A new antibiotic candidate, LY256, kills *Clostridium difficile* directly in the gut while leaving most other gut bacteria unharmed. This matters because *C. difficile* infection (CDI) causes severe diarrhoea, kills tens of thousands of people annually in the US and Europe, and frequently returns after treatment. Around 20–30% of patients relapse, and for those with multiple recurrences, the risk of further episodes climbs to 40–65%. Existing drugs like metronidazole are losing effectiveness, and resistant strains are emerging. The US CDC now classifies *C. difficile* as a serious immediate antibiotic-resistant threat. If LY256 succeeds, it could break the cycle of recurrence without resorting to crude approaches like faecal transplants. The drug is poorly absorbed from the gut, so it stays where it is needed, and the researchers plan to combine it with a probiotic to boost its effect. This would reduce the high healthcare costs of CDI—often exceeding £8,000 per patient—and offer a targeted alternative to broad-spectrum antibiotics that damage the gut’s protective flora.
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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.
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