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
Several nocathiacin I analogues (4-35) were synthesized and evaluated for their antibacterial activity. Most of these semi-synthetic analogues retained very good in vitro and in vivo antibacterial activity of 1.
Assuntos
Antibacterianos , Peptídeos , Aminas/síntese química , Aminas/química , Aminas/farmacologia , Antibacterianos/síntese química , Antibacterianos/farmacologia , Enterococcus faecalis/efeitos dos fármacos , Enterococcus faecalis/crescimento & desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular , Testes de Sensibilidade Microbiana , Estrutura Molecular , Peptídeos/síntese química , Peptídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
Several semi-synthetic bis- and mono-O-alkyl nocathiacin derivatives were synthesized and evaluated for antibacterial activity. Mono-O-alkyl N-hydroxyindole analogues 3a-l were prepared by regioselective alkylation. Bis-O-alkyl nocathiacins 4a-f were obtained by treatment with base and excess electrophile. A one-pot protection-alkylation-deprotection strategy was developed for the preparation of mono-O-alkyl hydroxypyridine analogues 5a,b. Most of the bis- and mono-O-alkyl nocathiacins maintained good in vitro activity but showed reduced in vivo efficacy when compared with the natural product. The excellent in vivo activity and improved water solubility of phosphate analogues 3m and 4g suggest their use as potential pro-drugs.