ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments

Yu Wu (1) , Valérie Pons (2) , Amélie Goudet (1) , Laetitia Panigai (3) , Annette Fischer (4) , Jo-Ana Herweg (4) , Sabrina Kali (5) , Robert A Davey (6) , Jérôme Laporte (3) , Céline Bouclier (1) , Rahima Yousfi (7) , Céline Aubenque (7) , Goulven Merer (2) , Emilie Gobbo (1) , Roman Lopez (2) , Cynthia Gillet (8) , Sandrine Cojean (9) , Michel R Popoff (10) , Pascal Clayette (11) , Roger Le Grand (12) , Claire Boulogne (8) , Noël Tordo (5) , Emmanuel Lemichez (13) , Philippe M Loiseau (9) , Thomas Rudel (4) , Didier Sauvaire (3) , Jean-Christophe Cintrat (2) , Daniel Gillet (1) , Julien Barbier (1)

1 SIMoS - Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO)
2 SCBM - Service de Chimie Bio-Organique et de Marquage
3 ANSM - Agence nationale de sécurité du médicament et des produits de santé [Saint-Denis]
4 JMU - Julius-Maximilians-Universität Würzburg
5 Stratégies antivirales
6 Texas Biomedical Research Institute
7 UGRA / SETA - CEA [Fontenay-aux-Roses]
8 I2BC - Institut de Biologie Intégrative de la Cellule
9 MBCIS - Molécules bioactives, conception, isolement et synthèse
10 Bactéries anaérobies et Toxines
11 Pharmacologie des rétrovirus
12 IMVA - U1184 - Immunologie des Maladies Virales et Autoimmunes
13 C3M - Centre méditerranéen de médecine moléculaire

Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity. This compound efficiently protects cells against various toxins and pathogens including viruses, intracellular bacteria and parasite. ABMA provokes Rab7-positive late endosomal compartment accumulation in mammalian cells without affecting other organelles (early endosomes, lysosomes, the Golgi apparatus, the endoplasmic reticulum or the nucleus). As the mechanism of action of ABMA is restricted to host-endosomal compartments, it reduces cell infection by pathogens that depend on this pathway to invade cells. ABMA may represent a novel class of broad-spectrum compounds with therapeutic potential against diverse severe infectious diseases.

Mots clés: High-throughput screening; Antimicrobials; Infectious diseases

Domaines: Bactériologie

Yu Wu, Valérie Pons, Amélie Goudet, Laetitia Panigai, Annette Fischer, et al.. ABMA, a small molecule that inhibits intracellular toxins and pathogens by interfering with late endosomal compartments. Scientific Reports, 2017, 7 (1), pp.15567. ⟨10.1038/s41598-017-15466-7⟩. ⟨pasteur-01675662⟩