Playing with pathogenicity and host response to tackle tolerance and resistance to antibiotics in persistent infections
Beside resistance, tolerance to antibiotics also participates to therapeutic failure. Tolerance is due to the capacity of bacteria to adopt specific lifestyles like intracellular survival or biofilm, which are poorly responsive to antibiotics. It can be explained by a lack of access of the antibiotics to the bacteria localized in these protected niches together with a switch to a dormant phenotype that is not susceptible to antibiotics. The aim of the research performed in the group of Prof F. Van Bambeke (cellular and molecular pharmacology; TFAR) is precisely to elucidate why and how bacteria become tolerant to antibiotics in these specific situations and to propose and to test innovative therapeutic strategies in this context. In parallel, strateges aiming at reducing bacterial virulence and at modulating host inflammatory response are also examined.
What are the mechanisms by which the innate immune system, bioactive lipids and the gut microbiota control host metabolism?
Obesity is characterized by cardio-metabolic risk factors (e.g., inflammation, hepatic steatosis, type 2 diabetes). Our pioneering studies have shown that gut microbes contribute to these disorders likely by modulating immunity, but also bioactive lipids production including endocannabinoids. Prof P. Cani and his team have developed several unique models (e.g., inducible cell specific deletion, pharmacological tools, organoids) targeting key enzymes/receptors linked with the endocannabinoid system, lipid congeners or specific immune response. Our project will allow us to unravel several axis of communication between the gut and peripheral organs such as the brain, the liver, and the adipose tissue and their role on energy, glucose, lipid metabolism, and inflammation.
How to prolong drug retention in the lungs and reduce dosing frequency of inhaled drugs?
Inhalation aerosols offer a targeted drug therapy for chronic respiratory diseases such as asthma. However, the rapid elimination of therapeutic proteins from the lungs implies the requirement to deliver them once daily and this imposes a significant therapy burden to patients. Prof R. Vanbever investigates the potential of PEGylation for sustaining the presence of therapeutic proteins in the lungs. Her team has demonstrated that the covalent attachment of a large polyethylene glycol chain to therapeutic proteins greatly prolongs their presence in the lungs. This prolonged pulmonary residency translates into an improved efficacy in reducing lung inflammation in murine models of asthma.
How interacting with bioactive lipids can be beneficial in inflammatory diseases?
Bioactive lipids are endogenous mediators regulating numerous homeostatic functions, including inflammation. During inflammation, specialized lipid molecules are responsible for coordinating the cascade of events starting with the initiation of inflammation and ending with the resolution phase. While some lipid mediators, such as prostaglandins, are well characterized, much remains to be discovered regarding the properties of other bioactive lipids. Therefore, Prof G.G. Muccioli and his team study the effect of bioactive lipids, such as endocannabinoids and related compounds, oxysterols, and lysophospholipids, on inflammation. Our aim is to reduce inflammation in a variety of diseases by interacting with the enzymes and receptors regulating bioactive lipid functions.
How to efficiently deliver drugs to the central nervous system?
The therapeutic potential of novel potent drug that address diseases of the central nervous system is often limited by a low bioavailability, off target toxicity and limited access of therapeutic molecules to the CNS (blood-brain-barrier). One strategy developed by Prof. A des Rieux and her team to address these limitations is to develop new drug delivery systems (nanomedicines) that would specifically deliver drugs to the CNS. Drug encapsulation in nanoparticles would protect the drug, increase its solubility and its transport across biological barriers. These systems are currently tested in models of multiple sclerosis and spinal cord injury but could be used for other pathologies.
How to improve the delivery, engraftment and survival of stem cells?
Regenerative medicine aims at restoring organ function that was lost due to a pathology or an accident. Most of the strategies that are being explored involve stem cells. Limiting factors are cell survival after injection, cell engraftment, potential formation of tumors and host rejection. Combination of biomaterials and drug delivery is one of the approaches that Prof A. des Rieux and her team use to address these issues. We are currently exploring the potential of dental stem cells for spinal cord injury and inflammatory diseases and developing different strategies to deliver them in the central nervous system.
How to enhance the oral delivery of drugs using nanomedicines?
Oral delivery of biologics and poorly water soluble drugs is hindered by both the physicochemical properties of the drug molecule and physiological barriers in the gastrointestinal tract. Therefore, to overcome these limitations, Prof V. Préat, Dr A. Beloqui and their team are exploring and optimizing nanomedicines as a promising drug delivery systems with applications in high-impact diseases such as inflammatory bowel disease, type 2 diabetes mellitus, and obesity. Nanoparticles can improve the oral bioavailability of both hydrophobic and hydrophilic drugs, as well as biologicals via different mechanisms: enhancing the solubility, prevention against premature degradation in the intestine, enhancing intestinal permeation and targeted drug delivery.