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Antimicrob. Agents Chemother. doi:10.1128/AAC.00607-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

A small molecule screen identified the anti-psychotic drug pimozide as an inhibitor of Listeria monocytogenes infection

Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115, USA

^* To whom correspondence should be addressed. Email: dhiggins{at}hms.harvard.edu.

	Abstract

We developed a screening procedure to identify small molecule compounds that altered infection by Listeria monocytogenes to gain insights into bacterial/host cellular processes required for intracellular pathogenesis. A small molecule library of 480 compounds with known biological function was screened and 21 compounds that altered L. monocytogenes infection of murine bone marrow-derived macrophages (BMM) were identified. The identified compounds affected various cellular functions, such as actin polymerization, kinase/phosphatase activity, calcium signaling, and apoptosis. Pimozide, an FDA-approved drug used to treat severe Tourette's syndrome and schizophrenia, was further examined and shown to decrease bacterial uptake and vacuole escape of L. monocytogenes in BMM. The inhibitory effect of pimozide on internalization was not specific for L. monocytogenes, as phagocytosis of other bacterial species (Bacillus subtilis, Salmonella enterica serovar Typhimurium and Escherichia coli K12) was significantly inhibited in the presence of pimozide. Invasion and cell-to-cell spread of L. monocytogenes during infection of non-professional phagocytic cells was also decreased by pimozide treatment. Although pimozide has been reported to be an antagonist of mammalian cell calcium channels, infection of BMM in calcium-free medium did not relieve the inhibitory effects of pimozide on L. monocytogenes infection. Our results provide a generalizable screening approach for identifying small molecule compounds that affect cellular pathways required for intracellular bacterial pathogenesis. We have also identified pimozide, a clinically approved anti-psychotic drug, as a compound that may be suitable for further development as a therapeutic for intracellular bacterial infections.