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mail : Elise BOREZEE-DURANT
Molecular mechanisms of metal acquisition pathways in Staphylococcus aureus
Metals are essential in many life processes. During bacterial infections, pathogens must obtain metals from the host to colonize and invade the tissue. To succeed, they have to face severe metal deprivation mechanisms used by the host to prevent growth, especially for iron, manganese and zinc, a phenomenon called “nutritional immunity”.
There is a link between metal acquisition and virulence potential. Identify and decipher the molecular mechanisms of new high affinity metal import systems, important for bacterial survival in the infected host, will provide new antimicrobial struggle strategies.
Our studies focus on new metal acquisition pathways in S. aureus, an opportunistic pathogen representing a major health issue. Among the transporters identified in the lab, the Cnt system is involved in metal import in complex with a metallophore, the staphylopine (Sp).
The genes encoding the transporter are located in an operon composed of 9 genes (cntKLMABCDFE). CntK, L, M catalyse the synthesis of Sp, then exported by CntE membrane protein. Sp binds several metals (Ni, Co, Cu, Zn and Fe(II)) in the extracellular medium and the metallophore/metal complex is imported by the CntABCDF transporter.
Importantly, the cnt operon is subjected to a differential and/or collaborative repression by Fur and Zur transcriptional regulators according to iron and zinc levels. We notably revealed the functional role of Cnt in zinc import and Cnt is required for efficient colonization of target organs in mice models of infection.
We suggest that these metal transporters have a role to sustain the bacterium in nutrient metals available at very low levels in the infected host. In collaboration with other teams working on Cnt-like systems in other pathogens, the overall results depict a new family of bacterial metallophores and constitute targets for new antimicrobials.
Bibliography (2015-2018) :
Fojcik C, Arnoux P, Ouerdane L, Aigle M, Alphonsi L, Borezée-Durant E. (2018) Independent and cooperative regulation of staphylopine biosynthesis and trafficking by Fur and Zur. Mol Microbiol doi: 10.1111/mmi.13927.
Lhospice S, Gomez NO, Ouerdane L, Brutesco C, Ghssein G, Hajjar C, Liratni A, Wang S, Richaud P, Bleves S, Ball G, Borezée-Durant E, Lobinski R, Pignol D, Arnoux P, Voulhoux R. (2017) Pseudomonas aeruginosa zinc uptake in chelating environment is primarily mediated by the metallophore pseudopaline. Sci Rep.7(1):17132. doi: 10.1038/s41598-017-16765-9.
Joubert L, Dagieu JB, Fernandez A, Derré-Bobillot A, Borezée-Durant E, Fleurot I, Gruss A, Lechardeur D. (2017) Visualization of the role of host heme on the virulence of the heme auxotroph Streptococcus agalactiae. Sci Rep. 7:40435
Moulin P, Patron K, Cano C, Zorgani MA, Camiade E, Borezée-Durant E, Rosenau A, Mereghetti L, Hiron A.(2016) The Adc/Lmb System Mediates Zinc Acquisition in Streptococcus agalactiae and Contributes to Bacterial Growth and Survival. J Bacteriol. 198(24):3265-3277.
Ghssein G, Brutesco C, Ouerdane L, Fojcik C, Izaute A, Wang S, Hajjar C, Lobinski R, Lemaire D, Richaud P, Voulhoux R, Espaillat A, Cava F, Pignol D, Borezée-Durant E, Arnoux P (2016). Biosynthesis of a broad-spectrum nicotianamine-like metallophore in Staphylococcus aureus. Science 352:1105-9.
Lebrette H, Borezée-Durant E, Martin L, Richaud P, Boeri Erba E, Cavazza C. (2015) Novel insights into nickel import in Staphylococcus aureus: the positive role of free histidine and structural characterization of a new thiazolidine-type nickel chelator. Metallomics 7(4):613-21.
Pascal Arnoux - CEA Cadarache- Bactéries et Métaux
Laurent Ouerdane - Université de Pau et des pays de l’adour - Chimie analytique
Romé Voulhoux - CNRS Aix-Marseille - Systèmes de sécrétion et pathogénicité chez Pseudomonas
Riccardo Torelli - Institut de Microbiologie Rome