title: Adrenergic antagonists restrict replication of Legionella.
abstract: Legionella pneumophila is a facultative intracellular bacterium, which upon inhalation can cause a potentially fatal pneumonia termed Legionnaires' disease. The opportunistic pathogen grows in environmental amoebae and mammalian macrophages within a unique membrane-bound compartment, the 'Legionella-containing vacuole'. Bacteria are exposed to many environmental cues including small signalling molecules from eukaryotic cells. A number of pathogenic bacteria sense and respond to catecholamine hormones, such as adrenalin and noradrenalin, a process mediated via the QseBC two-component system in some bacteria. In this study, we examined the effect of adrenergic compounds on L. pneumophila, and discovered that the adrenergic receptor antagonists benoxathian, naftopidil, propranolol and labetalol, as well as the QseC sensor kinase inhibitor LED209, reduced the growth of L. pneumophila in broth or amoebae, while replication in macrophages was enhanced. Growth restriction was common to members of the genus Legionella and Mycobacterium, and was observed for L. pneumophila in the replicative but not stationary phase of the biphasic life cycle. Deletion of the L. pneumophila qseBC genes indicated that growth inhibition by adrenergics or LED209 is mediated only to a minor extent by this two-component system, implying the presence of other adrenergic sensing systems. This study identifies adrenergic molecules as novel inhibitors of extra- and intracellular growth of Legionella and reveals LED209 as a potential lead compound to combat infections with Legionella or Mycobacterium spp.
authors: 1​Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors: Christopher F
authors: CF
authors: Harrison
authors: 2​Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland.
authors: Sébastien
authors: S
authors: Kicka
authors: 3​School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne, 1211 Geneva, Switzerland.
authors: Agata
authors: A
authors: Kranjc
authors: 1​Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich, 80336 Munich, Germany.
authors: Ivo
authors: I
authors: Finsel
authors: 3​School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne, 1211 Geneva, Switzerland.
authors: Gianpaolo
authors: G
authors: Chiriano
authors: 4​Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland.
authors: Hajer
authors: H
authors: Ouertatani-Sakouhi
authors: 2​Department of Biochemistry, University of Geneva, 1211 Geneva, Switzerland.
authors: Thierry
authors: T
authors: Soldati
authors: 3​School of Pharmaceutical Sciences, Department of Pharmaceutical Biochemistry, University of Geneva and University of Lausanne, 1211 Geneva, Switzerland.
authors: Leonardo
authors: L
authors: Scapozza
authors: 1​Max von Pettenkofer Institute, Department of Medicine, Ludwig-Maximilians University Munich, 80336 Munich, Germany 5​Institute of Medical Microbiology, Department of Medicine, University of Zurich, Gloriastrasse 30/32, 8006 Zurich, Switzerland.
authors: Hubert
authors: H
authors: Hilbi
mesh_terms: D048248:Acanthamoeba castellanii / Q000187:drug effects / Q000382:microbiology; D018674:Adrenergic Antagonists / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism*; D002460:Cell Line; D016952:Legionella pneumophila / Q000187:drug effects* / Q000254:growth & development*; D008264:Macrophages / Q000187:drug effects / Q000382:microbiology; D051379:Mice; D009161:Mycobacterium / Q000187:drug effects / Q000254:growth & development
chemical_list: D018674:Adrenergic Antagonists; D000900:Anti-Bacterial Agents