Adrenergic antagonists restrict replication of Legionella

Area of Science:

• Microbiology and Infectious Diseases
• Bacterial Pathogenesis
• Drug Discovery

Background:

• Legionella pneumophila causes Legionnaires' disease, a severe pneumonia.
• This bacterium resides within host macrophages in a specialized vacuole.
• Pathogenic bacteria can sense and respond to host signaling molecules like catecholamines.

Purpose of the Study:

• To investigate the impact of adrenergic compounds on L. pneumophila growth.
• To explore the role of the QseBC two-component system in adrenergic sensing.
• To identify potential therapeutic strategies against Legionella and Mycobacterium infections.

Main Methods:

• Treatment of L. pneumophila with adrenergic receptor antagonists (benoxathian, naftopidil, propranolol, labetalol) and a QseC inhibitor (LED209).
• Assessment of bacterial growth in broth, amoebae, and mammalian macrophages.
• Analysis of bacterial growth in L. pneumophila qseBC deletion mutants.

Main Results:

• Adrenergic compounds and LED209 significantly reduced L. pneumophila growth in broth and amoebae.
• These compounds enhanced L. pneumophila replication within macrophages.
• Growth inhibition was observed in Legionella and Mycobacterium genera, primarily during the replicative phase.
• The QseBC system mediated only a minor part of the growth inhibition, suggesting alternative sensing mechanisms.

Conclusions:

• Adrenergic molecules represent novel inhibitors of Legionella growth, both extracellularly and intracellularly.
• LED209 shows potential as a lead compound for treating Legionella and Mycobacterium infections.
• Further research is needed to elucidate additional adrenergic sensing systems in Legionella.