Research project
Efficient Chemistry for new antibiotics against C. difficile
How can efficient chemical synthesis and clinical microbiology be combined to identify new antibiotics against Clostridioides difficile infections?
- Duration
- 2025 - 2026
- Contact
- Miriam Van der Veer
- Funding
- KIEM grant (Leiden University)
Introduction
Antibiotics are indispensable to modern healthcare, but their use can also have unintended consequences. Because many antibiotics kill not only harmful bacteria but also beneficial microbes in the gut, patients are vulnerable to secondary infections. One of the most serious of these is caused by Clostridioides difficile, a bacterium that can lead to symptoms ranging from severe diarrhoea to life-threatening inflammation of the colon.
Although C. difficile infections can often be treated with existing antibiotics, recurrent infections, limited treatment options, and emerging resistance pose major clinical challenges. This project addresses the urgent need for new antibiotics by bringing together innovative chemical synthesis and state-of-the-art molecular microbiology to accelerate the discovery of effective treatments against C. difficile.
Research goal
The aim of this project is to identify new, promising antibiotic candidates against C. difficile by combining efficient chemical synthesis of tailored compound libraries with testing in clinically relevant bacterial strains. By closely integrating chemistry and molecular microbiology, the project seeks to increase the speed and success rate of early-stage antibiotic discovery.
Interdisciplinary approach
This project is a collaboration between the Faculty of Science and the Leiden University Medical Center (LUMC). The chemistry group at the Leiden Institute of Chemistry (LIC) contributes expertise in the rapid and efficient synthesis of covalent inhibitors—a class of compounds with high potential as antibiotics. The molecular microbiology group at LUMC brings extensive experience in culturing and testing C. difficile under anaerobic conditions and has access to clinically relevant strains through its role in the Dutch National Expertise Center for C. difficile infections.
By combining these complementary strengths, the project creates a cross-faculty research team that can test newly synthesised compounds directly in the most relevant clinical contexts.
Project description - Using Efficient Chemistry to Identify New Antibiotics to Treat Clinically Relevant C. difficile Infections
In this project, researchers develop and test new antibiotic candidates using a highly efficient ‘direct-to-biology’ approach. Instead of synthesising and purifying each compound individually—a time-consuming process—the chemistry team rapidly generates large libraries of candidate antibiotics using selective chemical reactions in multiwell plates. These compounds are immediately ready for biological testing, allowing a fast transition from synthesis to activity screening.
The project builds on an existing collection of chemical building blocks and expands it to create diverse libraries of covalent inhibitors. These compounds form strong, irreversible bonds with their bacterial targets, making them particularly effective as antibiotics. Earlier work using this approach has already demonstrated its potential against other dangerous bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA).
Once synthesised, the candidate antibiotics are tested by the molecular microbiology group against C. difficile. Initial screening is performed using well-characterised laboratory strains, followed by testing in a wide range of clinical isolates collected from Dutch hospitals. This ensures that promising compounds are effective not just in the lab, but also against the strains that cause real-world infections.
An important aspect of the project is the close feedback loop between chemistry and microbiology. Results from bacterial testing are rapidly fed back into the chemical design process, allowing the team to refine and optimize compound libraries in successive rounds. This iterative strategy maximises the chances of identifying potent and broadly effective antibiotic candidates.
Beyond identifying new compounds, the project also lays the foundation for long-term collaboration between chemistry and medical microbiology at Leiden University. The insights, methods, and partnerships developed here are expected to lead to follow-up research and future funding aimed at developing new treatments for C. difficile infections and other antibiotic-resistant pathogens.