Inhibition of Listeria monocytogenes infection by neurological drugs.
To gain insights into the cellular processes required for intracellular bacterial pathogenesis, we previously developed a generalisable screening approach to identify small molecule compounds that alter Listeria monocytogenes infection. In this report, a small molecule library enriched for compounds affecting neurological functions was screened and 68 compounds that disrupted L. monocytogenes infection of macrophages were identified. Many of these compounds were known antimicrobial agents, however 26 compounds were novel inhibitors of intracellular infection. Two of the compounds chosen for further study, the antipsychotic drug thioridazine and the calcium channel blocker bepridil, exhibited dose-dependent inhibition of vacuolar escape and intracellular replication of L. monocytogenes during infection of murine macrophages. These results suggest that clinically approved neurological drugs may provide a novel source of anti-infective agents that are suitable for development as therapeutics against intracellular bacterial infections.
Lieberman
Linda A
LA
Department of Microbiology and Molecular Genetics, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA.
Higgins
Darren E
DE
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D015764:Bepridil / Q000494:pharmacology*; D015169:Colony Count, Microbial; D003600:Cytosol / Q000382:microbiology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008089:Listeria monocytogenes / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000382:microbiology*; D051379:Mice; D013881:Thioridazine / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D015764:Bepridil; D013881:Thioridazine