Synthesis and pharmacomodulations of an antibiotic molecule directed against Gram-negative bacteria
Résumé
Gram-negative nosocomial pathogens such as Escherichia coli and Pseudomonas aeruginosa represent a major public health problem requiring the urgent development of new antibiotic molecules. The SIMBA laboratory (EA 7502, University of Tours) has been developing for several years methods for the synthesis and functionalization of natural molecules based on lactones, such as cytosporone E, a fungal secondary metabolite with interesting antibacterial activities. In collaboration with the BRMF laboratory (UMR ISP 1282), a chlorinated analogue of this natural product was synthesized and demonstrated to be (i) inactive against Gram-negative bacteria (ii) relatively cytotoxic and (iii) showing excellent activity against methicillin-resistant S. aureus (MRSA) strains. More recently, the work carried out in the framework of a Master 2 internship financed by the FéRI allowed to identify that efflux pumps, in synergy with membrane impermeability, were responsible for the resistance of Gram-negative bacteria towards this analogue. Based on these results, this research project would consist in (i) carrying out new pharmacomodulations of the molecule, in order to extend its spectrum of action to Gram-negative bacteria (introduction of an ionizable amine function) and to make it less cytotoxic (pharmacomodulation of the alkyl chain by a 4- trifluoromethylphenyl group); and (ii) testing the antibacterial activities and cytotoxicity of the new analogues against different reference bacteria and bacteria isolated from patients samples