RESUMO
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.
Assuntos
Proteínas de Bactérias/antagonistas & inibidores , Benzimidazóis/farmacologia , Pneumonia Bacteriana/patologia , Fatores de Transcrição/antagonistas & inibidores , Infecções por Yersinia pseudotuberculosis/patologia , Yersinia pseudotuberculosis/efeitos dos fármacos , Yersinia pseudotuberculosis/patogenicidade , Animais , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Benzimidazóis/administração & dosagem , Benzimidazóis/síntese química , Benzimidazóis/química , Linhagem Celular , Modelos Animais de Doenças , Feminino , Humanos , Pulmão/microbiologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pneumonia Bacteriana/tratamento farmacológico , Pneumonia Bacteriana/microbiologia , Pneumonia Bacteriana/mortalidade , Fatores de Transcrição/metabolismo , Resultado do Tratamento , Virulência , Yersinia pseudotuberculosis/metabolismo , Infecções por Yersinia pseudotuberculosis/tratamento farmacológico , Infecções por Yersinia pseudotuberculosis/microbiologia , Infecções por Yersinia pseudotuberculosis/mortalidadeRESUMO
The recent 44th annual Interscience Conference on Antimicrobial Agents and Chemotherapy provided a snapshot of the antibiotics most advanced in clinical development. New antibiotic discovery programs and novel efforts in the field of non-antibiotic treatment modalities were also presented. Some of the most pressing issues in antibiotic resistance were discussed at this meeting.