Can drugs that target host signaling pathways be used to eradicate antibiotic-resistant bacteria?

How do mycobacteria subvert the defenses of host immune cells?

The research described in this Thesis was aimed at designing and synthesizing nature-inspired compounds as part of TB vaccine discovery.

Autophagy is a fundamental degradative process, maintaining cellular homeostasis and functions in host defense against intracellular pathogens, including mycobacteria and Salmonella.

Promotores: A.H. Meijer, H.P. Spaink

New drugs for use as tuberculosis (TB) treatment are needed due to the constrains of classical antibiotics against TB and the rise of antibiotic-resistant strains, making TB a harder and harder disease to treat.

Tuberculosis is a major global health problem caused by the Mycobacterium tuberculosis complex, claiming more than a million lives annually.

How do lipases in Mycobacterium tuberculosis help the bacteria survive, and can we target them to create new antibiotics?

Tuberculosis (TB) is associated with 1.5 million deaths annually. There is a need exists to optimize both current as well as novel antibiotic combination treatment strategies to improve the effectiveness and safety of treatments against TB.

About nine million people worldwide contract tuberculosis each year. Research into new treatment for this disease has received fresh stimulus with more efficient techniques and a new understanding of how the tuberculosis bacteria works.

Can small molecule drugs restore the immune system’s ability to fight tuberculosis by boosting autophagy?

The infectious diseases malaria and tuberculosis are responsible for 2.1 million deaths every year. Leiden researchers are currently testing a new tuberculosis vaccine.

Promotor: H.P. Spaink, A.H. Meijer Co-promotor: R. Marin-Juez

In this thesis, I study 1) metabolic alterations in tuberculosis related to wasting syndrome in human patients as well as in rodent and fish animal models. 2) effects of the mutation of the leptin gene on cachexia and diabetes in rodent and zebrafish animal models.

IBL-researcher Phil Elks in the group of Annemarie Meijer won the Cell Observatory Publication of the Year 2013. He received the award for his paper in PLoS Pathogens, showing that activation of hypoxia signaling protects against mycobacterial infection.

The cellular recycling system in zebrafish is capable of eating harmful bacteria and thus resist infections such as tuberculosis and salmonellosis. That is written by Leiden biologists from the group of Annemarie Meijer. Stimulating this form of defence could be used in new treatment methods against…

Michiel van der Vaart with a team from Leiden University and the LUMC, led by IBL-researcher Annemarie Meijer, discovered that DRAM1 is a protein that regulates anti-bacterial autophagy, a defense mechanism against infections such as tuberculosis.

Mycobacterium tuberculosis (Mtb), the pathogen causing tuberculosis (TB), is the leader among all pathogens responsible for the most human deaths today and it is considered as one of the top 10 causes of death worldwide. There is an increasing occurrence of multidrug-resistant and even totally drug-resistant…

How do pathogenic mycobacteria alter lipid metabolism in human cells and patients, and which disrupted pathways could be targeted for new antibiotics?

Though tuberculosis can be cured today, new resistant strains of the bacteria are becoming a growing problem in the medical world. Biologist Annemarie Meijer and her colleagues are studying resistance to this disease. Their research is already yielding several interesting clues that could help the development…

This thesis focuses on the role of chemokine receptors CXCR3 and CCR2 in the inflammatory process and infection control using the zebrafish model.

Het proefschrift omschrijft de chemische synthese van fenolische glycolipiden van verschillende mycobacteriën met het doel om deze te kunnen gebruiken voor immunologisch onderzoek.

This thesis describes the structural and biochemical characterization of the β-lactamase BlaC from Mycobacterium tuberculosis (Mtb), and the Alr and YlmE proteins from Streptomyces coelicolor A3(2).Mtb is the main cause of tuberculosis.

The effective treatment of tuberculosis (TB) remains a major challenge to global health.

Researchers from Leiden have developed a promising TB vaccine that users can self-administer via a special patch. This could be beneficial for countries with limited health services, says PhD candidate Malene Neustrup.

Macrophages – the front line of our immune system – protect us from infections. But in the case of the tuberculosis bacteria, this often goes wrong. The group of Annemarie Meijer from the Leiden Institute of Biology has now discovered that macrophages in zebrafish are better able to eliminate tuberculosis…

Tuberculosis (TB) is a major global health problem caused by the bacterium Mycobacterium tuberculosis (Mtb). In 2015, there were estimated to be 10.4 million new cases and 1.8 million deaths ascribed to TB, making it one of the top 10 causes of death worldwide. Unfortunately, the only current registered…

Enzymes are innately sensitive to changes in the amino acid sequence, which largely constrains their evolutionary potential, i.e., evolvability. This evolutionary burden can be alleviated in the presence of stabilizing mutations, which increase the buffering capacity of enzymes to tolerate mutations…

The function of TLRs in innate immunity has aroused worldwide attention soon after its discovery. Because of the broad functions of TLR2 in innate immunity, the drive for the development of TLR2-targeted vaccines or therapeutic treatments has accelerated in the last decades.

Antimicrobial resistance is one of the biggest threats to human health worldwide in the coming decennia.

How is inflammation in tuberculosis controlled by interplay between autophagy and inflammasome signalling?

BlaC is the β-lactamase of Mycobacterium tuberculosis. We show that it can recover from inhibition by clavulanic acid and that phosphate helps it do so.

An international consortium of research groups is aiming to develop novel antibiotics against the tuberculosis bacteria and two other deadly bacteria. The European Union has awarded a total of 18 million euros to the RespiriTB and RespiriNTM projects. Researchers from the Leiden University Medical Centre…

In this thesis, bioorthogonal chemistry is combined with correlative light-electron microscopy to selectively label and study pathogenic intracellular bacteria within the host immune cell.

The research described in this thesis has, using the zebrafish as a model system, shed new light on the intricate relationship between TB and DM2, in particular on the role of leptin, SHP-1 and glucocorticoids.

We investigate the molecular basis underlying health and disease and provide answers to existing and emerging health problems. Within this theme, we study diseases ranging from rare genetic disorders to cancer and infectious diseases. We make use of a wide variety of model systems and pursue diverse…

On Monday 21 September Annemarie Meijer, Professor of Immunobiology, presented her inaugural lecture on immunobiology and infectious disease.

Meet the scientists within the LED3 community

The Translational Immuno-Pharmacology group works on translating the efficacy of anti-infective therapy from preclinical (e.g. in vivo) to clinical, and is led by Rob van Wijk. Infectious diseases, such as tuberculosis, are in constant need of new therapies that work better, faster, and with less risk…

Ever since the FDA approved the drug bedaquiline, which interferes with the bioenergetics of Mycobacterium tuberculosis by inhibiting the activity the F0F1-ATP synthase, respiratory-chain enzymes have been an active target space for the discovery of new antibiotics. To aid in this pursuit, we aim to…

β-Lactamases are enzymes that can break down β-lactam substrates, such as antibiotics, preventing the use of these antibiotics for the treatment of various infectious diseases. However, some compounds, β-lactamase inhibitors, can block these enzymes allowing for possible treatments using a combination…

Are Weyl particles the ideal conductors? Do cells without a cell wall play a role in chronic Tuberculosis infections? Carlo Beenakker and Dennis Claessen want to answer these questions. They both received a KLEIN grant from the NWO. With these grants, NWO wants to stimulate innovative, fundamental r…

Tuberculosis causes 1.5 million deaths yearly and anti-tuberculosis therapies are threatened by emergence of drug resistance. Development of innovative drug combinations should be accelerated with the use of translational pharmacological models. Moreover, host-directed therapies (HDT), which stimulate…