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

Publications

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Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011151/1 30/09/2015 29/09/2023
1802687 Studentship BB/M011151/1 30/09/2016 29/10/2021 Kirsty Smitten
 
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 09/2019 
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 09/2020 
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 04/2019 
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