysis of the Activity and Mechanism of Action of a Ruthenium(II)-Based Antimicrobial That Induces Minimal Evolution of Pathogen Resistance.
in ACS pharmacology & translational science
Saeed HK
(2020)
Photoactive metal complexes that bind DNA and other biomolecules as cell probes, therapeutics, and theranostics.
in Chemical communications (Cambridge, England)
Smitten KL
(2020)
Triazole-based osmium(ii) complexes displaying red/near-IR luminescence: antimicrobial activity and super-resolution imaging.
in Chemical science
Smitten KL
(2020)
Ruthenium based antimicrobial theranostics - using nanoscopy to identify therapeutic targets and resistance mechanisms in Staphylococcus aureus.
in Chemical science
Jarman P
(2018)
Exploring the Cytotoxicity, Uptake, Cellular Response, and Proteomics of Mono- and Dinuclear DNA Light-Switch Complexes
in Journal of the American Chemical Society
Raza A
(2020)
A Dinuclear Ruthenium(II) Complex Excited by Near-Infrared Light through Two-Photon Absorption Induces Phototoxicity Deep within Hypoxic Regions of Melanoma Cancer Spheroids
in Journal of the American Chemical Society
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| BB/M011151/1 | 01/10/2015 | 30/09/2023 | |||
| 1802687 | Studentship | BB/M011151/1 | 01/10/2016 | 30/10/2021 |
| Description | I have developed two new classes of antimicrobial compounds both based on ruthenium polypyridyl complexes. The lead compounds in both cases are more active on gram-negative bacteria and retain their high activities in mutli-drug resistant strains. The lead dinuclear compound has been shown to clear a pathogenic A. baumannii infection in an insect model.The mechanism of action has been probed through both classes of compound using TEM and super res microscopy as well as biological assays. A paper in ACS nano has just been accepted and a patent is pending. The leads are more active than clinically available antibiotics. |
| Exploitation Route | Further compounds could be developed. The two leads are being developed by MetalloBio, hopefully they will reach the clinic and be able to help in the fight against AMR. |
| Sectors | Chemicals,Creative Economy,Healthcare,Pharmaceuticals and Medical Biotechnology |
| URL | http://www.metallobio.com |
| Description | The findings have been used to form the spin-out company MetalloBio. |
| First Year Of Impact | 2017 |
| Sector | Chemicals,Creative Economy,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Impact Types | Cultural,Societal,Economic |
| Description | Confidence in concept - In-vitro antibacterial activity profile, genotoxicity and pharmacokinetic analysis of a novel broad-spectrum antibiotic active against therapeutically resistant pathogens. |
| Amount | £45,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2019 |
| End | 01/2020 |
| Description | EPSRC Knowledge Exchange Funding Matched by Heraeus |
| Amount | £30,000 (GBP) |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 03/2021 |
| End | 09/2021 |
| Description | Innovate UK 'Innovation to Commercialisation of University Research' (ICURe) |
| Amount | £50,000 (GBP) |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 10/2020 |
| End | 04/2021 |
| Description | Knowledge exchange funding - Exploring the activity of new antimicrobial leads against therapeutically resistant biofilm-forming ESKAPE bacteria |
| Amount | £40,000 (GBP) |
| Organisation | University of Sheffield |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 05/2019 |
| End | 09/2019 |
| Description | Pump prime funding - Ruthenium based antimicrobials targeting anaerobic pathogens |
| Amount | £4,000 (GBP) |
| Organisation | National Institute for Health Research |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 09/2020 |
| Description | The use of Ru(II) antimicrobials to treat E. coli biofilms. |
| Organisation | Nottingham Trent University |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | My lead Ruthenium compound has been given to trial its affects on E. coli biofilms. |
| Collaborator Contribution | The collaborator has tested the compound on E. coli biofilms. In addition she will be doing some RSeq DNA sequencing, to determine the compounds mechanism of action. |
| Impact | The collaboration is multi-disciplinary. Chemistry and microbiology are involved. |
| Start Year | 2018 |
| Description | The use of Ru(II) antimicrobials to treat biofilms. And the possibility of incorporating them into medical devices. |
| Organisation | University of Sheffield |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | Ruthenium compounds have been provided. In addition an exchange of knowledge is in place, whereby i will learn how to do the experiments myself. |
| Collaborator Contribution | Currently the project has not commenced. |
| Impact | Multi-disciplinary, Chemistry and microbiology. |
| Start Year | 2019 |
| Description | The use of Ru(II) antimicrobials to treat pathogenic infections caused by anaerobic bacteria |
| Organisation | University of Sheffield |
| Department | School of Clinical Dentistry Sheffield |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I provided the ruthenium compounds for the research group to test. . |
| Collaborator Contribution | The research group tested my compounds on a range of pathogenic anaerobic bacteria including ones known to cause dental infections |
| Impact | A small research grant was obtained from The University of Sheffield. |
| Start Year | 2020 |
| Description | The use of Ru(II) polypyridyl complexes as theranostic agents for E. coli infections |
| Organisation | University of Sheffield |
| Department | Department of Molecular Biology and Biotechnology |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This has made up a large part of my research. Stemming as an initial side project we made the collaboration at a Shamrok. I have synthesised the compounds used for this collaboration and completed the microscopy on my own. In conjunction with my collaborator I have also helped with all the microbiological testing. |
| Collaborator Contribution | My collaborators have offered microbiological advice on the direction of the project with great input on experiments to conduct. The postdoc working with me has helped me with all the biological assays, teaching me how to do them myself and also completing the majority with me. This includes MIC/MBC's, timekill assays, uptake experiments and membrane damage assays. The collaborator has taught me how to conduct research using Galleria Mellonella as an insect model for my antimicrobials. |
| Impact | We are in the process of producing a patent application. We are in the process of submitting a journal draft with two more follow up journals in the pipe line. |
| Start Year | 2017 |
| Title | Ruthenium compounds as antimicrobial agents |
| Description | Novel ruthenium antimicrobial compounds were synthesised and exhibited a potent activity on pathogenic multi-drug resistant bacteria. The activity was higher than that of clinically available antibiotics and the compounds showed high efficacy in an in vivo model. |
| IP Reference | 1904796.8 |
| Protection | Patent application published |
| Year Protection Granted | 2019 |
| Licensed | No |
| Impact | Grant funding has been received. In addition an additional patent application is in the process of being filed on the capability of the compounds as anti cancer agents. |
| Company Name | MetalloBio |
| Description | MetalloBio were awarded the funding to spin-out in January 2021. The spinout will work on developing the antimicrobial compound synthesised during Kirsty Smitten's PhD. |
| Year Established | 2021 |
| Impact | MetalloBio recently received funding for murine studies, there are 2 FTE and 4 0.2FTE employees. |
| Website | http://www.metallobio.com |
| Description | A school newsletter on my research |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A newsletter from my secondary school/sixth form on my research and future presentation at the houses of parliament. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Interview for local newspaper |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Public/other audiences |
| Results and Impact | My local paper contacted me about doing a press release for the research i have been doing at the university of sheffield. In particular about my future visit to parliament to discuss my research. |
| Year(s) Of Engagement Activity | 2019 |
| URL | https://solihullobserver.co.uk/news/knowle-student-set-to-present-research-to-parliament/ |
| Description | STEM for Britain |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Presenting my research at STEM for Britain in the houses of parliament. |
| Year(s) Of Engagement Activity | 2019 |