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Title: An Inhibitor of Gram-Negative Bacterial Virulence Protein Secretion

Author
item FELISE, HEATHER - UNIVERSITY OF WASHINGTON
item NGUYEN, HAI - UNIVERSITY OF WASHINGTON
item PFUETZNER, RICHARD - UNIVERSITY OF WASHINGTON
item BARRY, KATHLEEN - UNIVERSITY OF WASHINGTON
item JACKSON, STONA - UNIVERSITY OF WASHINGTON
item BLANC, MARIE - UNIVERSITY OF WASHINGTON
item KLINE, TONI - UNIVERSITY OF WASHINGTON
item Bronstein, Philip
item MILLER, SAMUEL - UNIVERSITY OF WASHINGTON

Submitted to: Cell Host and Microbe
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/6/2008
Publication Date: 10/16/2008
Citation: Felise, H.B., Nguyen, H.V., Pfuetzner, R.A., Barry, K.C., Jackson, S.R., Blanc, M.P., Kline, T., Bronstein, P., Miller, S.I. 2008. An Inhibitor of Gram-Negative Bacterial Virulence Protein Secretion. Cell Host and Microbe. 4(4):325-336.

Interpretive Summary: Systems used by pathogenic bacteria to cause disease are attractive targets for antibiotic development. Secretion systems, which are used by pathogens to bind to host cells and deliver toxins, could be on such therapeutic target; however, it is unknown whether these secretion systems are similar enough between pathogens to develop a single broad-spectrum pharmaceutical to affect them all. In this study, we developed and screened a collection of small molecules and identified a compound that blocked secretion and virulence functions of a wide array of bacterial pathogens. Evidence suggests that the target of the compound could be a conserved protein of Gram-negative secretion systems. This work provides a proof-of-concept that pharmaceuticals with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases.

Technical Abstract: Bacterial virulence properties are attractive novel targets for antibiotic development, because they are required for the pathogenesis of numerous global infectious disease agents. Secretion systems, which are used by bacterial pathogens to assemble surface structures to promote adherence and deliver protein virulence effectors to host cells could be an important therapeutic target; however, it is unknown whether the protein components of secretion systems are sufficiently conserved across species to develop broad spectrum pharmaceuticals. In this study, we developed and performed a high-throughput screen (HTS) of small molecule libraries and identified a small molecule, a 2-imino-5-arylidene thiazolidinone that blocked secretion and virulence functions of a wide array of animal and plant Gram-negative bacterial pathogens. Genetic and biochemical evidence suggests that the target of the compound could be a conserved outer membrane component of Gram-negative secretion apparati. This work provides a proof-of-concept that pharmaceuticals with a broad spectrum of activity against Gram-negative bacterial secretion systems could be developed to prevent and treat bacterial diseases.