The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus.
The FDA-approved anti-cancer drugs, streptozotocin and floxuridine, reduce the virulence of Staphylococcus aureus.
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DOI：
10.1038/s41598-018-20617-5
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发表时间：
2018-02-06
影响因子：
4.6
通讯作者：
Bae T
中科院分区：
文献类型：
--
作者：
Yeo WS;Arya R;Kim KK;Jeong H;Cho KH;Bae T
金黄色葡萄球菌是一种重要的革兰氏阳性致病菌，其SaeRS双组分系统是其致病所必需的，也是开发抗金黄色葡萄球菌毒力药物的良好靶点。在这项研究中，我们筛选了12，200种Sae抑制剂的小分子，并确定了两种抗癌药物，链脲佐菌素（STZ）和尿嘧啶核苷（FU），作为抗葡萄球菌感染的抗毒力药物开发的主要候选药物。与STZ相比，FU在抑制Sae调控的启动子和保护人中性粒细胞免受S.金色介导的杀戮FU抑制S.金黄色葡萄球菌生长有效，而STZ没有。有趣的是，RNA-seq分析表明，这两种化合物抑制其他毒力调节系统，如Agr，ArlRS和SarA比它们抑制Sae系统更有效。这两种化合物均能诱导S.金黄色葡萄球菌，表明它们会导致DNA损伤。令人惊讶的是，单次给药足以保护小鼠免受葡萄球菌腹膜内感染。两种化合物在血液感染的鼠模型中也显示出体内功效。最后，在实验剂量下，两种化合物都没有显示出对血糖水平或血细胞计数的任何明显副作用。基于这些结果，我们得出结论，STZ和FU是抗S.金黄色葡萄球菌感染。
In Staphylococcus aureus, an important Gram-positive human pathogen, the SaeRS two-component system is essential for the virulence and a good target for the development of anti-virulence drugs. In this study, we screened 12,200 small molecules for Sae inhibitors and identified two anti-cancer drugs, streptozotocin (STZ) and floxuridine (FU), as lead candidates for anti-virulence drug development against staphylococcal infections. As compared with STZ, FU was more efficient in repressing Sae-regulated promoters and protecting human neutrophils from S. aureus-mediated killing. FU inhibited S. aureus growth effectively whereas STZ did not. Intriguingly, RNA-seq analysis suggests that both compounds inhibit other virulence-regulatory systems such as Agr, ArlRS, and SarA more efficiently than they inhibit the Sae system. Both compounds induced prophages from S. aureus, indicating that they cause DNA damages. Surprisingly, a single administration of the drugs was sufficient to protect mice from staphylococcal intraperitoneal infection. Both compounds showed in vivo efficacy in a murine model of blood infection too. Finally, at the experimental dosage, neither compound showed any noticeable side effects on blood glucose level or blood cell counts. Based on these results, we concluded that STZ and FU are promising candidates for anti-virulence drug development against S. aureus infection.
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影响因子：
2.3
作者：
Linnebacher, Michael;Maletzki, Claudia;Klier, Ulrike;Klar, Ernst
通讯作者：
Klar, Ernst
影响因子：
6.7
作者：
Cho H;Jeong DW;Liu Q;Yeo WS;Vogl T;Skaar EP;Chazin WJ;Bae T
通讯作者：
Bae T
影响因子：
6.7
作者：
Liu Q;Cho H;Yeo WS;Bae T
通讯作者：
Bae T
影响因子：
9
作者：
Coley, W B
通讯作者：
Coley, W B
DOI：
10.1016/j.biocel.2007.10.032
发表时间：
2008-01-01
影响因子：
4
作者：
Cheung, Ambrose L.;Nishina, Koren A.;Tamber, Sandeep
通讯作者：
Tamber, Sandeep