MICA: Host-directed therapeutics to combat bacterial infections

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.

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.

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