The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.
The broad-spectrum antiviral compound ST-669 restricts chlamydial inclusion development and bacterial growth and localizes to host cell lipid droplets within treated cells.
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广谱抗病毒化合物 ST-669 限制衣原体包涵体发育和细菌生长，并定位于处理细胞内的宿主细胞脂滴。
DOI：
10.1128/aac.02064-13
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发表时间：
2014
影响因子：
4.9
通讯作者：
Rockey,DanielD
中科院分区：
文献类型：
--
作者：
Sandoz,KelsiM;Valiant,WilliamG;Eriksen,StevenG;Hruby,DennisE;Allen3rd,RobertD;Rockey,DanielD
新型广谱抗菌药物是对抗抗生素耐药病原体策略的关键组成部分。在这项研究中，我们探索了广谱抗病毒化合物 ST-669 对不同细胞内细菌的活性，并开始表征其抗菌作用机制。 ST-669 可抑制 Vero 和 HeLa 细胞中三种不同种类的衣原体和胞内细菌伯氏柯克斯体的生长，但不能抑制 McCoy（鼠）细胞中的生长。抗衣原体和抗C.伯内特菌活性谱与测试病毒观察到的活性谱一致，表明其具有共同的作用机制。 ST-669 存在下的环己酰亚胺处理消除了抑制作用，证明测试活性需要真核蛋白质合成。免疫荧光显微镜证明，不同的衣原体在 ST-669 存在的情况下生长异常，这表明该化合物会影响包涵体的形成和组织。对用 ST-669 荧光衍生物处理的细胞进行显微镜分析表明，该化合物定位于宿主细胞脂滴，但不定位于其他细胞器或宿主细胞质。这些结果表明，ST-669 以宿主细胞依赖性方式影响细胞内生长，并可能通过脂滴依赖性过程中断衣原体包涵体的正常发育。
Novel broad-spectrum antimicrobials are a critical component of a strategy for combating antibiotic-resistant pathogens. In this study, we explored the activity of the broad-spectrum antiviral compound ST-669 for activity against different intracellular bacteria and began a characterization of its mechanism of antimicrobial action. ST-669 inhibits the growth of three different species of chlamydia and the intracellular bacterium Coxiella burnetii in Vero and HeLa cells but not in McCoy (murine) cells. The antichlamydial and anti-C. burnetii activity spectrum was consistent with those observed for tested viruses, suggesting a common mechanism of action. Cycloheximide treatment in the presence of ST-669 abrogated the inhibitory effect, demonstrating that eukaryotic protein synthesis is required for tested activity. Immunofluorescence microscopy demonstrated that different chlamydiae grow atypically in the presence of ST-669, in a manner that suggests the compound affects inclusion formation and organization. Microscopic analysis of cells treated with a fluorescent derivative of ST-669 demonstrated that the compound localized to host cell lipid droplets but not to other organelles or the host cytosol. These results demonstrate that ST-669 affects intracellular growth in a host-cell-dependent manner and interrupts proper development of chlamydial inclusions, possibly through a lipid droplet-dependent process.