Developing a new class of antibiotics based on efflux resistant 4-oxoquinolizines for multidrug-resistant ESKAPE pathogens
Lead Research Organisation:
Public Health England
Department Name: National Infection Service Porton
Abstract
Antibiotics have been a mainstay of modern medicine of the last 60 years and have been the principle means of treating infections. Although not a new problem, there is increasing evidence that antibiotics are becoming less effective in certain settings, due to the emergence of bacteria which are no longer susceptible to treatment with antibiotics. This is defined as antibiotic / antimicrobial resistance, AMR. In recent years there has been a rapid rise in bacteria which are resistant to multiple antibiotics, leading in some cases, to essentially untreatable infections associated with high mortality. These so-called multidrug resistant (MDR) bacteria come from a variety of different species and are a major cause for concern. There are a wide range of documents which aim to define this phenomenon, understand what impact it will have on public health worldwide, estimate the likely costs of AMR and identify solutions to the problem. These include research strategy documents from the Department of Health and Social Care, a review of AMR commissioned by the UK government (the AMR Review chaired by Lord O'Neil) and recent documents from the World Health Organisation, European Union, and Centres for Disease Control in the US.
A common feature in AMR is the ability of bacteria to increase the presence or abundance of certain proteins which are able to pump an antibiotic out of the bacterial cell, which stops them working. These so-called "efflux pumps" are common and can work on many different types of antibiotic. Although an attractive approach would be block these pumps to stop them working, using efflux-pump inhibitors (EPIs), this has proved to be difficult to achieve. This is at least partly due to the toxicity of some of the drugs that have been tried in this context.
The project team have developed a new approach which uses state of the art computational methods to identify where and how different molecules bind to the efflux pumps. The team identified that inhibitors bind to specific parts of the pump which are different from antibiotics that may be exported through the pump. This has led to a new approach, where hybrid molecules are made, which keep the active part of the antibiotic and add on specific parts of the inhibitor molecule. This means the modified antibiotics can no longer be exported from the cell, which makes them work better. This approach is applied here to a new class of antibiotics that have not been used in the clinic previously and this potentially allows us to bring a new class of antibiotics into clinical use. We will focus on a high priority group of bacteria, which were identified previously by WHO as those most urgently needing new antibiotics. These bacteria are associated with lung infections, especially in hospital environments, and patients who are infected may have very poor outcomes with current treatment.
Although focussed on a very specific class of new antibiotics, the method can be used with other types of antibiotic and we have already proved this in the laboratory. This means that findings from this study may be useful for other drug developers and may contribute to improved approaches for antibiotic development.
A common feature in AMR is the ability of bacteria to increase the presence or abundance of certain proteins which are able to pump an antibiotic out of the bacterial cell, which stops them working. These so-called "efflux pumps" are common and can work on many different types of antibiotic. Although an attractive approach would be block these pumps to stop them working, using efflux-pump inhibitors (EPIs), this has proved to be difficult to achieve. This is at least partly due to the toxicity of some of the drugs that have been tried in this context.
The project team have developed a new approach which uses state of the art computational methods to identify where and how different molecules bind to the efflux pumps. The team identified that inhibitors bind to specific parts of the pump which are different from antibiotics that may be exported through the pump. This has led to a new approach, where hybrid molecules are made, which keep the active part of the antibiotic and add on specific parts of the inhibitor molecule. This means the modified antibiotics can no longer be exported from the cell, which makes them work better. This approach is applied here to a new class of antibiotics that have not been used in the clinic previously and this potentially allows us to bring a new class of antibiotics into clinical use. We will focus on a high priority group of bacteria, which were identified previously by WHO as those most urgently needing new antibiotics. These bacteria are associated with lung infections, especially in hospital environments, and patients who are infected may have very poor outcomes with current treatment.
Although focussed on a very specific class of new antibiotics, the method can be used with other types of antibiotic and we have already proved this in the laboratory. This means that findings from this study may be useful for other drug developers and may contribute to improved approaches for antibiotic development.
Technical Summary
Antimicrobial resistance (AMR) is a major concern, with increased levels of multidrug resistance (MDR) in many pathogens, resulting in treatment breakdown in the clinic. The O'Neil report suggested that infections caused by antibiotic resistant bacteria could become the leading cause of mortality worldwide, with up to 10 million deaths per year by 2050. The situation is exacerbated by the very poor pipeline of new antibiotics, especially in the case of high priority pathogens identified as being of critical concern by WHO and others.
