MICA: Host-directed therapeutics to combat bacterial infections
Lead Research Organisation:
Queen's University Belfast
Department Name: Centre for Experimental Medicine
Abstract
The control of bacterial infections is perhaps the most important achievement of modern medicine. However, the rapid emergence and spread of antibiotic resistance is fast becoming one of the major scientific and health issues of modern times. According to the "National Risk Register of Civil Emergencies", more than 80,000 deaths are estimated in the UK if there is a widespread outbreak of a resistant microbe. The development of new antibiotics is slow and difficult work but bacterial resistance is decreasing our arsenal of existing drugs. A post-antibiotic era - in which common infections and minor injuries can kill - far from being an apocalyptic fantasy, is a very real possibility for the 21st Century. The O'Neill review on antibiotic resistance sets out the global threat by highlighting that "drug-resistant infections already kill hundreds of thousands a year globally, and by 2050 that figure could be more than 10 million". Of particular concern is the mounting prevalence of infections caused by multidrug resistant (MDR) Gram-negative bacteria, in particular Klebsiella pneumoniae. This pathogen has been singled out as an "urgent threat to human health" by the UK Government, the U.S. Centers for Disease Control and Prevention, and the World Health Organization due to extremely drug resistant strains. In 2014, the percentage of MDR K. pneumoniae isolates was above 10% in more than half of all reporting European countries, including the UK. K. pneumoniae infections are particularly a problem among neonates, elderly and immunocompromised individuals within the healthcare setting, but this organism is also responsible for a significant number of community-acquired infections including pneumonia and sepsis. Very few therapeutic options are left for patients infected with MDR K. pneumoniae with additional resistance to carbapenems, and are often limited to combination therapy and to colistin. Alarmingly, recent studies have recognised that several K. pneumoniae virulent and MDR clones have access to a mobile pool of virulence and antimicrobial resistance genes; hence making possible the emergence of a MDR, hypervirulent K. pneumoniae clone capable of causing untreatable infections in healthy individuals. K. pneumoniae is exemplary of the mismatch between unmet medical needs and the current antimicrobial development pipeline. Therefore, it is an urgent priority to develop effective therapeutics based on new targets and concepts. Unfortunately, at present, we cannot identify candidate compounds in late-stage development for treatment of MDR Klebsiella infections. Rising to this health challenge, and by capitalizing on a decade of studies on K. pneumoniae infection biology of the Bengoechea laboratory, in this project we will provide solid pre-clinical evidence demonstrating that inhibition of a host protein (Src kinase) targeted by Klebsiella to ablate our defences will influence decisively the outcome of host-Klebsiella interaction thereby limiting pathogen survival. By teaming up with AstraZeneca, we will demonstrate that treatment with a company proprietary Src kinase inhibitor will favour pathogen clearance. The proven excellent safety, and tolerability of the Src inhibitor may anticipate a fast-track transition from the pre-clinical stage to further clinical clinical development hence bypassing several initial hurdles of the drug development process. Altogether, we envision that our results will encourage other academics as well as other pharmaceutical companies to follow this avenue of research to tackle the problem of lack of therapies for microbes resistant to antibiotics.
Technical Summary
Globalisation has increased the risk of pandemics, and the rise of antibiotic-resistant microbes threatens to render existing drugs useless. Of concern is the mounting prevalence of infections caused by multidrug resistant Gram-negative bacteria, in particular Klebsiella pneumoniae. Shockingly, the increasing isolation of strains resistant to "last resort" antimicrobials has narrowed, and in some settings completely removed, the treatment options against these infections. Not surprisingly, Klebsiella has been singled out by the UK government, WHO and the CDC as an "urgent threat to human health." Unfortunately, we cannot identify candidate compounds in late-stage development for treatment of multidrug Klebsiella infections; this pathogen is exemplary of the mismatch between unmet medical needs and the current antimicrobial development pipeline. Therefore, it is an urgent priority to develop effective therapeutics based on new targets and concepts. Host-directed therapeutics for infectious diseases are receiving increasing attention. By targeting host factors crucial in the infection biology of a pathogen it can be enhanced innate host resistance to infection leading to reduced morbidity, mortality, and end-organ damage. Interference with signalling pathways hijacked by pathogens is thought to apply less selective pressure for the development of resistance than traditional strategies targeting the pathogen. In this proposal, we will provide compelling pre-clinical rationale for host-directed therapeutics against K. pneumoniae infections. We will demonstrate that by antagonizing the activation of the Src kinase by Klebsiella we will decisively influence the outcome of host-Klebsiella interactions thereby limiting pathogen survival. The excellent safety, tolerability and pharmacology of the Src inhibitor may anticipate a fast-track transition from the pre-clinical stage to further clinical development of the inhibitor to treat Klebsiella infections.
