Metals and microorganisms: biology, chemistry and applications (Team I. Schalk/G. Mislin)
Our group brings together biochemists, molecular biologists, microbiologists and organic chemists. This combination of different skills allows us to use a multidisciplinary approach to investigate iron homeostasis in bacteria.
Iron is an essential nutriment for almost all living organisms because it is a cofactor of enzymes involved in key metabolic processes like cell respiration, nucleotide biosynthesis, DNA replication, transcription and repair. This nutriment being poorly bioavailable, bacteria produce siderophores to scavenge iron(III) from their environment. Siderophores are small organic iron chelators, having a very high affinity for iron(III) and produced in any bacterial environment and especially in the host during infections. Our model is Pseudomonas aeruginosa, a human opportunist pathogen that uses at least 20 different iron uptake pathways.
Study of the molecular mechanisms involved in iron uptake. We study the molecular interactions between the proteins involved in this metal acquisition, their organization and distribution in the cell wall and how the resulting protein machineries enable iron acquisition. We also investigate the molecular mechanisms involved in regulating the expression of the different iron uptake pathways in P. aeruginosa.
New targets for innovative antibiotics. P. aeruginosa cause many hospital-acquired infections and lethal infections in cystic fibrosis patients. Unfortunately, the resistance to classical antibiotics is increasing. In this context, iron uptake pathways constitute promising targets for new generations of antibiotics. We are developing two strategies, based on the notions that iron is important for bacteria growth and that iron uptake pathways are efficient and selective:
- Synthesis of inhibitors of the proteins involved in iron uptake. By inhibiting some of these proteins, it may be possible to block iron acquisition by the bacteria, thereby inhibiting their proliferation.
- Synthesis of siderophore-antibiotic conjugates that behave like “Trojan Horses” and use iron uptake pathways to transport the antibiotic into the bacteria and kill them. Antibiotic vectorized in these approaches are approved molecules or innovative bactericidal compounds (metal complexes, antibacterial peptides).
Bioremediation. We also study the metal specificity of siderophore-mediated iron uptake pathways for other heavy metals. We aim to validate the use of bacterial iron uptake pathways for the development of new bioremediation processes for liquid waste or grounds contaminated with heavy metals.