Efficient production of first in class antimicrobial therapeutics from an integrated synthetic biology approach

Lead Research Organisation: University of Plymouth
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.

Planned Impact

As described in proposal submitted to TSB

Publications

10 25 50
 
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 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 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