Small molecule inhibitors of LcrF, a Yersinia pseudotuberculosis transcription factor, attenuate virulence and limit infection in a murine pneumonia model.

نویسندگان

  • Lynne K Garrity-Ryan
  • Oak K Kim
  • Joan-Miquel Balada-Llasat
  • Victoria J Bartlett
  • Atul K Verma
  • Michael L Fisher
  • Cynthia Castillo
  • Warangkhana Songsungthong
  • S Ken Tanaka
  • Stuart B Levy
  • Joan Mecsas
  • Michael N Alekshun
چکیده

LcrF (VirF), a transcription factor in the multiple adaptational response (MAR) family, regulates expression of the Yersinia type III secretion system (T3SS). Yersinia pseudotuberculosis lcrF-null mutants showed attenuated virulence in tissue culture and animal models of infection. Targeting of LcrF offers a novel, antivirulence strategy for preventing Yersinia infection. A small molecule library was screened for inhibition of LcrF-DNA binding in an in vitro assay. All of the compounds lacked intrinsic antibacterial activity and did not demonstrate toxicity against mammalian cells. A subset of these compounds inhibited T3SS-dependent cytotoxicity of Y. pseudotuberculosis toward macrophages in vitro. In a murine model of Y. pseudotuberculosis pneumonia, two compounds significantly reduced the bacterial burden in the lungs and afforded a dramatic survival advantage. The MAR family of transcription factors is well conserved, with members playing central roles in pathogenesis across bacterial genera; thus, the inhibitors could have broad applicability.

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عنوان ژورنال:
  • Infection and immunity

دوره 78 11  شماره 

صفحات  -

تاریخ انتشار 2010