Planned Impact
Who will benefit from this research? Our industrial partner, AstraZeneca, will benefit from our findings offering the opportunity to further developments thereby getting closer to the goal of delivering therapeutics based on manipulation of the host-pathogen interplay. Academics will be short to medium term beneficiaries, as the research will provide a knowledge platform to develop host-directed therapeutics in other infection models. Industry: The growing number of organisms resistant to available antibiotics has become a public health threat worldwide, being Klebsiella a paradigm of an emerging pathogen. There is a need to develop effective therapeutics based on new targets and approaches. The successful completion of this project may leverage additional collaborations with SME and big pharma to exploit host-directed therapeutics. Public bodies: The UK Government is committed to taking an integrated approach to tackle the antimicrobial resistance challenge as part of the one health agenda at a national and international level. This proposal is aligned with the strategic action "supporting the development of new antimicrobials and alternative treatments" outline in the UK antimicrobial resistance strategy 2013- 2018. General public: Infections are one of the major global threats that are unfortunately very likely to become more urgent in the near future. It is not appropriate to generate an atmosphere of fear since medical care in UK is at a very high level. However, it is advisable to increase public awareness about the potential threats and to provide the UK national regulatory bodies, with a top-class knowledge platform to maintain the unique position of UK as an area of research excellence on infection biology.
How will they benefit from this research?: Collaboration agreements will regulate our industrial partnerships balancing the importance of disseminating the research and protection of industrial property. Knowledge of value to the academic sector will be communicated by publication in peer-reviewed journals, oral and poster presentations at conferences and via invited lectures. Exchange of staff and students will promote knowledge transfer between collaborative groups. Staff working on the project will receive training on complementary skills (group management, know-how transfer, and entrepreneurship) which together with the cutting-edge research training received will give the PDRA all options for either an excellent career in academia, industry, or to develop a business plan for their own start-up enterprise. Knowledge transfer to industry on new therapeutics to treat infections might have economic potential since royalty payments can reach numbers in the magnitude of several millions or tens of millions. Furthermore, this new treatment(s) will benefit the UK health system. The grant will have impact on the wider public sector by continuing our program of scientific communication. The laboratory hosts undergraduates and A/AS level students to engage them in the fundamentals of scientific research. A video clip on infection biology will serve to disseminate our research work. Social media will be targeted via Twitter (@josebengoechea). Queen's University Belfast and the Bengoechea laboratory web pages will be additional channels to promote this MRC-funded research
How will they benefit from this research?: Collaboration agreements will regulate our industrial partnerships balancing the importance of disseminating the research and protection of industrial property. Knowledge of value to the academic sector will be communicated by publication in peer-reviewed journals, oral and poster presentations at conferences and via invited lectures. Exchange of staff and students will promote knowledge transfer between collaborative groups. Staff working on the project will receive training on complementary skills (group management, know-how transfer, and entrepreneurship) which together with the cutting-edge research training received will give the PDRA all options for either an excellent career in academia, industry, or to develop a business plan for their own start-up enterprise. Knowledge transfer to industry on new therapeutics to treat infections might have economic potential since royalty payments can reach numbers in the magnitude of several millions or tens of millions. Furthermore, this new treatment(s) will benefit the UK health system. The grant will have impact on the wider public sector by continuing our program of scientific communication. The laboratory hosts undergraduates and A/AS level students to engage them in the fundamentals of scientific research. A video clip on infection biology will serve to disseminate our research work. Social media will be targeted via Twitter (@josebengoechea). Queen's University Belfast and the Bengoechea laboratory web pages will be additional channels to promote this MRC-funded research
Publications
Rodgers AM
(2019)
Control of Klebsiella pneumoniae Infection in Mice by Using Dissolving Microarray Patches Containing Gentamicin.
in Antimicrobial agents and chemotherapy
Bengoechea JA
(2019)
Klebsiella pneumoniae infection biology: living to counteract host defences.
in FEMS microbiology reviews
Coya JM
(2022)
Cooperative action of SP-A and its trimeric recombinant fragment with polymyxins against Gram-negative respiratory bacteria.
in Frontiers in immunology
Dumigan A
(2019)
A Porcine Ex Vivo Lung Perfusion Model To Investigate Bacterial Pathogenesis
in mBio
Bengoechea JA
(2017)
Vibrio cholerae amino acids go on the defense.
