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Your search keyword '"Ariel Mechaly"' showing total 3 results
Start Over Author "Ariel Mechaly" Topic microbiology
3 results on '"Ariel Mechaly"'

1. Molecular mechanism of a triazole-containing inhibitor of Mycobacterium tuberculosis DNA gyrase

Author

Antoine Gedeon, Emilie Yab, Aurelia Dinut, Elodie Sadowski, Estelle Capton, Aurore Dreneau, Julienne Petit, Bruna Gioia, Catherine Piveteau, Kamel Djaout, Estelle Lecat, Anne Marie Wehenkel, Francesca Gubellini, Ariel Mechaly, Pedro M. Alzari, Benoît Deprez, Alain Baulard, Alexandra Aubry, Nicolas Willand, and Stéphanie Petrella

Subjects
Multidrug resistant organisms, Drugs, Molecular Structure, Microbiology, Science
Abstract

Summary: Antimicrobial resistance remains a persistent and pressing public health concern. Here, we describe the synthesis of original triazole-containing inhibitors targeting the DNA gyrase, a well-validated drug target for developing new antibiotics. Our compounds demonstrate potent antibacterial activity against various pathogenic bacteria, with notable potency against Mycobacterium tuberculosis (Mtb). Moreover, one hit, compound 10a, named BDM71403, was shown to be more potent in Mtb than the NBTI of reference, gepotidacin. Mechanistic enzymology assays reveal a competitive interaction of BDM71403 with fluoroquinolones within the Mtb gyrase cleavage core. High-resolution cryo-electron microscopy structural analysis provides detailed insights into the ternary complex formed by the Mtb gyrase, double-stranded DNA, and either BDM71403 or gepotidacin, providing a rational framework to understand the superior in vitro efficacy on Mtb. This study highlights the potential of triazole-based scaffolds as promising gyrase inhibitors, offering new avenues for drug development in the fight against antimicrobial resistance.

Published
2024
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2. Interactions of Severe Acute Respiratory Syndrome Coronavirus 2 Protein E With Cell Junctions and Polarity PSD-95/Dlg/ZO-1-Containing Proteins

Author

Yanlei Zhu, Flavio Alvarez, Nicolas Wolff, Ariel Mechaly, Sébastien Brûlé, Benoit Neitthoffer, Sandrine Etienne-Manneville, Ahmed Haouz, Batiste Boëda, and Célia Caillet-Saguy

Subjects
SARS-CoV-2, envelope protein, host–pathogen interactions, PDZ-binding motif, PDZ-containing protein, protein–protein interaction, Microbiology, QR1-502
Abstract

The C-terminus of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein E contains a PBM (PDZ-binding motif) targeting PDZ (PSD-95/Dlg/ZO-1) domains, which is identical to the PBM of SARS-CoV. The latter is involved in the pathogenicity of the virus. Recently, we identified 10 human PDZ-containing proteins showing significant interactions with SARS-CoV-2 protein E PBM. We selected several of them involved in cellular junctions and cell polarity (TJP1, PARD3, MLLT4, and LNX2) and MPP5/PALS1 previously shown to interact with SARS-CoV E PBM. Targeting cellular junctions and polarity components is a common strategy by viruses to hijack cell machinery to their advantage. In this study, we showed that these host PDZ domains TJP1, PARD3, MLLT4, LNX2, and MPP5/PALS1 interact in a PBM-dependent manner in vitro and colocalize with the full-length E protein in cellulo, sequestrating the PDZ domains to the Golgi compartment. We solved three crystal structures of complexes between human LNX2, MLLT4, and MPP5 PDZs and SARS-CoV-2 E PBM highlighting its binding preferences for several cellular targets. Finally, we showed different affinities for the PDZ domains with the original SARS-CoV-2 C-terminal sequence containing the PBM and the one of the beta variant that contains a mutation close to the PBM. The acquired mutations in the E protein localized near the PBM might have important effects both on the structure and the ion-channel activity of the E protein and on the host machinery targeted by the variants during the infection.

