Efficient production of first in class antimicrobial therapeutics from an integrated synthetic biology approach
Lead Research Organisation:
Plymouth University
Department Name: Sch of Biomedical and Healthcare Sci
Abstract
Antibiotic resistant bacteria kill over 25,000 people a year in Europe and threaten a return to a time when minor infections can be fatal and routine surgery poses high risks. With development pipelines empty, there is a critical need for novel therapies to kill antibiotic resistant bacteria and serve as scaffolds for derivatisation, diversification and enhancement of efficacy, which proved successful with drugs like penicillin. Epidermicins are an exciting new class of antimicrobial biologics (ABs) that rapidly kill bacteria, at very low doses and have great potential to prevent or treat bacterial infections including those caused by resistant bacteria. However, the development of the epidermicins is greatly hampered by their very low production in the native host and synthetic production would be prohibitively expensive. This project aims to develop efficient, scalable microbial production systems for epidermicins, enabling their development into a new platform of effective antibiotics.
Technical Summary
Antibiotic resistant bacteria kill over 25,000 people a year in Europe and threaten a return to a time when minor infections can be fatal and routine surgery poses high risks. With development pipelines empty, there is a critical need for novel therapies to kill antibiotic resistant bacteria and serve as scaffolds for derivatisation, diversification and enhancement of efficacy, which proved successful with drugs like penicillin. Epidermicins are an exciting new class of antimicrobial biologics (ABs) that rapidly kill bacteria, with nanomolar level potency and have great potential to prevent or treat bacterial infections including those caused by resistant bacteria. In recent in vivo trials, a single dose of epidermicin was as effective as 6 doses of the gold standard treatment for nasal MRSA carriage - this is the initial target market for epidermicin. This represents significant competitive advantage over current and developmental agents in this ~$100M per year market. Epdiermicin has a good in vitro profile for use in therapy of dermatological infections, including impetigo, with significantly larger markets.
However, the development of the epidermicins is greatly hampered by their very low production in the native host and synthetic production would be prohibitively expensive. This project aims to use Ingenza's cutting-edge, propriety technology to develop efficient, scalable microbial production systems for epidermicins and other peptides, enabling their development into a new platform of effective antibiotics.
However, the development of the epidermicins is greatly hampered by their very low production in the native host and synthetic production would be prohibitively expensive. This project aims to use Ingenza's cutting-edge, propriety technology to develop efficient, scalable microbial production systems for epidermicins and other peptides, enabling their development into a new platform of effective antibiotics.
Planned Impact
As described in proposal submitted to TSB
People |
ORCID iD |
| Mathew Upton (Principal Investigator) |
Publications
Hammond K
(2020)
Flowering Poration-A Synergistic Multi-Mode Antibacterial Mechanism by a Bacteriocin Fold.
in iScience
Hesketh-Best PJ
(2021)
Galleria mellonella larvae exhibit a weight-dependent lethal median dose when infected with methicillin-resistant Staphylococcus aureus.
in Pathogens and disease
| Description | We have made developments in the search for new antimicrobials and have established a system for producing epidermicin at a commercially viable scale, the primary aim of the project. |
| Exploitation Route | The findings will support additional funding requests to relevant funding bodies |
| Sectors | Healthcare,Manufacturing, including Industrial Biotechology |
| Description | Capital equipment for AMR research |
| Amount | £142,000 (GBP) |
| Funding ID | 86184-540263 |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2017 |
| End | 03/2017 |
| Description | Health and Life Sciences call |
| Amount | £933,000 (GBP) |
| Funding ID | TS/R008396/1 |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2017 |
| End | 07/2020 |
| Description | Pre-clinical validation of a potent candidate in the fight against AMR HCAI |
| Amount | £1,182,041 (GBP) |
| Funding ID | 971631 |
| Organisation | Innovate UK |
| Sector | Public |
| Country | United Kingdom |
| Start | 02/2019 |
| End | 01/2021 |
| Description | SfAM PhD |
| Amount | £67,000 (GBP) |
| Organisation | Society for Applied Microbiology |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 10/2017 |
| End | 09/2020 |
| Description | Development of expression system for commercial scale production |
| Organisation | Ingenza Ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Ingenza have partnered with us to develop the recombinant expression system for production of epidermicin and related peptides. This work is now supported by a TSB/Innovate UK IBC award (starting April 2015). My research team will be evaluating the peptides that are produced in the Ingenza expression pipeline. |
| Collaborator Contribution | Ingenza are bringing 14 years of IB expertise to the project to maximise the chance of successfully achieving our target level of expression |
| Impact | None yet |
| Start Year | 2014 |
| Description | National Physical Laboratory/IBM for creation of novel antimicrobials based on epidermicin |
| Organisation | National Physical Laboratory |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | This is part of a new Innovate UK funded project with NPL, the University of Plymouth and Ingenza Ltd. Our role in the project is to guide design of new antimicrobials based on epidermicin and investigate the activity of variants. This will include assessment of spectrum of antimicrobial activity against clinically relevant bacteria and investigation of toxicity of novel antimicrobials. |
