Small Molecule Inhibitors of LcrF, a Yersinia pseudotuberculosis Transcription Factor, Attenuate Virulence and Limit Infection in a Murine Pneumonia Model

作者：Lynne Garrity-Ryan, Oak K. Kim, Joan-Miquel Balada-Llasat, Victoria J. Bartlett, Atul Kumar Verma, Michael L. Fisher, Cynthia Castillo, Warangkhana Songsungthong, Sébastien Tanaka, Stuart B. Levy, Joan Mecsas, Michael N. Alekshun · 发表于：Infection and Immunity · 年份：2010 · DOI：10.1128/iai.01305-09 · 被引用次数：72 · 研究领域：Yersinia bacterium, plague, ectoparasites research、Plant-based Medicinal Research、Bacillus and Francisella bacterial research

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.