The FUR protein (ferric uptake regulator) is an iron-dependent global transcriptional regulator. Specific to bacteria, FUR is an attractive antibacterial target since virulence is correlated to iron bioavailability. Recently, four anti-FUR peptide aptamers, composed of 13 amino acid variable loops inserted into a thioredoxinA scaffold, were identified, which were able to interact with Escherichia coli FUR (EcFUR), inhibit its binding to DNA and to decrease the virulence of pathogenic E. coli in a fly infection model. The first characterization of anti-FUR linear peptides (pF1 6 to 13 amino acids) derived from the variable part of the F1 anti-FUR peptide aptamer is described herein. Theoretical and experimental approaches, in original combination, were used to study interactions of these peptides with FUR in order to understand their mechanism of inhibition. After modeling EcFUR by homology, docking with Autodock was combined with molecular dynamics simulations in implicit solvent to take into account the flexibility of the partners. All calculations were cross-checked either with other programs or with experimental data. As a result, reliable structures of EcFUR and its complex with pF1 are given and an inhibition pocket formed by the groove between the two FUR subunits is proposed. The location of the pocket was validated through experimental mutation of key EcFUR residues at the site of proposed peptide interaction. Cyclisation of pF1, mimicking the peptide constraint in F1, improved inhibition. The details of the interactions between peptide and protein were analyzed and a mechanism of inhibition of these anti-FUR molecules is proposed.

FUR (Ferric Uptake Regulator) protein is a global transcriptional regulator that senses iron status and controls the expression of genes involved in iron homeostasis, virulence, and oxidative stress. Ubiquitous in Gram-negative bacteria and absent in eukaryotes, FUR is an attractive antivirulence target since the inactivation of the fur gene in various pathogens attenuates their virulence. The characterization of 13-aa-long anti-FUR linear peptides derived from the variable part of the anti-FUR peptide aptamers, that were previously shown to decrease pathogenic E. coli strain virulence in a fly infection model, is described herein. Modeling, docking, and experimental approaches in vitro (activity and interaction assays, mutations) and in cells (yeast two-hybrid assays) were combined to characterize the interactions of the peptides with FUR, and to understand their mechanism of inhibition. As a result, reliable structure models of two peptide-FUR complexes are given. Inhibition sites are mapped in the groove between the two FUR subunits where DNA should also bind. Another peptide behaves differently and interferes with the dimerization itself. These results define these novel small peptide inhibitors as lead compounds for inhibition of the FUR transcription factor.

L’objectif de ce travail était de mener une enquête ethnobotanique dans quatre marchés des zones soudanienne (Bamako et Sikasso) et sahélienne (Banamba et Kolokani) du Mali afin de recenser les fruits de cueillette vendus et leurs usages médicinaux. L’enquête a été réalisée à l’aide de questionnaires et d’entretiens auprès des vendeurs de fruits. Les résultats ont montré que vingt-deux fruits de cueillette appartenant à dix-sept familles faisaient l’objet de commerce dans les marchés enquêtés et que la cueillette et la vente de ces fruits sauvages étaient une activité largement dominée par les femmes (88%). Les familles des Arecacées, Annonacées, Apocynacées et Fabacées étaient les plus représentées. Les fruits de Balanites aegyptiaca, Zizyphus mauritiana et Saba senegalensis étaient les plus cités. Six des vingt-deux fruits vendus (27,27%) : Lannea microcarpum, Parkia biglobosa, Saba senegalensis, Tamarindus indica, Vitellaria paradoxa, Zizyphus mauritiana étaient communs aux marchés des quatre villes. Il ressort également que ces fruits étaient non seulement consommés pour les besoins nutritionnels mais aussi pour la prise en charge traditionnelle de certaines pathologies (hypertension, diabète, paludisme, stérilité, etc.). Ces résultats constituent une base de données pour d’autres travaux visant à évaluer les potentialités nutritionnelles et antimicrobiennes de ces fruits.

Most of the genome-wide association studies (GWAS) for lipid traits focus on single lipid traits. There are limited GWASs evaluating the variants associated with two or more lipid traits in African ancestry. To further identify and localize genetic loci with pleiotropic effects on lipid traits, we conducted a genome-wide meta-analysis, multi-trait analysis of genome-wide association studies (MTAG), and multi-trait fine mapping of up to 125,000 individuals of African ancestry. Our GWAS meta-analysis and MTAG identified four and 14 novel loci associated with lipid traits in individuals of African ancestry, respectively. flashfm multi-trait fine-mapping, which leverages information between the traits, yielded an 18% mean reduction in the 99% credible set size, compared to single-trait fine-mapping with JAM. Moreover, we identified more genetic variants with a posterior probability of causality > 0.9 with flashfm than JAM. In conclusion, we have identified additional novel loci associated with lipid traits in individuals of African ancestry and our flashfm fine-mapping significantly reduced the 99% credible set size to identify the causal genetic variants associated with multiple lipid traits in individuals of African ancestry.