In many Gram-negative bacteria, efflux pumps play a significant role in resistance to antibiotics and, simultaneously, the ability of bacteria to develop stable high level resistance through target site modifications. Although the development of stand-alone efflux pump inhibitors, which can be used in conjunction with antibiotics to suppress this response, is an attractive idea, it has not been possible to advance candidates to the clinic. We have taken a different approach, by identifying differential binding sites of inhibitors and substrates to efflux pumps, and generating hybrid molecules where efflux-resistance is a feature of the molecule. Such efflux resistance breaker (ERB) modified antibiotics have significant potential for therapeutic development as stand alone therapies and/or as part of a combination therapy. We have good evidence that these compounds are effective against Acinetobacter baumannii, and the medicinal chemistry optimisation and validation of the technology will extend the utility to other WHO priority pathogens, for which new antibiotics are urgently required. Data generated in this project will provide a framework for the development of efflux-resistant antibiotics, which are potentially more robust in clinical use. The project will focus on lung infection as the primary indication, aiming to [provide early data to support development of new treatments for hospital and ventilator-associated pneumonia.
In many Gram-negative bacteria, efflux pumps play a significant role in resistance to antibiotics and, simultaneously, the ability of bacteria to develop stable high level resistance through target site modifications. Although the development of stand-alone efflux pump inhibitors, which can be used in conjunction with antibiotics to suppress this response, is an attractive idea, it has not been possible to advance candidates to the clinic. We have taken a different approach, by identifying differential binding sites of inhibitors and substrates to efflux pumps, and generating hybrid molecules where efflux-resistance is a feature of the molecule. Such efflux resistance breaker (ERB) modified antibiotics have significant potential for therapeutic development as stand alone therapies and/or as part of a combination therapy. We have good evidence that these compounds are effective against Acinetobacter baumannii, and the medicinal chemistry optimisation and validation of the technology will extend the utility to other WHO priority pathogens, for which new antibiotics are urgently required. Data generated in this project will provide a framework for the development of efflux-resistant antibiotics, which are potentially more robust in clinical use. The project will focus on lung infection as the primary indication, aiming to [provide early data to support development of new treatments for hospital and ventilator-associated pneumonia.
Description | Development of TPPs for new therapies for people with Cystic Fibrosis |
Geographic Reach | Multiple continents/international |
Policy Influence Type | Participation in a guidance/advisory committee |
URL | https://cfamr.org.uk/therapeutic-tpp/ |
Title | Open Innovation in AMR programme at UKHSA |
Description | The development of a new open innovation research access model to support academic and SME research into new interventions |
Type Of Material | Improvements to research infrastructure |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | The programme has supported early stage evaluation of a number of different interventions including novel therapeutics, diagnostics and infection prevention and control measures. The programme is linked to an infrastructure award from NIHR (NIHR200658; Open Innovation in AMR 2020-2022). The programme continues to support researchers in this area and also contributes to addressing a recognised skills gap in this area, with the continued exit of large pharma from the antibiotic discovery space. |
URL | https://research.ukhsa.gov.uk/documents/UKHSA-AMR-Open-Innovation-Factsheets-Oct-2021.pdf |
Description | Collaboration on funding application for new application of efflux resistance breaker (ERB) series; under review |
Organisation | King's College London |
Department | Institute of Pharmaceutical Science |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Pilot data used to support application |
Collaborator Contribution | Expertise in medicinal chemistry and animal models |
Impact | Outcome of funding application awaited |
Start Year | 2023 |
Description | Collaboration on grant application related to compound series submitted to JPIAMR (unsuccessful) |
Organisation | Defence Science & Technology Laboratory (DSTL) |
Country | United Kingdom |
Sector | Public |
PI Contribution | Shared compounds and data |
Collaborator Contribution | Early stage evaluation of compounds |
Impact | Shared data used to support grant application |
Start Year | 2022 |
Description | Collaboration on grant application related to compound series submitted to JPIAMR (unsuccessful) |
Organisation | University of Leuven |
Country | Belgium |
Sector | Academic/University |
PI Contribution | Shared compounds and data |
Collaborator Contribution | Early stage evaluation of compounds |
Impact | Shared data used to support grant application |
Start Year | 2022 |
Description | AMR Conference, Basel March 2023 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Presentations on iFAST technology given by Team Member, Dr Lucy Bock and CEO of iFAST Diagnostics Toby King. Discussions around Open Innovation in AMR Programme supporting development of new antimicrobials |