Published
2022
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3. Role of the major determinant of polar flagellation FlhG in the endoflagella‐containing spirochete Leptospira

Author

Gerald L. Murray, Célia Fontana, Jun Liu, Hugo Varet, Ben Adler, Ruben Halifa, Mathieu Picardeau, David R. Hendrixson, Shuaiqi Guo, Alejandro Buschiazzo, Jean Yves Coppée, Lenka Fule, Odile Sismeiro, Rachel Legendre, Biologie des Spirochètes / Biology of Spirochetes, Institut Pasteur [Paris], Integrative Microbiology of Zoonotic Agents [Paris and Montevideo] (IMiZA), Institut Pasteur de Montevideo, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris], Université de Paris (UP), Boehringer Ingelheim Pharma GmbH & Co. KG, Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris]-Institut Pasteur [Paris], Transcriptome et Epigénome (PF2), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Monash University [Clayton], University of Texas Southwestern Medical Center, Réseau International des Instituts Pasteur (RIIP), Yale University School of Medicine, This research was supported by ANR LEPTOMOVE (18-CE15-0027-01) and the Pasteur International Unit « Integrative Microbiology of Zoonotic Agents » (IMiZA) to MP, NIH R01AI065539 to DRH, and NIAID R01AI087946 to JL. This work is part of the PhD of Lenka Fule., We thank Olivier Gorgette (UBI platform, Institut Pasteur, Paris, France) and Ariel Mechaly (Plateforme de Cristallographie, Institut Pasteur, Paris, France) for help in electron microscopy and protein structure analysis, respectively. We thank Christophe Becavin for RNA-seq analysis, Sébastien Le Hu Nghia for genetic studies and Meng Shao and Qin Gong for their assistance in cryo-ET sample preparation and segmentation. We also thank David Šmajs for the gift of Borrelia DNA, ANR-18-CE15-0027,LEPTOMOVE,Mécanismes moléculaires de la motilité chez les spirochètes: le modèle de l'endoflagelle des leptospires(2018), Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut Pasteur [Paris] (IP), Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), and Yale School of Medicine [New Haven, Connecticut] (YSM)

Subjects
endoflagellum, [SDV]Life Sciences [q-bio], Mutant, Virulence, Flagellum, Microbiology, 03 medical and health sciences, Bacterial Proteins, Leptospira, Humans, Leptospirosis, spirochetes, Molecular Biology, Pathogen, Monomeric GTP-Binding Proteins, 030304 developmental biology, 0303 health sciences, biology, 030306 microbiology, Gene Expression Profiling, Cryoelectron Microscopy, Genetic Complementation Test, Gene Expression Regulation, Bacterial, Periplasmic space, biology.organism_classification, Complementation, motility, Flagella, Spirochaetales, Mutation, FlhG, Bacteria
Abstract

International audience; Spirochetes can be distinguished from other bacteria by their spiral-shaped morphology and subpolar periplasmic flagella. This study focused on FlhF and FlhG, which control the spatial and numerical regulation of flagella in many exoflagellated bacteria, in the spirochete Leptospira. In contrast to flhF which seems to be essential in Leptospira, we demonstrated that flhG- mutants in both the saprophyte L. biflexa and the pathogen L. interrogans were less motile than the wild-type strains in gel-like environments but not hyperflagellated as reported previously in other bacteria. Cryo-electron tomography revealed that the distance between the flagellar basal body and the tip of the cell decreased significantly in the flhG- mutant in comparison to wild-type and complemented strains. Additionally, comparative transcriptome analyses of L. biflexa flhG- and wild-type strains showed that FlhG acts as a negative regulator of transcription of some flagellar genes. We found that the L. interrogans flhG- mutant was attenuated for virulence in the hamster model. Cross-species complementation also showed that flhG is not interchangeable between species. Our results indicate that FlhF and FlhG in Leptospira contribute to governing cell motility but our data support the hypothesis that FlhF and FlhG function differently in each bacterial species, including among spirochetes.

Published
2021

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