| Collaborator Contribution | Max Ryadnov at NPL has been working with colleagues at IBM Hartree to develop novel epidermicin variants, using cognitive computing. The NPL/IBM approaches will provide new sequence variants that will be investigated in silico at IBM. Promising molecules will be synthesised at NPL and initial bioactivity assessments will be carried out. Promising candidates will be passed to my group for further testing (above). Any candidates worth progressing to larger scale evaluation will be passed to Ingenza for recombinant expression process development and scaleup. |
| Impact | This collaboration was cemented and current work facilitated by an award from Innovate UK (Health and Life Sciences award) |
| Start Year | 2017 |
| Description | Pseudo-allergenic activity of epidermicin NI01 |
| Organisation | RefLab |
| Country | Denmark |
| Sector | Private |
| PI Contribution | We provided NI01 peptide to the collaboration and some costs (€1200) for analysis probes were paid for by Amprologix, the University of Plymouth spinout that is commercialising NI01 |
| Collaborator Contribution | Michelle Vang was a staff member working on NI01 and she moved to RefLab in 2020 and then established a collaboration with us and proposed the work with NI01 in a model of human ex-vivo skin to examine pseudo-allergic responses to the peptide NI01. |
| Impact | None yet |
| Start Year | 2020 |
| Description | Wound healing activity of epidermcin |
| Organisation | Roskilde University |
| Country | Denmark |
| Sector | Academic/University |
| PI Contribution | Discussions we held at the International Antimicrobial Peptide meeting in Leiptzig, Germany in August 2016 about using epidermicin in Havard Jenssen's wound healing assays. An MTA was put in place and epidermicin was sent to Roskilde for use in assays. |
| Collaborator Contribution | The epidermicin provided was used in wound healing and preliminary cytokine assays |
| Impact | An out line patent application has been submitted based on this work and Michelle Vang from Havard Jenssen's group is planning a 3 month visit to the UK to work in my lab to develop the data set further, to support a future grant application. |
| Start Year | 2017 |
| Company Name | AMPROLOGIX LIMITED |
| Description | A University of Plymouth spin out established to commercialize epidermicin IPR arising from work in University of Manchester and University of Plymouth. |
| Year Established | 2018 |
| Impact | Shortly after company formation, an award was made from the Department of Health and Social Care (via Innovate UK/SBRI) for a contract valued at £12.m to progress the lead compound (epidermicin) through pre-clinical development. |
| Description | BBC radio 4 Today programme interview, 1st October 2015 |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Public/other audiences |
| Results and Impact | Radio interview that was picked up by various groups across the UK and resulted in a request from the Chief Medical Officer's office for more information on the work I am doing |
| Year(s) Of Engagement Activity | 2015 |
| Description | Opinion piece in local print news |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | Regional |
| Primary Audience | Media (as a channel to the public) |
| Results and Impact | Opinion piece drafted and submitted to regular media outlets. This article aimed to increase awareness about antibiotic resistance during World Antibiotic Awareness week in November 2017 and mentioned briefly the work in my group developing new antibiotics. The story was picked up by the Cornish Times and I was subsequently approached by the Mail on Sunday for comment and input into a short piece on the health related importance of marine environments (this was around the time BBC were showing the Blue Planet series. |
| Year(s) Of Engagement Activity | 2017 |
| URL | http://www.cornish-times.co.uk/article.cfm?id=112541&headline=World%20Antibiotic%20Awareness%20Week&... |
| Description | Press release on company formation |
| Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | A press release from the University of Plymouth was made to publicize the formation of Amprologix Ltd. This was coordinated with releases from Ingenza (industrial partners) and a 'reach' article by Frontier IP ltd, the University of Plymouth commercialisation partners, who have an equity share in Amprologix. This story was picked up by various local media outlets and international business sites. The release and a subsequent one about award of an SBRI contract (971631) generated interest in academic an industry quarters and resulted in invites to present at Bioinfect, Manchester Nov 2018 and the conference on Novel Antimicrobials and AMR Diagnostics, Berlin, March 2019. It also resulted in many offers of service provision etc to assist with company development or R&D. Examples of relevant sites referencing the original release - https://cen.acs.org/pharmaceuticals/antibiotics/UK-antibiotics-firm-Amprologix-launches/96/i39 http://www.pharmtech.com/amprologix-ingenza-get-funding-antibiotic-development https://www.bloomberg.com/research/stocks/private/snapshot.asp?privcapId=588605641 |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.plymouth.ac.uk/news/university-spinout-company-to-develop-new-antibiotics |
| Description | TEDx Talk |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Public/other audiences |
| Results and Impact | Based on my expertise and profile in antibiotic resistance and discovery (from UKRI funded research), I was invited to present a TEDx talk. This talk has now had nearly 2000 views on Youtube since January 2019. |
| Year(s) Of Engagement Activity | 2018 |
| URL | https://www.youtube.com/watch?v=makV286ZFDk&t=11s |