in The Journal of biological chemistry
Description | Antimicrobial resistance |
Amount | krĀ 20,000,000 (NOK) |
Organisation | Bergen Research Foundation |
Sector | Academic/University |
Country | Norway |
Start | 01/2020 |
End | 12/2023 |
Title | Ex vivo porcine lung perfusion model |
Description | The implementation of infection models that approximate human disease is essential to understand infections and for testing new therapies before they enter into clinical stages. Rodents are used in most of pre-clinical studies, although the differences between mouse and man have fueled the conclusion that murine studies are unreliable predictors of human outcomes. Here, we have developed a whole lung porcine model of infection using the established ex vivo lung perfusion (EVLP) system established to re-condition human lungs for transplant. As a proof-of-principle, we provide evidence demonstrating that infection of the porcine EVLP with the human pathogen K. pneumoniae recapitulates the known features of Klebsiella-triggered pneumonia. Moreover, our data revealed the porcine EVLP model is useful to reveal features of the virulence of K. pneumoniae including the manipulation of immune cells. Altogether, this study supports the utility of the EVLP model using pig lungs as surrogate host for assessing respiratory infections. |
Type Of Material | Technology assay or reagent |
Year Produced | 2019 |
Provided To Others? | Yes |
Impact | This model will lead to a reduction in the number of rodents probed to assess respiratory infections, and investigate new treatments. |
Title | In vivo delvery of drugs |
Description | We have gathered evidence of the most effective route to deliver drugs in order to target lung bacterial infection and to limit the metastasis to other organs. |
Type Of Material | Technology assay or reagent |
Year Produced | 2018 |
Provided To Others? | No |
Impact | We have reduced the number of animals to be infected, and the number of treatment doses. |
Title | Method to assess the interaction between pathogens and immune cells in vivo using mass cytometry |
Description | We have developed a novel method to detect the interaction between Klebsiella pneumoniaer and immune cells in vivo and ex vivo by exploiting mass cytometry. This method allows the simultaneous detection of bacteria, and immune cells characterized with more than 30 markers. |
Type Of Material | Technology assay or reagent |
Year Produced | 2021 |
Provided To Others? | Yes |
Impact | This method has allowed to detect interactions between K. pneumoniae and cells never reported before. These findings will allow to investigate how Klebsiella manipulate immune cells, and to better understand how the immune system senses this infection. |
Description | Collaboration AstraZeneca |
Organisation | AstraZeneca |
Country | United Kingdom |
Sector | Private |
PI Contribution | We are providing knowledge platform to validate host-directed therapeutics against acute bacterial infections. |
Collaborator Contribution | The company is providing support on the drug we are testing, as well as guiding aspects of drug delivery and outcomes. |
Impact | There are no outputs yet other than that the mandatory reports submitted to the funder (Medical Research Research) to assess the progress of the project. |
Start Year | 2018 |
Description | Collaboration GSK-Siena vaccines |
Organisation | GlaxoSmithKline (GSK) |
Department | GSK Vaccines Institute for Global Health |
Country | Italy |
Sector | Private |
PI Contribution | My team is providing expertise on pre clinical animal models to assess the effect of new therapeutics on the clearance of K. pneumoniae infections. |
Collaborator Contribution | GSK provides expertise assessing bacterial vaccines and correlates of protection. |
Impact | There are no outputs yet, although teh collabioration has resulted in teh coomitemnt to support a CAST PhD studenship. The collaboration is multidisciplinary bridging Immunology and Microbiology, and leveraging our leading expertise on K. pneumoniae infection biology. |
Start Year | 2022 |
Description | Escaping the antibtioc apocalyse-Medicine at the Crick |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | We presented to the general public, including school kids and patients' groups, the global health issue of the AMR pandemic, and how our research is addressing the problem by translating the knowledge platform of our discovery science. Particularly, the presentation discussed the opportunity of the so-called host-directed therapeutics as an innovative way to tackle infections. |
Year(s) Of Engagement Activity | 2023 |
Description | Niorthern Ireland Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | The laboratory organized a stand presenting how our RCUK-funded research is tackling the problem of antibiotic resistant infections. The purpose was to increase awareness of the health problem. More than 300 persons (including school kids) attended the event and our stand, the feedback indicates an increase awareness of the health problem and has translated into donations to our research team |
Year(s) Of Engagement Activity | 2019 |
URL | https://www.nisciencefestival.com/ |
Description | Northern Ireland Science Festival |
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 | Public/other audiences |
Results and Impact | We presented to the general public, including school kids and patients' groups, the global health issue of the AMR pandemic, and how our research is addressing the problem. The presentation was facilitated by on-hands laboratory work. The presentation attracted questions and change the views on the urgency of the AMR problem. |
Year(s) Of Engagement Activity | 2023 |
Description | Northern Ireland Science Festival |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Public/other audiences |
Results and Impact | 100 visitors from all ages attended a range of demonstrations and interactive laboratory research activities on eye disease, diabetes/vascular disease, respiratory/infectious disease. |
Year(s) Of Engagement Activity | 2020 |
URL | https://www.nisciencefestival.com/event.php?e=186 |
Description | Northern Ireland Science Festival COVID19 research |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Public/other audiences |
Results and Impact | More than 4000 viewers watched the videos on Covid19 research posted in YouTube by the Northern Ireland Science Festival. The videos sparked questions and comments, and resulted in additional interactions. |
Year(s) Of Engagement Activity | 2021 |
URL | https://nisciencefestival.com/e21486-spotlight-on-covid-19-research-at-the-wellcome-wolfson-institut... |
Description | School visit (South Eastern Regional College, SERC) |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | 55 students attended for a school visit to the Institute. the visit riase awareness of research, and what the lab is doing to tackle antimicrobial resistance. Also students learnt about risk assessment, and lab management. |
Year(s) Of Engagement Activity | 2019 |