Our team, specialized in the structural study of membrane proteins, focuses its research on the public health problem of antibiotic resistance responsible for the dramatic increase of multi-resistant bacteria all over the word.
Team research topics :
Among the different ways used by bacteria to resist to antibiotics, the active efflux through tripartite efflux pumps is one of the most important. Our main target is Pseudomonas aeruginosa (PA), a nosocomial opportunistic pathogen that contributes to the decline of respiratory function in cystic fibrosis (CF) patients. PA possesses mainly four efflux pumps proven to be involved in the efflux of antibiotics, with some specificities concerning the family of antibiotics taken in charge, and concerning the activation of their transcription leading to an overexpression of the pumps. The different strategies to develop molecules blocking the function or the expression of these pumps are listed on the figure. We are conducting this research by complementary approaches linking structural biology (X-ray crystallography, SAXS, Cryo-EM) with in cellulo functional analysis.
We recently managed to describe the assembly of MexA-MexB-OprM by cryo-electronic microscopy in close collaboration with the team of Dr Lambert in Bordeaux University. We now want to isolate the different steps of one complete cycle of the efflux mechanism to address remaining questions, like the order of the assembly of the three protein partners, and that of the disassembly, the activation events, the efflux pathway, the reason why the same bacterium possesses so many transporters, what makes their specificity, and so on. We actually extend the efflux pump project to the study of their regulators, in close collaboration with the team of Dr C. Llanes (University of Besançon).
Connected side projects
- In collaboration with the team of Pr P. Plesiat (CHU Besançon, “Centre National de Référence de la Résistance aux Antibiotiques”) we model the possible effect of single-mutations identified in clinical PA strains isolated from the spits of cystic fibrosis patients.
- In collaboration with the team of Dr J. Hardouin (University of Rouen) we want to understand the role of post-translational modifications (PTM) in regulation functions in P. aeruginosa and in A. baumannii with a particular focus on lysine acetylation. This could permit to identify new targets to develop anti-resistance therapeutic drugs.