New therapeutic strategies against antibiotic-resistant bacterial infections, including tuberculosis (TB),  are urgently needed. This project explores a novel approach: boosting the body’s natural ability to fight infections by enhancing a cellular process called autophagy, in which cells fight infections by ‘eating’ harmful bacteria and clearing out damaged components. By targeting the transcription factor TFEB, which plays a key role in activating autophagy, we aim to restore the immune system’s ability to combat Mycobacterium tuberculosis (Mtb) infections.

Research goal

This study seeks to identify small molecules that can activate TFEB and enhance autophagy, restoring the body's ability to fight TB. Recent discoveries suggest that an endogenous (naturally occurring) metabolite can activate TFEB, raising the possibility that synthetic molecules could mimic this effect. Using luminescence assays, medicinal chemistry, and mass spectrometry, we aim to identify and validate compounds that can serve as the basis for new host-directed antibiotics.

Interdisciplinary approach

This project combines the expertise of chemical biologists from the Leiden Institute of Chemistry (LIC) and the Mycobacterial Research group at the Leiden University Medical Center (LUMC). By bridging chemistry and infectious disease research, we aim to develop innovative therapeutic strategies that enhance the immune system’s natural defenses against TB. This interdisciplinary collaboration allows us to design, synthesize, and test novel compounds while also investigating the underlying mechanisms of immune evasion by Mtb.

Project description: Covalently activating autophagy to develop novel host-direct antibiotics

Bacterial infections, such as tuberculosis (TB), are a growing global health threat, causing over 1.3 million deaths every year. Existing drugs to treat TB cause toxic side effects and are increasingly becoming ineffective due to the development of antibiotic resistant bacteria. As such, there is an urgent need for new approaches to treat these infections. Instead of developing drugs that directly target the bacteria, one novel strategy is to enhance the body's own natural immune defense system.

Our immune cells use a process called autophagy to help fight infections. During autophagy, cells 'eat' harmful bacteria and clear out damaged parts within themselves. However, the tuberculosis bacteria (M. tuberculosis) have learned how to disable this process, making it harder for the body to fight the infection. Recent research has shown that a specific protein, TFEB, plays a key role in activating autophagy. This discovery opens up the possibility of developing small drug molecules that can activate TFEB and restore the body’s ability to fight off tuberculosis infections.

This project aims to find and develop such drug molecules. We will use a combination of advanced laboratory techniques, including luminescence assays and high-resolution mass spectrometry, to identify the right activator of TFEB. We will then use a combination of medicinal chemistry and biological experiments to optimise these compounds into potential drug candidates that help combat TB.

By bringing together experts in chemical, biology, medicinal chemistry, immunology and mycobacterial research, this interdisciplinary research project not only aims to develop new treatments for tuberculosis but also opens up the possibility of using similar approaches for other diseases linked to problems with autophagy.

• antibiotic resistance
• drug discovery
• host-microbe interactions
• immunity
• infectious disease
• intracellular pathogens
• kiem grant
• tuberculosis

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