MICA: Host-directed therapeutics to combat bacterial infections

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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.