Fernandez-Brando Romina J, Yamaguchi Nao, Tahoun Amin, McAteer Sean P, Gillespie Trudi, Wang Dai, Argyle Sally A, Palermo Marina S, Gally David L
Division of Immunity and Infection, The Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, United Kingdom Laboratory of Pathogenesis and Immunology of Infectious Diseases, IMEX-CONICET, National Academy of Medicine, Buenos Aires, Argentina.
Division of Immunity and Infection, The Roslin Institute and R(D)SVS, The University of Edinburgh, Easter Bush, Midlothian, United Kingdom.
Antimicrob Agents Chemother. 2015 Nov 2;60(1):459-70. doi: 10.1128/AAC.02085-15. Print 2016 Jan.
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.
一部分革兰氏阴性细菌病原体利用III型分泌系统（T3SS）在真核细胞中打开一条通道，以便注入效应蛋白。这些效应蛋白调节细胞内信号通路以增强细菌定植。在本研究中，我们筛选了已有的生物活性化合物，寻找能够抑制肠出血性大肠杆菌（EHEC）O157中T3SS表达的物质。酮内酯类药物泰利霉素以及随后的索利霉素在低于最低抑菌浓度（sub-MICs）时均对细菌T3SS的表达表现出抑制作用，导致细菌在上皮细胞上的黏附以及富含肌动蛋白的菌台形成显著减少。用索利霉素对上皮细胞进行预孵育，可使大肠杆菌O157的黏附显著减少。此外，表达T3SS的细菌对索利霉素更敏感，当将大肠杆菌O157添加到预先接触过酮内酯类药物的上皮细胞中时，会出现对大肠杆菌O157细菌的显著优先杀伤作用。这种杀伤作用依赖于T3SS的表达。综上所述，本研究表明在上皮细胞中积累的酮内酯类药物可能通过T3SS回流到细菌中。鉴于两种酮内酯类药物均不诱导SOS反应，这类抗生素中的无毒成员，如索利霉素，应考虑用于未来评估其治疗EHEC感染用途的测试和试验。这些抗生素对于治疗由其他表达T3SS的致病细菌（包括细胞内细菌）引起的感染可能也具有更广泛的意义。
