LY256: A novel and potent antibiotic for treating Clostridium difficile infection

Lead Research Organisation: University of Nottingham
Department Name: Sch of Pharmacy

Abstract

Clostridium difficile infection (CDI) is a serious global public health threat, and is associated with significant morbidity, mortality and healthcare resource utilisation. Recent estimates suggest over 400,000 cases of CDI occur annually in Europe, and nearly half a million CDI cases and over 29,000 deaths reported in the US in 2011/2015. However, we also know that many cases are missed due to the lack of testing or use of sub-optimal diagnostics. Approximately 20-30% of patients experience disease recurrence, with around a third of patients presenting with severe CDI at the recurrent episode. For those with more than one previous recurrence, the risk of further recurrences increases to 40-65%. The effectiveness of a former mainstay of CDI treatment, metronidazole, is now compromised and antimicrobial resistant strains are emerging. The US CDC has recently classified this "superbug" among the serious immediate antibiotic-resistant infectious public health threats that require immediate and aggressive action (https://www.cdc.gov/drugresistance/biggest_threats.html). There is a real unmet need to develop new narrow-spectrum antibiotics that can prevent relapse of CDI, and thus reduce overall high healthcare-related expenditure on this infection, which can exceed £8,000 per patient.
In this project, we propose to further develop a promising new pre-clinical lead compound developed by researchers at the University of Nottingham. This drug 'LY256' has shown targeted (the majority of normal gut flora are insensitive to LY256) and potent antimicrobial activity against multiple strains of Clostridium difficile. In two different small animal models of CDI, orally administered drug given twice daily for 5 days was effective in treating CDI. During the project, individual work packages aligned to specific checkpoints will (i) develop methods for large scale manufacture of LY256, (ii) determine effective orally administered doses for treatment of both primary and recurrent infection using small animal and human in vitro gut models of CDI, and (iii) investigate if this new anti-C. difficile therapy can be combined with probiotic treatment approaches to exert an even greater therapeutic response. Specifically, attention will focus on combining a well-established gut commensal micro-organism with LY256. Our proposed solution may be immensely important in treating CDI without the use of more rudimentary approaches like faecal microbiota transplantation (FMT) or other less targeted antimicrobial strategies. LY256 can kill vegetative cells, has targeted activity against C. difficile, and is poorly absorbed from the gastrointestinal tract, making it an ideal candidate for further development.

Technical Summary

Clostridium difficile infection (CDI) is the most common cause of hospital-acquired infection, with high rates of morbidity and mortality in elderly patients. The infection is invariably due to broad-spectrum antibiotic-induced dysbiosis of the gut microbiome. Treatments with the front-line antibiotics, metronidazole and vancomycin, are of major concerns, primarily due to their lack of C. difficile selectivity and low gut concentrations. Recurrent CDI occurs in 20-30% of the patients, after which the rate increases to 40-65%. The recently introduced fidaxomicin has limited effectiveness in preventing recurrent CDI, particularly CDI caused by the hypervirulent strain, NAP1/BI/027. Faecal microbiota transplantation (FMT) is the only approved treatment for patients with multiple recurrent CDI. Thus, there is a real unmet need for new targeted-spectrum antibiotics that prevent relapse of CDI.
We have recently discovered a pre-clinical lead compound, LY256 that showed selective and potent in vitro and in vivo activity against several C. difficile strains. In two different small animal (hamster and mouse) models of CDI, orally administered LY256 2.5-5.0 mg/kg BID for 5 days was efficacious in treating CDI. In the present proposal, we have outlined a robust translation pathway for early-stage pre-clinical development of LY256 for the treatment of CDI. The project will generate new product specific IP covering: methods of large scale manufacture of LY256, effective orally administered doses for treatment of both primary and recurrent CDI, and the potentially disruptive adjunct therapy by combining chemo- and microbiome/biologic approaches which would result in additional market exclusivity.

