Assuntos
Antibacterianos/uso terapêutico , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Lactamas Macrocíclicas/uso terapêutico , Antibacterianos/classificação , Antibacterianos/farmacologia , Clostridioides difficile/efeitos dos fármacos , Infecções por Clostridium/epidemiologia , Enterocolite Pseudomembranosa/tratamento farmacológico , Enterocolite Pseudomembranosa/epidemiologia , Humanos , Lactamas Macrocíclicas/classificação , Lactamas Macrocíclicas/farmacologia , Testes de Sensibilidade Microbiana/métodos , Resultado do TratamentoRESUMO
In the course of screening for an inhibitor of ER stress-induced XBP1 activation, we isolated a new member of the triene-ansamycin group compound, trierixin, from a culture broth of Streptomyces sp. AC 654. Trierixin was purified by column chromatography on silica gel and by HPLC. The molecular formula of trierixin is C(37)H(52)N(2)O(8)S. Trierixin inhibited thapsigargin-induced XBP1-luciferase activation in HeLa/XBP1-luc cells and endogenous XBP1 splicing in HeLa cells with an IC(50) of 14 ng/ml and 19 ng/ml, respectively. Moreover, in the process of isolating trierixin, we isolated structurally related mycotrienin II and trienomycin A as inhibitors of ER stress-induced XBP1 activation from a culture broth of a trierixin-producing strain. This study provides the first observation that triene-ansamycins have a novel inhibitory effect against XBP1 activation.