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Targeting bacterial virulence functions in order to disarm pathogens represents a promising alternative to classical antibiotic therapy. Type IV secretion systems, which are multiprotein complexes in the cell envelope that translocate effectors into host cells, are critical bacterial virulence factors in many pathogens and excellent targets for such \u201cantivirulence\u201d drugs. The VirB8 protein from the mammalian pathogen<jats:italic>Brucella<\/jats:italic>was chosen as a specific target, since it is an essential type IV secretion system component, it participates in multiple protein-protein interactions, and it is essential for the assembly of this translocation machinery. The bacterial two-hybrid system was adapted to assay VirB8 interactions, and a high-throughput screen identified specific small-molecule inhibitors. VirB8 interaction inhibitors also reduced the levels of VirB8 and of other VirB proteins, and many of them inhibited<jats:italic>virB<\/jats:italic>gene transcription in<jats:italic>Brucella abortus<\/jats:italic>2308, suggesting that targeting of the secretion system has complex regulatory effects<jats:italic>in vivo<\/jats:italic>. One compound strongly inhibited the intracellular proliferation of<jats:italic>B. abortus<\/jats:italic>2308 in a J774 macrophage infection model. The results presented here show that<jats:italic>in vivo<\/jats:italic>screens with the bacterial two-hybrid assay are suited to the identification of inhibitors of<jats:italic>Brucella<\/jats:italic>type IV secretion system function.<\/jats:p>","DOI":"10.1128\/iai.00993-10","type":"journal-article","created":{"date-parts":[[2010,12,21]],"date-time":"2010-12-21T04:53:02Z","timestamp":1292907182000},"page":"1033-1043","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":73,"title":["An<i>In Vivo<\/i>High-Throughput Screening Approach Targeting the Type IV Secretion System Component VirB8 Identified Inhibitors of<i>Brucella abortus<\/i>2308 Proliferation"],"prefix":"10.1128","volume":"79","author":[{"given":"Athanasios","family":"Paschos","sequence":"first","affiliation":[{"name":"McMaster University, Department of Pathology and Molecular Medicine and Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"den Hartigh","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of California at Davis, One Shields Avenue, Davis, California 95616-8645"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark A.","family":"Smith","sequence":"additional","affiliation":[{"name":"Universite\u0301 de Montre\u0301al, De\u0301partement de biochimie, C. 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