The team "Metals and Microorganisms: Biology, Chemistry and Applications" (MMBCA) member of the UMR7242 Biotechnology and Cell Signalling, is located in the Innovation Center of Illkirch (10 km from Strasbourg down-town). In this team, chemists and biologists (15 peoples, 8 with permanent positions) are developing research projects at the interface of biology and chemistry, with a particular focus on metal homeostasis in pathogenic bacteria. In this context, the research currently dedicated to the development of new metallo-antibiotics is promising and a PhD recruitment is proposed under the scientific supervision of Dr. Gaëtan Mislin (PhD, Habilitation University of Strasbourg, CNRS Research Director).
Iron is an essential element for the proliferation of pathogenic bacteria. To meet their needs for this crucial nutrient, microorganisms secrete chelating molecules called siderophores. These metabolites complex iron(III) in the extracellular medium and the corresponding ferric complex is recognized and transported through the bacterial envelope through a transmembrane uptake system. This active transport system allows the import of the ferric siderophore from the extracellular medium into the bacterium. The outer membrane of Gram-negative bacteria is their first-line defense against many antibiotics families. The hijacking of siderophore-dependent iron uptake systems by siderophore-antibiotic conjugates leads to a drug accumulation in the bacterium by a Trojan Horse strategy. This approach is now well mastered with so-called "approved" antibiotics but only little exploited for the vectorization of organometallic antibacterials. The use of photo-reactive organometallics combines the intrinsic antibacterial activity of the metal with that of reactive chemical species generated under irradiation. The vectorization of such organometallic photosensitizers by siderophores was never reported so far despite the potential in the context of antibacterial photodynamic therapy (PDT), described as a promising alternative in the struggle against antibiotic-resistant infections. In this context, the PhD project is focused on the development of synthetic vectors derived from bacterial siderophores such as enterobacin, desferrioxamine, pyocheline or ferrichrome. These vectors will retain their iron chelation properties in order to benefit from the efficiency and selectivity of import by dedicated bacterial uptake systems. Reactive functions on these vectors will allow the conjugation with a antibacterial metal complex. Iridium(III) is one of the most suitable metals for this type of approach and will be preferred in a first approach. Organometallic chemistry will be performed in a partner laboratory (LCMT Caen) and will not directly involve the PhD. Depending on PhD wishes/skills, he/she will also be involved in the evaluation of molecules.