Planned Impact

Clostridium difficile infection (CDI) remains a major global public healthcare issue in hospitals, long-term care facilities, and increasingly in the wider community. Established antimicrobial treatment options are less effective at managing recurrent or severe CDI and 30-day mortality remains unacceptably high. In addition to these impacts, the societal impacts (e.g. family, economic) have not been adequately quantified but are likely to be substantial. Most developed countries that are at least the size of the UK have reported several tens of thousands of CDI cases per annum. There is an urgent unmet need to develop new therapeutic strategies, which selectively target this pathogen and its principal virulence determinants but do not adversely affect the gut microbiota. Our proposed solution, LY256 is a novel and potent treatment for CDI that has excellent potential for translating into clinical practice, thus having far-reaching impacts, given the number of people who suffer from primary and recurrent CDI.
This project brings together a formidable collaborative group of international experts in the fields of C. difficile microbiology and microbiomics, gastroenterology, medicinal chemistry and leading blue chip commercial companies with extensive expertise in delivering drug discovery solutions. There is considerable scope for the research staff involved in this project to participate in multidisciplinary training, as well as unique opportunities for hands-on experience across the disciplines involved. Given that CDI continues to be a major public health problem, urgently in need of new therapeutic strategies, this timely partnership is extremely well placed to advance the production and pre-clinical development of the proposed lead candidate LY256.
The primary objectives of this project are not only acquisition of new knowledge and scientific advancement, but to build capacity and detailed knowledge for the translation of a powerful pathogen-specific antibiotic from laboratory to clinic. Although the project focuses on the treatment of Clostridium difficile infection, the approach is relevant to the development of other infection-focused antibacterial agents, in which the patient's specific infection is the centre pillar of the research programme.
From a societal perspective, introduction of LY256 into the clinical setting could have far-reaching benefits for the tax payer and policy makers. In an unprecedented climate of financial pressure for our national health service, our proposed drug candidate has the potential to help treat primary CDI and prevent relapsed or recurrent CDI, thereby improving patient healthcare and quality-of-life, and critically reducing community and hospital-associated healthcare costs associated with infection.
The Project PI will ensure that frequent and open communication occurs among all project partners on a regular (monthly basis) so that progress reports are analysed and targets are achieved. PI Chan has sought early input from an experienced clinician (Co-I Monaghan) so that pre-clinical experiments and work packages are designed with the appropriate foresight needed to meet the approval standards by clinical trial review bodies, can help plan for future trial funding, and facilitate patient recruitment by connecting potential trial participants with trial investigators. This layered approach is pivotal in accelerating the path from basic drug discovery to the clinic.
In order to engage with the public most effectively, we plan to be involved in the University-wide community open-day, "Mayfest" and Café Scientifique. At UoN, Monaghan has access to the support of the NIHR NDDC's own patient and public involvement officer (PPI) who will be approached to set up patient advisory group meetings aimed at raising awareness and understanding of patient and public perceptions of using LY256 alone and in combination with probiotics as a means to treating and preventing CDI.

Publications

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Description In vivo effect of LY256 on murine microbiome 
Organisation Evotec (UK) Ltd
Country United Kingdom 
Sector Private 
PI Contribution My research team synthesised and provided the test articles, LY256, LY299 and ridinilazole
Collaborator Contribution Evotec will carry out the in vivo study.
Impact This is an on-going study.
Start Year 2020
 
Description Non-GMP manufacture of LY256 
Organisation Almac Group
Department Almac Sciences
Country United Kingdom 
Sector Private 
PI Contribution Scalable methods for the total synthesis of LY256 were developed by my research team. These methods and associated chemical technology were transferred to Almac for the development of large-scale manufacturing processes.
Collaborator Contribution The scalable methods developed by my research team were used as the starting point for large-scale manufacture of key building blocks and LY256. Almac applied these methods, with further refinements, for the large-scale manufacture of the building blocks and LY256.
Impact The project is ongoing.
Start Year 2019