Year(s) Of Engagement Activity | 2023 |
URL | https://amr-conference.com/programme-2023/ |
Description | Asthma and Lung UK workshop |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Workshop exploring new diagnostics and treatments for patients with chronic respiratory infections |
Year(s) Of Engagement Activity | 2023 |
Description | BBC News Interview on Development of New Antibiotics |
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 | Media (as a channel to the public) |
Results and Impact | I was interviewed on BBC News for their Six O'Clock and News at Ten on the discovery of the new antibiotic Zosurabalpin, and the challenges associated with new antibiotics discovery. |
Year(s) Of Engagement Activity | 2024 |
URL | https://www.bbc.co.uk/programmes/m001txfc |
Description | BBSRC AMR Community event; linked to transdisciplinary research network call |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Other audiences |
Results and Impact | Workshop scoping new transdisciplinary network in AMR applications |
Year(s) Of Engagement Activity | 2023 |
Description | BSAC Presentation |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Presentation given by Team Member Lucy Bock Presentation given by PI J. Mark Sutton Poster given by students affiliated to work Bethany Martin and Caitlin Daniels |
Year(s) Of Engagement Activity | 2022 |
URL | https://bsac.org.uk/infection-2022/ |
Description | BSAC meeting UTIs |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Meeting on urinary tract infections, looking at new therapeutic and diagnostic applications |
Year(s) Of Engagement Activity | 2023 |
Description | British Pharmaceutical Society Meeting |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | research presentation in session on AMR |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.bps.ac.uk/news-events/events-calendar/2022/pharmacology-2022#:~:text=Join%20us%20from%20... |
Description | British Society for Antimicrobial Chemotherapy (BSAC) Winter Conference "Nouveau Frontiers in Infection, This time it's personal! Personalised medicine approaches in improving patient outcomes and reducing AMR", London, UK, 13th - 14th December 2022, |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Professional Practitioners |
Results and Impact | Discussion panel on the use of personalised therapeutics to address AMR |
Year(s) Of Engagement Activity | 2023 |
Description | Engagement with School Children |
Form Of Engagement Activity | Participation in an open day or visit at my research institution |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Visited schools to discuss the drug discovery process and the contribution of people from different disciplines to the drug discovery process. The main goal of the visit was to encourage school children to consider research in the STEM subjects as a career option. |
Year(s) Of Engagement Activity | 2022 |
Description | Future of Advanced Therapies, STFC event Harwell campus |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Invited talk about new interventions for AMR |
Year(s) Of Engagement Activity | 2024 |
URL | https://www.harwellcampus.com/advanced-therapies-and-personalised-medicine/ |
Description | Invited research seminar presentation at Anglia Ruskin University |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Postgraduate students |
Results and Impact | I was invited to give a talk on the development of new generation antimicrobial agents by Anglia Ruskin University. The talk was given in person on 18 October at ARU Cambridge. |
Year(s) Of Engagement Activity | 2024 |
Description | Joint UK - South Korea, AMR research meeting University Southampton |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Professional Practitioners |
Results and Impact | Invited talk on new interventions for AMR |
Year(s) Of Engagement Activity | 2023 |
Description | National Biofilm Innovation Centre (NBIC) Showcase 2023 |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Showcase event |
Year(s) Of Engagement Activity | 2023 |
Description | STFC - 150 Years of Infectious Disease Research and Innovation meeting ; panel discussion |
Form Of Engagement Activity | A formal working group, expert panel or dialogue |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Professional Practitioners |
Results and Impact | Expert panel on new solutions for AMR in the diagnostic and therapeutic space |
Year(s) Of Engagement Activity | 2023 |
Description | Television Interview |
Form Of Engagement Activity | A broadcast e.g. TV/radio/film/podcast (other than news/press) |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Media (as a channel to the public) |
Results and Impact | I was interviewed by a national TV channel in Bangladesh as part of the antimicrobial resistance awareness week. The channel broadcasts its programmes in Asia, Europe and USA. |
Year(s) Of Engagement Activity | 2022 |
URL | https://www.channel24bd.tv/ |
Description | UKHSA Industry Day |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | International |
Primary Audience | Industry/Business |
Results and Impact | Presentation on Research activities at UKHSA of interest to business. Work will describe various aspects of ongoing research linked to the development and translation of new antimicrobial agents and rapid diagnostic tests |
Year(s) Of Engagement Activity | 2023 |
Description | UKRI Infection Transmission Sandpit Event: Liverpool |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Industry/Business |
Results and Impact | Sandpit event looking at the development of new interventions for AMR |
Year(s) Of Engagement Activity | 2024 |