Huagang Peng, Yifan Rao, Weilong Shang, Yi Yang, Li Tan, Lu Liu, Zhen Hu, Yuting Wang, Xiaonan Huang, He Liu, Mengyang Li, Zuwen Guo, Juan Chen, Yuhua Yang, Jianghong Wu, Wenchang Yuan, Qiwen Hu, Xiancai Rao
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引用次数: 0
摘要
万古霉素(VAN)中间金黄色葡萄球菌(VISA)是导致全球 VAN 治疗失败的一个重要原因。据报道,多种基因变化与 VISA 的形成有关,而 VISA 菌株通常具有共同的表型,如自溶减少和细胞壁增厚。然而,突变基因如何导致 VISA 的共同表型仍不清楚。在这里,我们展示了一个代谢调控级联(CcpA-GlmS),其中突变的双组分系统(TCS)与 VISA 的共同表型相关联。我们发现,在具有不同遗传背景的 VISA 菌株中,ccpA 缺失会降低 VAN 抗性。VISA 的代谢改变与 ccpA 的上调有关,而 ccpA 的上调直接受 TCS WalKR 和 GraSR 的控制。RNA 测序揭示了 CcpA 在改变 VISA 的碳流和氮流以促进 VAN 抗性方面的关键作用。在 VISA 中,一种驱动碳流进入细胞壁前体生物合成的门酶(GlmS)被上调。CcpA 直接控制着 glmS 的表达。阻断 CcpA 可使 VISA 菌株在体外和体内对 VAN 处理敏感。总之,这项研究发现了 VISA 表型的形成与常见突变基因之间的联系。抑制 CcpA-GlmS 级联是恢复 VAN 对 VISA 感染的治疗效率的一种有前途的策略。
Vancomycin (VAN)-intermediate Staphylococcus aureus (VISA) is a critical cause of VAN treatment failure worldwide. Multiple genetic changes are reportedly associated with VISA formation, whereas VISA strains often present common phenotypes, such as reduced autolysis and thickened cell wall. However, how mutated genes lead to VISA common phenotypes remains unclear. Here, we show a metabolism regulatory cascade (CcpA-GlmS), whereby mutated two-component systems (TCSs) link to the common phenotypes of VISA. We found that ccpA deletion decreased VAN resistance in VISA strains with diverse genetic backgrounds. Metabolic alteration in VISA was associated with ccpA upregulation, which was directly controlled by TCSs WalKR and GraSR. RNA-sequencing revealed the crucial roles of CcpA in changing the carbon flow and nitrogen flux of VISA to promote VAN resistance. A gate enzyme (GlmS) that drives carbon flow to the cell wall precursor biosynthesis was upregulated in VISA. CcpA directly controlled glmS expression. Blocking CcpA sensitized VISA strains to VAN treatment in vitro and in vivo. Overall, this work uncovers a link between the formation of VISA phenotypes and commonly mutated genes. Inhibition of CcpA-GlmS cascade is a promising strategy to restore the therapeutic efficiency of VAN against VISA infections.