Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides.
Type III Secretion-Dependent Sensitivity of Escherichia coli O157 to Specific Ketolides.
复制标题
大肠杆菌O157对特异性酮醇的型III型分泌依赖性敏感性。
DOI：
10.1128/aac.02085-15
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发表时间：
2016-01
影响因子：
4.9
通讯作者：
Gally DL
中科院分区：
文献类型：
--
作者：
Fernandez-Brando RJ;Yamaguchi N;Tahoun A;McAteer SP;Gillespie T;Wang D;Argyle SA;Palermo MS;Gally DL
革兰氏阴性细菌病原体的一个子集使用III型分泌系统（T3SS）打开进入真核细胞的管道以注射效应蛋白。这些调节途径以增强细菌定植。在这项研究中，我们筛选了任何建立的生物活性化合物，可以抑制肠出血性大肠杆菌（EHEC）O157中的T3SS表达。酮内酯泰利霉素和随后的索利霉素都表现出在亚MIC下对细菌T3SS表达的抑制作用，导致细菌结合和上皮细胞上富含肌动蛋白的基座形成显著减少。用索利霉素预孵育上皮细胞导致E. coli O157。此外，表达T3SS的细菌对索利霉素更敏感，并且E.大肠杆菌O157细菌，当他们加入到上皮细胞，已预先暴露于酮内酯。这种杀伤依赖于T3SS的表达。总之，这项研究表明，在上皮细胞中积累的酮内酯可能通过T3SS返回细菌。考虑到酮内酯都不会诱导SOS反应，这类抗生素的无毒成员，如索利霉素，应考虑用于未来的测试和试验，评估其用于治疗EHEC感染。这些抗生素也可能对治疗由表达T3SS的其他病原菌（包括细胞内细菌）引起的感染具有更广泛的意义。
A subset of Gram-negative bacterial pathogens uses a type III secretion system (T3SS) to open up a conduit into eukaryotic cells in order to inject effector proteins. These modulate pathways to enhance bacterial colonization. In this study, we screened established bioactive compounds for any that could repress T3SS expression in enterohemorrhagic Escherichia coli (EHEC) O157. The ketolides telithromycin and, subsequently, solithromycin both demonstrated repressive effects on expression of the bacterial T3SS at sub-MICs, leading to significant reductions in bacterial binding and actin-rich pedestal formation on epithelial cells. Preincubation of epithelial cells with solithromycin resulted in significantly less attachment of E. coli O157. Moreover, bacteria expressing the T3SS were more susceptible to solithromycin, and there was significant preferential killing of E. coli O157 bacteria when they were added to epithelial cells that had been preexposed to the ketolide. This killing was dependent on expression of the T3SS. Taken together, this research indicates that the ketolide that has accumulated in epithelial cells may traffic back into the bacteria via the T3SS. Considering that neither ketolide induces the SOS response, nontoxic members of this class of antibiotics, such as solithromycin, should be considered for future testing and trials evaluating their use for treatment of EHEC infections. These antibiotics may also have broader significance for treating infections caused by other pathogenic bacteria, including intracellular bacteria, that express a T3SS.